Liclo4 catalyzed aza-Michael addition of secondary amines to α,β-unsaturated esters under a solvent-free condition - Dau Xuan Duc

Journal of Science and Technology 54 (2C) (2016) 537-542 LiClO4 CATALYZED AZA-MICHAEL ADDITION OF SECONDARY AMINES TO α,β-UNSATURATED ESTERS UNDER A SOLVENT-FREE CONDITION Dau Xuan Duc1, Stephen Pyne2 1Faculty of Chemistry, Vinh University, 182 Le Duan Street, Vinh city, Nghe An province 2School of Chemistry, University of Wollongong, Northfields Ave, Wollongong city, NSW 2522, Australia *Email: xuanduc80@gmail.com Received: 15 June 2016; Accepted for publication: 29 October 2016 ABSTRACT An efficient aza-Michael addition of secondary amines to some α,β-unsaturated esters has been carried out using LiCLO4 as a catalyst. β-amino esters were obtained in high yields at room temperature without using solvent. Keywords: aza-Michael reaction, secondary amines, α,β-unsaturated esters, β-amino esters. 1. INTRODUCTION The Michael reaction and its modified form such as aza-Michael, thio-Michael and carba- Michael reaction are among the most exploited reactions in organic chemistry [1]. Aza-Michael reaction products such as β-amino esters/ketones/nitriles are useful synthons for the preparation of several nitrogen containing bioactive natural products [2], antibiotics [3], and chiral auxiliaries [4]. Because a large number of biologically active compounds contain β-amino- ketone or ester moiety [5], the development of novel methodologies for the preparation of these compounds is an attractive area of research in synthetic organic chemistry. The conjugate addition of a nitrogen nucleophile to an α,β-unsaturated ester leads to the formation of a β-amino ester [6]. β-Amino esters are not only building units of biologically important natural products including β-lactams but also versatile nitrogen-containing intermediates for compounds such as β-amino alcohol, β-aminoacids, β-lactam antibiotics, and 1,2-diamines [7].The conjugate addition of nitrogen nucleophiles to an unsaturated system requires either basic or acidic catalysts [8]. Lewis acid catalysts, such as SnCl4, AlCl3, or TiCl4 [9], have been employed to effect this addition, but their use in stoichiometric amounts often cause severe environmental problems. As a result of our continuing interest in studying the Michael reaction under solvent free and environmentally benign conditions, herein we report a process at room temperature using Dau Xuan Duc, Stephen Pyne 538 LiClO4 as catalyst for the Michael addition of some secondary amines. The process is mild, easy to perform and gives excellent yield. 2. EXPERIMENTS All reactions were monitored by thin-layer chromatography (TLC) using silicagel (Merck, 60–120 mesh). Column chromatography was performed using Merck silica gel (40-63 μm) packed by the slurry method, under a positive pressure of air. The 1H and 13C NMR spectra were recorded on a Varian Inova NMR Spectrometer (1H NMR running at 500 MHz and 13C NMR running at 125 MHz). The CDCl3 was used as the NMR solvent unless otherwise stated. All products were characterized by comparison of their 1H NMR and13C NMR spectra with those of in literature.The starting chemicals were obtained from commercial suppliers and used without further purification. General procedure for aza-Michael addition: a mixture of α,β-unsaturated ester (10 mmol), amine (11 mmol, 1.1 equiv) and LiClO4 (106.5 mg, 1.0 mmol, 0.1 equiv.) were stirred at room temperature for three days. The excess of organic components then were evaporated in vacuo. All products were purified by column chromatography and their structures were confirmed by 1H NMR and 13C NMR. Ethyl 3-(diethylamino)propanoate:Colourless liquid. The1H NMR (500 MHz, CDCl3) δ 4.06 (q, J = 7.0 Hz, 2H, H6), 2.72 (t, J = 7.5 Hz, 2H, H3), 2.44 (q, J = 7.0 Hz, 4H, H4), 2.36 (t, J = 7.5 Hz, 2H, H2), 1.18 (t, J = 7.0 Hz, 3H, H7), 0.95 (t, J = 7.0 Hz, 6H, H5). The13C NMR (125 MHz, CDCl3) δ 172.8 (C1), 60.2 (C6), 48.1 (C3), 46.8 (C4), 32.4 (C2), 14.1 (C7), 11.9 (C5). NMR spectroscopic data matched with the published data [10]. Ethyl 3-(pyrrolidin-1-yl)propanoate:Colourless liquid. The 1H NMR (500 MHz, CDCl3) δ 4.11 (q, J = 7.0 Hz, 2H, H6), 2.74 (t, J = 7.5 Hz, 2H, H3), 2.52-2.47 (m, 6H, H4 and H2), 1.77- 1.72 (m, 4H, H5), 1.23 (t, J = 7.0 Hz, 3H, H7). The13C NMR (125 MHz, CDCl3) δ 172.4 (C1), 60.3 (C6), 54.0 (C4), 51.4 (C3), 34.2 (C2), 23.5 (C5), 14.2 (C7). NMR spectroscopic data matched with the published data [10]. Ethyl 3-(piperidin-1-yl)propanoate: Colourless liquid. The 1H NMR (500 MHz, CDCl3) δ 4.11 (q, J = 7.0 Hz, 2H, H7), 2.64 (t, J = 7.5 Hz, 2H, H3), 2.47 (t, J = 7.5 Hz, 2H, H2), 2.40-2.33 (m, 4H, H4), 1.59 – 1.52 (m, 4H, H5), 1.44-1.37 (m, 2H, H6), 1.23 (t, J = 7.0 Hz, 3H, H8). The13C NMR (125 MHz, CDCl3) δ 172.7 (C1), 60.2 (C7), 54.2 (C3), 54.1 (C4), 32.3 (C2), 25.9 (C5), 24.3 (C6), 14.2 (C8). NMR spectroscopic data matched with the published data [11]. Ethyl 3-morpholinopropanoate: Colourless liquid. The 1H NMR (500 MHz, CDCl3) δ 4.11 (q, J = 7.0 Hz, 2H, H6), 3.67-3.62 (m, 4H, H5), 2.64 (t, J = 7.0 Hz, 2H, H3), 2.47-2.39 (m, 6H, H4 and H2), 1.21 (t, J = 7.0 Hz, 3H, H7). 13C NMR (125 MHz, CDCl3) δ 172.3 (C1), 66.9 LiClO4 catalyzed Aza-Michael addition of secondary amines to α,β-saturated esters under ... 539 (C5), 60.3 (C6), 53.9 (C3), 53.3 (C4), 32.1 (C2), 14.2 (C7). NMR spectroscopic data matched with the published data [10]. Methyl 2-methyl-3-(piperidin-1-yl)propanoate: Colourless liquid. 1H NMR (500 MHz, CDCl3) δ 3.66 (s, 3H, H7), 2.73 – 2.63 (m, 1H, H2), 2.59 (dd, J = 12.0, 8.5 Hz, 1H, H3), 2.38 – 2.24 (m, 5H, H4 and H2), 1.56 – 1.47 (m, 4H, H5), 1.38 (t, J = 5.0 Hz, 2H, H6), 1.12 (d, J = 7.0 Hz, 3H, H1'). 13C NMR (125 MHz, CDCl3) δ 176.7 (C1), 62.4 (C3), 54.6 (C4), 51.4 (C7), 37.9 (C2), 26.0 (C5), 24.4 (C6), 15.7 (C1'). NMR spectroscopic data matched with the published data [11]. Methyl 2-methyl-3-morpholinopropanoate: Colourless liquid. 1H NMR (500 MHz, CDCl3) δ 3.65 (s, 3H, H6), 3.65 – 3.61 (m, 3H, H5), 2.71 – 2.64 (m, 1H, H2), 2.61 (dd, J = 12.0, 9.0 Hz, 1H, H3), 2.48 – 2.32 (m, 4H, H4), 2.27 (dd, J = 12.0, 6.0 Hz, 1H, H3), 1.12 (d, J = 7.0 Hz, 3H, H1'). 13C NMR (125 MHz, CDCl3) δ 176.3 (C1), 67.0 (C5), 62.0 (C3), 53.7 (4), 51.5 (C6), 37.5 (C2), 15.4 (C1'). NMR spectroscopic data matched with the published data [10]. Methyl 2-methyl-3-(pyrrolidin-1-yl)propanoate: Colourless liquid. 1H NMR (500 MHz, CDCl3) δ 3.69 (s, 3H, H6), 2.77 (dd, J = 11.5, 8.5 Hz, 1H, H3), 2.71 – 2.62 (m, 1H, H2), 2.53- 2.37 (m, 5H, H2 và H4), 1.74 (m, 4H, H5), 1.17 (d, J = 7.0 Hz, 3H, H1'). 13C NMR (125 MHz, CDCl3) δ 176.6 (C1), 59.6 (C3), 54.2 (C4), 51.6 (C6), 39.6 (C2), 23.5 (C5), 15.8 (C1'). NMR spectroscopic data matched with the published data [10]. 3. RESULTS AND DISCUSSION In our study we did not employ primary amines to avoid double addition, which could lead to a mixture of products.At first, we examined the reaction of pyrolidine with ethyl acrylate and 10 % mole of LiClO4 at room temperature in CH2Cl2. The reaction was not complete after three days (TLC analysis). Then the reaction was carried out under solvent-free condition. Partial conversion took place within 1 day, leading toaza-Michael reaction adduct. Complete conversion was observed in 3 days. We then continued reactions between diethylamine, piperidine and morpholine andethyl acrylate at the same conditions. After 2-3 d, the reactions were completed with very good yields of the Michael adducts (Scheme 1).The results are shown in the Table 1. Scheme 1. Aza-Michael addition of secondary amine to ethyl acrylate. Dau Xuan Duc, Stephen Pyne 540 Table 1. Aza-Michael addition of secondary amine to ethyl acrylate. Reaction Amines Time (Days) Yield (%) 1 (C2H5)2NH 2 85 2 2 89 3 2.5 98 4 3 81 Finally, we carried out the aza-Michael addition between pyrolidine, piperidine and morpholine and methylmetacrylate at the same conditions described above (Scheme 2). The results were shown in Table 2. Scheme 2. Aza-Michael addition of secondary amine to methylmetacrylate. Table 2. Aza-Michael addition of secondary amine to methylmetacrylate. Reaction Amines Time (Days) Yield (%) 5 2 76 6 2.5 85 7 3 81 4. CONCLUSION Seven aza-Michael reactions between selected secondary amines and ethylacrylate as well as methylmetacrylate using LiCLO4 as catalyst were carried out with high yields. This is the first time theaza-Michael addition with this catalyst was carried out under solvent free conditions. LiClO4 catalyzed Aza-Michael addition of secondary amines to α,β-saturated esters under ... 541 REFERENCES 1. Jung M. E. - In Comprehensive Organic Synthesis, Trost B. M., Fleming I. 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TÓM TẮT PHẢN ỨNG CỘNG AZA- MICHAEL CỦA MỘT SỐ AMIN BẬC HAI VÀO α,β-ESTERS KHÔNG NO SỬ DỤNG XÚC TÁC LiCLO4 TRONG ĐIỀU KIỆN KHÔNG DUNG MÔI Đậu Xuân Đức1, *, Stephen Pyne2 1Khoa Hóa học, Đại học Vinh, 182 Lê Duẩn, Tp. Vinh 2Đại Học Wollongong, Đại lộ Northfields, thành phố Wollongong, NSW 2522, Australia *Email: xuanduc80@gmail.com Dau Xuan Duc, Stephen Pyne 542 Phản ứng cộng aza-Michael của amin bậc hai vào α,β-este không nođã được thực hiện với xúc tác LiClO4 ở nhiệt độ thường và trong điều kiện không dung môi. Các β-amino este thu được với hiệu suất cao. Từ khóa: phản ứng aza-Michael, amin bậc hai, α,β-este không no, β-amino este.