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Open AccessArticle

Aza-Michael Mono-addition Using Acidic Alumina under Solventless Conditions

Department of Chemistry, University of Malta, Msida MSD 2080, Malta
*
Author to whom correspondence should be addressed.
Academic Editor: Alessandro Palmieri
Molecules 2016, 21(6), 815; https://doi.org/10.3390/molecules21060815
Received: 20 May 2016 / Revised: 10 June 2016 / Accepted: 16 June 2016 / Published: 22 June 2016

Abstract

Aza-Michael reactions between primary aliphatic and aromatic amines and various Michael acceptors have been performed under environmentally-friendly solventless conditions using acidic alumina as a heterogeneous catalyst to selectively obtain the corresponding mono-adducts in high yields. Ethyl acrylate was the main acceptor used, although others such as acrylonitrile, methyl acrylate and acrylamide were also utilized successfully. Bi-functional amines also gave the mono-adducts in good to excellent yields. Such compounds can serve as intermediates for the synthesis of anti-cancer and antibiotic drugs.
Keywords: Aza-Michael reactions; mono-addition; acidic alumina; solvent-free; primary amines Aza-Michael reactions; mono-addition; acidic alumina; solvent-free; primary amines

1. Introduction

The aza-Michael addition involves the formation of a C-N bond between nitrogen donors and α,β-unsaturated compounds [1,2,3]. This reaction is particularly important in the production of antibiotics, anticancer agents and bioactive molecules such as β-amino acid oligomers that can mimic the biological activity of cationic α-helical antimicrobial peptides without getting broken down by the body [4,5].
Primary amines react with Michael acceptors to form the corresponding mono-adduct, which can react further to give the bis-adduct (Scheme 1). Unfortunately it is quite difficult to selectively and separately obtain the mono-adduct and the bis-adduct from the same starting materials and in fact there has been little emphasis on this.
Originally the aza-Michael reaction was catalysed by harsh bases, which resulted in the formation of several side products [2]. With time came the advent of Lewis acid catalysts such as lanthanum trichloride [6], cerium (IV) ammonium nitrate (V) [7], zirconium (IV) chloride [8], samarium (III) triflate [9], and cadmium (II) chloride [10]. These catalysts present a lot of disadvantages: they are expensive, require harsh conditions and hazardous solvents, need relatively long reaction times, and they are homogeneous and hence difficult to separate and recycle. Ionic liquids, despite being homogeneous, have also became popular and provide good results, despite the fact that the procedures involving their reuse and recovery are always time-consuming, elaborate and costly [11].
Recently there has been an ideological shift towards green organic chemistry [12,13], not least in the aza-Michael reaction. As a result there has been the advent of heterogeneous catalysts such as silica-supported sulphuric (VI) acid [14], polymer-supported catalysts [15,16] metal organic frameworks [17], graphene oxide [18], Amberlyst-15 [19], and basic alumina [20]. In addition of microwave- and ultrasound-assisted reactions have been introduced [21]. Although most of these catalysts are recoverable, these studies have rarely focused on selective formation of mono-adducts from primary amines or they only focused on a few substrates. In some cases toxic solvents were still required and long reaction times were needed.
Continuing our efforts to explore heterogeneous catalysis in organic synthesis under green conditions [22] we have recently reported an environmentally-friendly procedure to efficiently obtain selectively mono- or bis- aza-Michael adducts using acidic alumina as heterogeneous catalyst [23].
Consequently, in continuation of previous studies performed by our research group on aza-Michael reactions, we here further explore the scope and efficiency of acidic alumina as a heterogeneous catalyst for aza-Michael additions [23,24]. We have widened the range of substrates in order to selectively form mono-adducts in solvent-free conditions under reflux.

2. Results and Discussion

Following our previously optimized procedure all reactions were performed by mixing the two starting materials in the presence of 0.2 g of acidic alumina per mmol of substrate whilst heating to reflux under solventless conditions [23]. The molar ratio of the Michael donor and acceptor was always kept at 1.5:1 and the aza-Michael adduct products were purified by column chromatography. We found that several Michael acceptors, different from methyl acrylate, as well as a variety of functionalised amines, together with a combination of both, were also effective under the developed procedure conditions, confirming the versatility and main advantages of this catalyst. In fact it does not require special preparation, it is cheap and easily available and it is used under neat conditions.
Ethyl acrylate (2) (Table 1) was the main Michael acceptor used to study the activity of the catalyst. Linear aliphatic primary amines (entries 1 and 2) provided good yields (78%–76%) albeit lower than those of cyclic ones, as expected according to their smaller steric hindrance. c-Pentylamine (entry 4) for example, produced the mono-adduct at 90% yield after heating for 3 h at 70–80 °C. Multi-functional amines such as allyl amine and propargyl amine (entries 5 and 6) gave good to excellent results, showing that negative inductive effects are short ranged and not very effective in decreasing the electron density on the nitrogen. However, 2-aminobutanol (entry 3) gave a lower yield because of the competing oxa-Michael addition and probably also because of product adsorption onto the catalyst. Meanwhile, primary aromatic amines (entries 8, 10 and 11) afforded the mono-adducts in excellent yields (89%–98%) in between 3 and 5 h, whereas a poor yield was only obtained when 2-aminothiazoline (entry 7) was used as a Michael donor, even after allowing the reaction to proceed for over 68 h at 90 °C. The end product was a thick yellow oil with a pungent smell similar to that of rotten eggs. A possible reason for the low yield could be the negative mesomeric effect which decreases the charge density on the nitrogen [3]. The good yields obtained for functionalised amines stimulated us to try them out with methyl acrylate (5) as Michael acceptor and very good results were once more obtained (Table 2).
Other Michael acceptors were then tested and tried out (Table 3). Excellent yields were obtained for acrylonitrile acceptor (83%–100%) and for acrylamide (90%–95%) despite the fact that for the latter acceptor slightly longer reaction times were needed (entries 8 and 9). Contrastingly, the yields obtained for the additions of n-alkylamines to methyl methacrylate (12), methyl trans-crotonate (14) and methyl trans-cinnamate (16) were slightly less impressive, even if the reaction time was increased (entries 10–14). These observations can be explained in terms of steric reasons. To further prove this, no bis-adduct was observed to be formed during the course of their reaction.
Finally other challenging Michael acceptors were tested. When β-nitrostyrene was used, the mono-adduct which was supposedly formed could not be characterized by 1H-NMR. This could be because the mono-adduct or the Michael acceptor itself were not stable. In fact, it is reported that β-nitrostyrene undergoes [2 + 2] cycloaddition in the presence of sunlight [25]. Even when the reaction was repeated in the absence of light, the product obtained was still not characterized by proton NMR because the crude was exposed to light during column chromatography. Moreover, the silica used in the column could itself have caused the product to decompose. Styrene yielded only very small traces with n-butylamine, whilst no product was formed with aniline. This confirmed that without the presence of electron withdrawing groups, the benzene ring by itself is not enough to decrease the electron density in the double bond.
The products of addition of primary n-alkyl amines to α,β-unsaturated aldehydes/ketones such as: trans-cinnamaldehyde, 2-hexenal, 2-heptenal, 2-cyclopentenone and 2-cyclohexenone could not be characterized. When column chromatography was performed, the eluted products which were obtained soon turned dark and very viscous. A probable explanation for this could be that these acceptors were forming α,β-unsaturated imines instead of the mono-adducts. These are reportedly very unstable and can oligomerize easily [26].

3. Materials and Methods

3.1. General Information

All commercially available chemicals were purchased from Aldrich (St. Louis, MO, USA) and used without further purification. Acidic alumina (grain size: 0.05–0.2 mm, 70–290 mesh ASTM, pH 4.5, activity degree 1, Scharlau, Barcelona, Spain) was used without further activation. IR spectra were recorded on a IRAffinity-1 FTIR spectrometer (Shimadzu, Kyoto, Japan) calibrated against a 1602 cm−1 polystyrene absorbance spectrum. Samples were analysed as a thin film or in a Nujol™ mull between sodium chloride plates. The 1H and 13C-NMR spectra were recorded on an Avance III HD® NMR spectrometer (Bruker, Coventry, England), equipped with an Ascend 500 11.75 Tesla Superconducting Magnet, operating at 500.13 MHz for 1H and 125.76 MHz for 13C, and a Multinuclear 5 mm PABBO Probe (Bruker, Coventry, England). Samples were dissolved in deuterated chloroform (with TMS). For a few products NMR analysis was performed using a Bruker AM250 NMR spectrometer fitted with a dual probe at frequencies of 250 MHz for 1H-NMR and 62.9 MHz for 13C-NMR. Processing was carried out using an Aspect 3000 computer having 16 K and 64 K complex points for 1H and 13C-NMR respectively. Mass spectra were performed using a ACQUITY® TQD system (Waters®,En Yvelines Cedex, France) with a tandem quadrupole mass spectrometer after dissolving the sample in methanol. Reactions were monitored using TLC and GC on a Shimadzu GC-2010 plus gas chromatograph equipped with a flame ionisation detector and HiCap 5 GC column with dimensions of 0.32 mm (internal diameter) × 30 m (length) × 0.25 mm (film thickness), using nitrogen as carrier gas.

3.2. Procedure for Preparation of Mono-Adducts

The amine (7.5 mmol) and the Michael acceptor (5 mmol) in a molar ratio of 1.5:1 were refluxed with stirring in the presence of acidic alumina (1 g, 200 mol%). Heating was performed using an oil bath and the reaction was followed by TLC and GC until completion. The reaction was then allowed to cool down to room temperature and filtered through a filter paper. The catalyst was rinsed with ethyl acetate/hexane and then concentrated by rotary evaporation. The crude reaction mixture was purified using a silica-filled chromatographic column using hexane/ethyl acetate as eluents. Usually, for aliphatic amines, the mono-adduct was eluted using 7:3, 6:4 or 5:5 hexane/ethyl acetate whilst for aromatic ones the solvent mixture used was 8:2 hexane/ethyl acetate. The yields of the purified products were recorded and then IR and NMR spectroscopy and MS spectrometry were performed.

3.3. Product Identification

Ethyl 3-(butylamino)propanoate (3a) [26,27]. Yellow oil. IR (neat, cm−1): ν = 3323, 2958, 2931, 2860, 1724, 1463, 1373, 1348, 1184, 1126, 1030, 852, 787. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 4.14 (q, J = 7.2 Hz, 2H), 2.88 (t, J = 6.5, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.51 (t, J = 6.6 Hz, 2H), 1.50–1.39 (m, 2H), 1.38–1.33(m, 2H), 1.26 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.4, 3H).
Ethyl 3-(hexylamino)propanoate (3b) [28]. Yellow oil. IR (neat, cm−1): ν = 3323, 2957, 2927, 2857, 1732, 1456, 1373, 1180, 1126, 1030, 787. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 4.14 (q, J = 7.2 Hz, 2H), 2.88 (t, J = 6.5 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.51 (t, J = 6.6 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H), 1.33–1.25 (m, 8H), 0.88 (t, J = 6.9 Hz, 3H). 13C-NMR (CDCl3, 126 MHz): δ (ppm) 172.81, 60.32, 49.82, 45.09, 34.78, 31.74, 30.01, 26.98, 22.58, 14.18, 14.00. MS (ES+) m/z (%) = 202 [MH+] (20), 114 (100), 44 (48).
Ethyl 3-(1-hydroxybutan-2-ylamino)propanoate (3c). Very thick yellow oil. IR (neat, cm−1): ν = 3362, 3316, 2965, 2934, 2876, 1724, 1558, 1454, 1373, 1348, 1313, 1249, 1250, 1188, 1146, 1096, 1049, 1032, 794. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 4.16 (q, J = 7.2 Hz, 2H), 3.61 (dd, J = 10.7, 4.0 Hz, 1H), 3.28 (dd, J = 10.70, 6.8 Hz, 1H), 3.02–2.97 (m, 1H), 2.83–2.79 (m, 1H), 2.55–2.53 (m, 1H), 2.49 (t, J = 6.4 Hz, 2H), 1.54–1.41 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H). 13C-NMR (CDCl3, 126 MHz): δ (ppm) 172.83, 62.64, 60.52, 60.23, 42.00, 35.09, 24.20, 14.16, 10.34. MS (ES+) m/z (%) = 190 [MH+] (22), 102 (100), 30 (8).
Ethyl 3-(cyclopentylamino)propanoate (3d) [29]. Yellow oil. IR (neat, cm−1): ν = 3323, 2955, 2868, 1728, 1465, 1373, 1350, 1242, 1184, 1165, 1047, 1030, 854, 785. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 4.14 (q, J = 7.2 Hz, 2H), 3.07 (quin, J = 6.8 Hz, 1H), 2.86 (t, J = 6.6 Hz, 2H), 2.51 (t, J = 6.6 Hz, 2H), 1.88–1.81 (m, 2H), 1.73–1.64 (m, 3H), 1.56–1.48 (m, 2H), 1.38–1.29 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H). 13C-NMR (CDCl3, 126 MHz): δ (ppm) 176.34, 52.80, 51.55, 49.80, 39.94, 29.69, 22.54, 13.99. MS (ES+) m/z (%) = 186 [MH+] (30), 98 (100), 30 (26).
Ethyl 3-(prop-2-en-1-ylamino)propanoate (3e) [30]. Light-yellow oil. IR (neat, cm−1): ν = 3323, 3076, 2980, 1736, 1643, 1558, 1463, 1456, 1373, 1254, 1242, 1184, 1115, 1030, 997, 918, 790. 1H-NMR (CDCl3, 500 MHz): δ(ppm) 5.91–5.83 (m, 1H), 5.17 (dq, J = 17.1, 1.6 Hz, 1H), 5.08 (dq, J = 10.3, 1.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.25 (t, J = 6.1 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H), 2.50 (t, J = 6.5 Hz, 2H), 1.77 (s, NH, 1H), 1.24 (t, J = 7.2 Hz, 3H). 13C-NMR (CDCl3, 126 MHz): δ (ppm) 172.67, 136.40, 116.11, 60.39, 52.11, 44.31, 34.62, 14.16.
Ethyl 3-(propargylamino)propanoate (3f). Dark-yellow oil. IR (neat, cm−1): ν = 3418, 3391, 3291, 2982, 2935, 2909, 2851, 1724, 1466, 1459, 1373, 1258, 1184, 1119, 1096, 1030, 910, 856, 756. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 4.15 (q, J = 7.2 Hz, 3H), 3.44 (d, J = 2.5 Hz, 1H), 2.97 (t, J = 6.5 Hz, 2H), 2.52 (t, J = 6.5 Hz, 2H), 2.20 (t, J = 2.4 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3, 126 MHz): δ (ppm) 172.58, 81.88, 71.50, 60.49, 60.39, 43.92, 38.10, 34.56. MS (ES+) m/z (%) = 156 [MH+] (46), 88 (13), 68 (100).
Ethyl 3-(4,5-dihydro-1,3-thiazol-2-ylamino)propanoate (3g) [31]. Yellow oil. IR (neat, cm−1): ν = 3395, 3051, 2955, 2858, 1728, 1651, 1612, 1558, 1504, 1447, 1416, 1373, 1354, 1308, 1277, 1238, 1169, 1115, 1042, 984, 941, 918, 928, 733, 698. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 4.10 (q, J = 8.1 Hz, 2H), 3.75–3.61 (m, 2H), 3.61–3.45 (m, 2H). 3.22–3.14 (m, 2H), 2.71–2.59 (m, 2H), 1.24 (t, J = 8.3 Hz, 3H).
Ethyl 3-(phenylamino)propanoate (3h) [32]. Orange oil. IR (neat, cm−1): ν = 3401, 3053, 3022, 2980, 2933, 2904, 2870, 1736, 1720, 1604, 1558, 1506, 1375, 1317, 1251, 1180, 1114, 1099, 1047, 1028, 869, 858, 750, 692. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 7.18 (t, J = 7.4 Hz, 2H), 6.72 (t, J = 6.4 Hz, 1H), 6.62 (d, J = 8.7 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 4.02 (broad s, 1H), 3.45 (t, J = 6.4 Hz, 2H), 2.61 (t, J = 6.4 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).
Ethyl 3-(benzylamino)propanoate (3i) [30]. Yellow oil. IR (neat, cm−1): ν = 3325, 3086, 3062, 3028, 2981, 2904, 2835, 1732, 1496, 1454, 1373, 1350, 1180, 1119, 1095, 1029, 737, 698. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 7.31 (d, J = 4.7 Hz, 4H), 7.28–7.19 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 2.90 (t, J = 6.5 Hz, 2H), 2.53 (t, J = 6.5 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H).
Ethyl 3-(4-ethylphenylamino)propanoate (3j) [33]. Dark-brown oil. IR (neat, cm−1): ν = 3395, 3101 2963, 2932, 2870, 1732, 1616, 1520, 1473, 1458, 1396, 1373, 1315, 1242, 1180, 1126, 1095, 1045, 1026, 822. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 7.00 (d, J = 8.5 Hz, 2H), 6.56 (d, J = 8.5 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.89 (broad s, 1H), 3.42 (t, J = 6.4 Hz, 2H), 2.59 (t, J = 6.4 Hz, 2H), 2.52 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H). 13C-NMR (CDCl3, 126 MHz): δ (ppm) 172.47, 145.58, 133.64, 128.63, 113.28, 60.59, 39.83, 34.04, 27.93, 15.95, 14.21. MS (ES+) m/z (%) = 222 [MH+] (10), 134 (100), 119 (1).
Ethyl 3-(4-methoxyphenylamino)propanoate (3k) [34]. Dark-brown oil. IR (neat, cm−1): ν = 3383, 3237, 3067, 2986, 2955, 2940, 2909, 2835, 1724, 1627, 1513, 1465, 1458, 1442, 1373, 1296, 1238, 1180, 1119, 1092, 1034, 826, 760, 725. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 6.77 (d, J = 9.0 Hz, 2H), 6.60 (d, J = 9.0 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H) 3.73 (s, 3H), 3.39 (t, J = 6.4 Hz, 2H), 2.58 (t, J = 6.4 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H).
Ethyl 3-(isobutylamino)propanoate (3l) [35]. Yellow oil. IR (neat, cm−1): υ = 2964, 2927, 2875, 2247, 1454, 1377, 698. 1H-NMR (CDCl3, 250 MHz): δ (ppm) 0.91 (t, J = 7.33 Hz, 3H), 1.05 (d, J = 6.1 Hz, 3H), 1.27–1.57 (m, 1H), 2.05 (s, 1H), 2.51 (t, J = 6.7 Hz, 1H), 2.61 (sx, J = 6.7 Hz, 1H), 2.85-3.05 (m, 1H), 3.48 (q, J = 6.7 Hz, 1H), 4.55 (q, J = 6.7 Hz, 1H). 13C-NMR (CDCl3, 62.9 MHz): δ (ppm) 10.1, 19.1, 19.8, 29.5, 42.5, 53.9, 118.8.
Methyl 3-(prop-2-en-1-yl)propanoate (6e) [36]. Light-yellow oil. IR (neat, cm−1): ν = 3323, 3076, 2953, 1736, 1728, 1643, 1558, 1456, 1436, 1364, 1238, 1196, 1177, 920, 854, 790. 1H-NMR (CDCl3, 500 MHz): δ(ppm) 5.91–5.83 (m, 1H), 5.18 (dq, J = 17.2, 1.7 Hz, 1H), 5.10 (dq, J = 10.3, 1.6 Hz, 1H), 3.69 (s, 3H), 3.26 (dt, J = 3.0, 1.4 Hz, 2H), 2.89 (t, J = 6.5 Hz, 2H), 2.53 (t, J = 6.5 Hz, 2H). 13C-NMR (CDCl3, 126 MHz): δ(ppm) 173.19, 136.51, 116.11, 52.19, 51.62, 44.38, 34.51.
Methyl 3-(prop-2-yn-1-ylamino)propanoate (6f). Dark-orange oil. IR (neat, cm−1): ν = 3291, 2982, 2954, 2928, 2851, 2098, 1732, 1458, 1438, 1373, 1246, 1177, 1119, 1045, 1018, 910, 844, 756. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 3.70 (s, 3H), 3.44 (d, J = 2.4 Hz, 2H), 2.98 (t, J = 6.5 Hz, 2H), 2.54 (t, J = 6.5 Hz, 2H), 2.22 (t, J = 2.4 Hz, 1H). 13C-NMR (CDCl3, 126 MHz): δ (ppm) 172.56, 81.88, 71.51, 60.49, 48.99, 43.92, 38.10, 34.56, 14.21. MS (ES+) m/z (%) = 142 [MH+] (10), 75 (13), 68 (100).
Methyl 3-(4-methoxybenzylamino)propanoate (6m) [27]. Yellow oil. IR (neat, cm−1): ν = 3421, 3067, 2997, 2951, 2909, 2835, 1732, 1612, 1585, 1512, 1458, 1439, 1416, 1362, 1300, 1246, 1172, 1107, 1034, 818, 775, 756, 702. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 7.21 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 2H), 3.66 (s, 3H), 2.87 (t, J = 6.5 Hz, 2H), 2.52 (t, J = 6.5 Hz, 2H).
3-(Hexylamino)propanenitrile (9b) [37]. Pale yellow oil. IR (neat, cm−1): υ = 3313, 2954, 2990, 2856, 2247, 1465, 1377, 1128. 1H-NMR (CDCl3, 250 MHz): δ (ppm) 0.85-0.95 (m, 3H), 1.20–1.40 (m, 6H), 1.40–1.55 (m, 3H), 2.53 (t, J = 6.3 Hz, 2H), 2.62 (t, J = 6.7 Hz, 2H), 2.92 (t, J = 6.72 Hz, 2H). 13C-NMR (CDCl3, 62.9 MHz): δ (ppm) 14.0, 18.7, 22.6, 26.9, 30.0, 31.75, 45.1, 49.3, 118.8.
3-(Cyclopentylamino)propanenitrile (9d) [38]. Yellow oil. IR (neat, cm−1): ν = 3310, 2955, 2866, 2245, 1473, 1458, 1419, 1373, 1350, 1246, 1123, 1045, 875, 771. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 3.09 (q, J = 6.7 Hz, 1H); 2.89 (t, J = 6.7 Hz, 2H), 2.50 (t, J = 6.6 Hz, 2H), 1.82–1.79 (m, 2H), 1.72–1.64 (m, 2H), 1.57–1.48 (m, 2H), 1.33–1.27 (m, 2H).
3-(Prop-2-yn-1-ylamino)propanenitrile (9f) [39]. Yellow oil. IR (neat, cm−1): ν = 3287, 2920, 2859, 2249, 2102, 1732, 1670, 1654, 1627, 1458, 1419, 1373, 1331, 1246, 1123, 1045, 910, 763, 656. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 3.47 (d, J = 2.5 Hz, 2H), 3.00 (t, J = 6.7 Hz, 2H), 2.53 (t, J = 6.6 Hz, 2H), 2.40 (t, J = 2.5 Hz, 1H). MS (ES+) m/z (%) = 109 [MH+] (74), 68 (100), 39 (2).
3-(Phenylamino)propanenitrile (9h) [40]. Thick brown oil. IR (neat, cm−1): ν = 3410, 3363, 3217, 3036, 3013, 2928, 2249, 1620, 1605, 1507, 1496, 1465, 1419, 1312, 1269, 1176, 1119, 1026, 995, 880, 752, 694. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 7.21–7.18 (m, 2H), 6.78–6.72 (m, 1H), 6.67 (dd, J = 8.5, 1.1 Hz, 2H), 3.63 (broad s, 1H), 3.52 (q, J = 6.5 Hz, 2H), 2.62 (t, J = 6.6 Hz, 2H).
3-((Pyridin-2-ylmethyl)amino)propanenitrile (9n) [41]. Orange oil. IR (neat, cm−1): υ = 3307, 3174, 2927, 2852, 2247, 1593, 1471, 1435, 1126, 997, 761. 1H-NMR (CDCl3, 250 MHz): δ(ppm) 2.56 (t, J = 6.71 Hz, 2H), 2.99 (t, J = 6.71 Hz, 2H), 3.99 (s, 2H), 7.19 (dd, J = 4.88, 7.32 Hz, 1H), 7.32 (d, J =7.33 Hz, 1H), 7.67 (td, J = 1.83, 7.33, 7.33 Hz, 1H), 8.53–8.60 (m, 1H). 13C-NMR (CDCl3, 62.9 MHz): δ (ppm)18.8, 44.7, 54.3, 118.7, 122.3, 122.4, 136.7, 149.3, 158.8.
3-(4-Methoxybenzylamino)propanenitrile (9o). Yellow oil. IR (neat, cm−1): ν = 3337, 3062, 3001, 2935, 2909, 2835, 1732, 1612, 1585, 1512, 1465, 1458, 1420, 1300, 1177, 1034, 1111, 1033, 817, 772, 756, 702. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 7.22 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H), 3.76 (s, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.49 (t, J = 6.7 Hz, 2H). 13C-NMR (126 MHz, CDCl3): δ (ppm) 158.87, 131.60, 129.26, 118.76, 55.30, 52.58, 44.25, 18.77. MS (ES+) m/z (%) = 121 (100), 77 (43). (70), 69 (57) 71 (100), 30 (66).
3-Isopropylamino)propanenitrile (9p) [28]. Yellow oil. IR (neat, cm−1): ν = 3394, 3310. 2967, 2932, 2870, 2249, 1732, 1654, 1474, 1450, 1420, 1377, 1327, 1246, 1177, 1130, 1092, 1045, 848, 756. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 2.93 (t, J = 6.7 Hz, 2H), 2.86 (sep, J = 6.3 Hz, 1H), 2.51 (t, J = 6.7 Hz, 2H), 1.08 (d, J = 6.3 Hz, 6H).
3-(Butylamino)propanamide (11a) [42]. Very thick colourless oil. IR (neat, cm−1): ν = 2986, 2940, 2909, 1739, 1446, 1373, 1242, 1049, 937, 848. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 5.38 (broad s, 2H), 2.88 (t, J = 5.9 Hz, 2H), 2.63 (t, J = 7.1 Hz, 2H), 2.38 (t, J = 5.9 Hz, 2H), 1.51–1.45 (m, 2H), 1.36 (m, 2H), 0.92 (t, J = 7.3Hz, 3H).
3-(Phenylamino)propanamide (11h). Very thick light-yellow oil. IR (neat, cm−1): ν = 3341, 3194, 3045, 3012, 2963, 2862, 2245, 1664, 1645, 1614, 1508, 1423, 1320, 1265, 1180, 1118, 991, 910, 875, 810, 733, 694. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 7.22 (t, J = 7.4 Hz, 2H), 6.76 (t, J = 7.4 Hz, 1H), 6.67 (d, J = 8.2 Hz, 2H), 5.35 (broad s, 2H), 3.96 (broad s, 1H), 3.51 (t, J = 6.0 Hz, 2H), 2.56 (t, J = 6.0 Hz, 2H). 13C-NMR (126 MHz, CDCl3): δ (ppm) 175.63, 49.15, 45.47, 35.35, 20.39, 13.90. MS (ES+) m/z (%) = 165 [MH+] (11), 106 (100), 77 (14).
Methyl 3-(butylamino)-2-methylpropanoate (13a) [26]. Yellow oil. IR (neat, cm−1): ν = 3327, 2957, 2932, 2874, 2860, 2821, 1740, 1558, 1463, 1454, 1435, 1377, 1361, 1255, 1196, 1199, 1177, 1165, 1138, 987, 833, 758. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 3.69 (s, 3H), 2.88 (dd, J = 11.7, 7.9 Hz, 1H), 2.69–2.55 (m, 4H), 1.50–1.42 (m, 3H), 1.37–1.29 (m, 2H); 1.17 (d, J = 7.0 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 13C-NMR (CDCl3, 126 MHz): δ (ppm) 172.84, 62.64, 60.52, 60.23, 42.00, 35.10, 24.21, 14.17, 10.34. MS (ES+) m/z (%) = 174 [MH+] (30), 86 (100), 57 (2), 44 (16).
Methyl 3-(hexylamino)-2-methylpropanoate (13b) [43]. Yellow oil. IR (neat, cm−1): ν = 3327, 2955, 2928, 2872, 2857, 1732, 1558, 1463, 1456, 1435, 1377, 1361, 1259, 1201, 1175, 1138, 989, 893, 833, 761, 727. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 3.69 (s, 3H), 2.88 (dd, J = 11.5, 7.8 Hz, 1H), 2.70–2.59 (m, 4H), 1.50–1.42 (m, 3H), 1.37–1.29 (m, 6H); 1.16 (d, J = 6.9 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H). MS (ES+) m/z (%) = 202.10 [MH+] (22), 114 (100), 44 (46).
Methyl 3-(pentylamino)-2-methylpropanoate (13q) [43]. Yellow oil. IR (neat, cm−1): ν = 3327, 2955, 2930, 2873, 2859, 1732, 1558, 1463, 1456, 1435, 1379, 1361, 1257, 1196, 1177, 1138, 1060, 989, 833, 750. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 3.69 (s, 3H), 2.90 (dd, J = 11.6, 7.8 Hz, 1H), 2.74–2.52 (m, 4H), 1.50–1.42 (m, 2H), 1.34–1.30 (m, 5H), 1.19 (d, J = 7.0 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). MS (ES+) m/z (%) = 210 [MH+] (100), 101 (20), 73 (7).
Methyl 3-(butylamino)-3-methylpropanoate (15a) [44]. Yellow oil. IR (neat, cm−1): ν = 3390, 2958, 2931, 2874, 1732, 1458, 1439, 1377, 1304, 1250, 1196, 1180, 1096, 1053, 1010, 879, 756, 710. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 3.66 (s, 3H), 3.14–3.01 (m, 1H), 2.68–2.59 (m, 1H), 2.59–2.51 (m, 1H), 2.47 (dd, J = 15.3, 6.8 Hz, 1H), 2.32 (dd, J = 15.3, 6.1 Hz, 1H), 1.48–1.40 (m, 2H), 1.38–1.32 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H).
Methyl 3-(butylamino)-3-phenylpropanoate (17a) [45]. Thick light-yellow oil. IR (neat, cm−1): ν = 3395, 3063, 3028, 2954, 2932, 2862, 1716, 1663, 1635, 1578, 1543, 1496, 1450, 1435, 1373, 1330, 1315, 1277, 1242, 1204, 1173, 1045, 980, 864, 768, 702. 1H-NMR (CDCl3, 500 MHz): δ (ppm) 7.52–7.50 (m, 1H), 7.40–7.32 (m, 3H), 7.28–7.25 (m, 1H), 3.66 (s, 3H), 3.45–3.35 (m, 1H), 2.72 (dd, J = 15.6, 8.6 Hz, 1H), 2.63 (dd, J = 15.6, 5.4 Hz, 1H), 2.48–2.39 (m, 2H), 1.61–1.55 (m, 2H), 1.50–1.47 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). MS (ES+) m/z (%) = 221 [MH+] (7), 82 (100), 57 (53).

4. Conclusions

This study expanded the scope of our previously reported protocol for the synthesis of aza-Michael mono-adducts and confirmed the significant advantage of this method in producing the mono-adducts with high selectivity. Acidic alumina has shown to be a suitable catalyst to selectively obtain the mono-adducts in aza-Michael reactions with the additional advantage of the solvent-free heterogeneous conditions. A wide range of aliphatic/aromatic primary amines and Michael acceptor combinations have been tested successfully, while preserving several other functionalities.
All reactions were performed under green, heterogeneous and solventless conditions in the presence of 0.2 g of acidic alumina per mmol of substrate. Aliphatic amines gave good to excellent yields with the highest (100%) obtained in the addition of 4-methoxybenzylamine to acrylonitrile. Interestingly, cyclic amines provided better results than linear ones, whilst aromatic amines formed only the mono-adducts in excellent yields, with the highest yield of 98% in the reaction between ethyl acrylate and 4-methoxyaniline, and no trace of bis-addition product. Methyl methacrylate and methyl trans-cinnamate provided slightly lower yields due to steric hindrance. Bifunctional amines reacted successfully, the highest yield being that of 93% obtained for addition of propargylamine to ethyl acrylate.

Acknowledgments

The authors thank the University of Malta for financial support. The authors would also like to thank (Malta) for the financing of the testing equipment through the projects: “Strengthening of the Organic, Inorganic, Physical Chemistry Facilities” (Ref. No. 309)” and “Strengthening of Analytical Chemistry, Biomedical Engineering and Electromagnetics RTDI Facilities (Ref. No. 018)”.

Author Contributions

G.B. conceived and designed the experiments; R.A. performed the experiments; G.B. and R.A. analyzed the data; G.B. wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Perlmutter, P. Conjugate addition reactions in organic synthesis. Tetrahedron 1992, 9, 114–136. [Google Scholar]
  2. Rulev, A.Y. Aza-Michael reaction: Achievements and prospects. Russ. Chem. Rev. 2011, 80, 197–218. [Google Scholar] [CrossRef]
  3. Mather, B.D.; Viswanathan, K.; Miller, K.M.; Long, T.E. Michael addition reactions in macromolecular design for emerging technologies. Prog. Polym. Sci. 2006, 31, 487–531. [Google Scholar] [CrossRef]
  4. Cardillo, G.; Tomasini, C. Asymmetric synthesis of beta-amino acids and alpha-substituted beta-amino acids. Chem. Soc. Rev. 1996, 25, 117–128. [Google Scholar] [CrossRef]
  5. Hradil, P.; Hlavac, J.; Soural, M.; Hajduch, M.; Kolar, M.; Vecerova, R. 3-Hydroxy-2-phenyl-4(1H)-quinolinones as promising biologically active compounds. Mini Rev. Med. Chem. 2009, 9, 696–702. [Google Scholar] [CrossRef] [PubMed]
  6. Yadav, J.S.; Ramesh Reddy, A.; Gopal Rao, Y.; Narsaiah, A.V.; Reddy, B.V.S. Lanthanum trichloride (LaCl3): An efficient catalyst for conjugate addition of amines to electron-deficient olefins. Lett. Org. Chem. 2007, 4, 462–464. [Google Scholar]
  7. Duan, Z.; Xuan, X.; Li, T.; Yang, C.; Wu, Y. Cerium (IV) ammonium nitrate (CAN) catalyzed aza-Michael addition of amines to α,β-unsaturated electrophiles. Tetrahedron Lett. 2006, 47, 5433–5436. [Google Scholar] [CrossRef]
  8. Meshram, H.M.; Lakshindra, C.; Reddy, P.N.; Sadashiv, K.; Yadav, J.S. Zirconium(IV) chloride-mediated chemoselective conjugate addition of aliphatic amines to α,β-ethylenic compounds. Synth. Commun. 2006, 36, 795–801. [Google Scholar] [CrossRef]
  9. Yadav, J.S.; Ramesh Reddy, A.; Gopal Rao, Y.; Narsaiah, A.V.; Subba Reddy, B.V. Samarium(III) triflate catalyzed conjugate addition of amines to electron-deficient alkenes. Synthesis 2007, 3447–3450. [Google Scholar] [CrossRef]
  10. Vijender, M.; Kishore, P.; Satyanarayana, B. Cadmium chloride (CdCl2): An efficient catalyst for conjugate addition of amines to electron-poor alkenes. Synth. Commun. 2007, 37, 591–594. [Google Scholar] [CrossRef]
  11. Ying, A.; Wang, L.; Deng, H.; Chen, J.; Chen, X.; Ye, W. Aza-Michael addition of aliphatic or aromatic amines to α,β-unsaturated compounds catalyzed by a DBU-derived ionic liquid under solvent-free conditions. Tetrahedron Lett. 2009, 50, 1653–1657. [Google Scholar] [CrossRef]
  12. Wang, Y.; Yuan, Y.; Guo, S.-R. Silica sulfuric acid promotes aza-Michael addition reactions under solvent-free conditions as a heterogeneous and reusable catalyst. Molecules 2009, 14, 4779–4789. [Google Scholar] [CrossRef] [PubMed]
  13. Gawande, M.B.; Bonifácio, V.D.B.; Luque, R.; Branco, P.S.; Varma, R.S. Benign by design: Catalyst­free in­water, on­water, green chemical methodologies in organic synthesis. Chem. Soc. Rev. 2013, 42, 5522–5551. [Google Scholar] [CrossRef] [PubMed]
  14. Gawande, M.B.; Bonifácio, V.D.B.; Luque, R.; Branco, P.S.; Varma, R.S. Solvent­free and catalyst­free chemistry: A benign pathway to sustainability. ChemSusChem 2014, 7, 24–44. [Google Scholar] [CrossRef] [PubMed]
  15. Likhar, P.R.; Kantam, M.L.; Bhargava, S. Polyaniline-supported metal catalysts for green synthesis. Indian J. Chem. Sect. A 2012, 51A, 155–165. [Google Scholar]
  16. Dai, L.; Zhang, Y.; Dou, Q.; Wang, X.; Chen, Y. Chemo/regioselective aza-Michael additions of amines to conjugate alkenes catalyzed by polystyrene-supported AlCl3. Tetrahedron 2013, 69, 1712–1716. [Google Scholar] [CrossRef]
  17. Nguyen, L.T.L.; Nguyen, T.T.; Nguyen, K.D.; Phan, N.T.S. Metal-organic framework MOF-199 as an efficient heterogeneous catalyst for aza-Michael reaction. Appl. Catal. A Gen. 2012, 425–426, 44–52. [Google Scholar] [CrossRef]
  18. Verma, S.; Mungse, H.P.; Kumar, N.; Choudhary, S.; Jain, S.L.; Sain, B.; Khatri, O.P. Graphene oxide: An efficient and reusable carbocatalyst for aza-Michael addition of amines to activated alkenes. Chem. Commun. 2011, 47, 12673–12675. [Google Scholar] [CrossRef] [PubMed]
  19. Esteves, A.P.; Silva, M.E.; Rodrigues, L.M.; Oliveira-Campos, A.M.F.; Hrdina, R. Aza-Michael reactions with vinyl sulfones and Amberlyst-15 as catalyst. Tetrahedron Lett. 2007, 48, 9040–9043. [Google Scholar] [CrossRef]
  20. Ai, X.; Wang, X.; Liu, J.; Ge, Z.; Cheng, T.; Li, R. An effective aza-Michael addition of aromatic amines to electron-deficient alkenes in alkaline Al2O3. Tetrahedron 2010, 66, 5373–5377. [Google Scholar] [CrossRef]
  21. Xu, H.; Liao, W.M.; Li, H.F. A mild and efficient ultrasound-assisted synthesis of diaryl ethers without any catalyst. Ultrason. Sonochem. 2007, 14, 779–782. [Google Scholar] [CrossRef] [PubMed]
  22. Bosica, G.; Gabarretta, J. Unprecedented one-pot multicomponent synthesis of propargylamines using Amberlyst A-21 supported CuI under solvent-free conditions. RSC Adv. 2015, 5, 46074–46087. [Google Scholar] [CrossRef]
  23. Bosica, G.; Spiteri, J.; Borg, C. Aza-Michael reaction: Selective mono- versus bis-addition under environmentally friendly conditions. Tetrahedron Lett. 2014, 70, 2449–2454. [Google Scholar] [CrossRef]
  24. Bosica, G.; Debono, A.J. Uncatalyzed, green aza-Michael addition of amines to dimethyl maleate. Tetrahedron 2014, 70, 6607–6612. [Google Scholar] [CrossRef]
  25. Hoganson, E.D.E. Photocycloaddition Reactions of trans-β-nitrostyrene. Ph.D. Thesis, Iowa State University of Science and Technology, Ames, IA, USA, 1965. [Google Scholar]
  26. Ellman, J.A.; Bergman, R.G.; Colby, D.A. Stereoselective alkylation of α,β-unsaturated imines via C-H bond activation. J. Am. Chem. Soc. 2006, 128, 5604–5605. [Google Scholar]
  27. Moringa, H.; Morikawa, H.; Sudo, A.; Endo, T. A new water-soluble branched poly(ethylene imine) derivative having hydrolyzable imidazolidine moieties and its application to long-lasting release of aldehyde. J. Polym. Sci. A1 2010, 48, 4529–4536. [Google Scholar] [CrossRef]
  28. Zhang, H.; Zhang, Y.; Liu, L.; Zu, H.; Wang, Y. RuCl3 in poly(ethylene glycol): A highly efficient and recyclable catalyst for the conjugate addition of nitrogen and sulfur nucleophiles. Synthesis 2005, 13, 2129–2136. [Google Scholar] [CrossRef]
  29. Wendelin, W.; Riedl, R. N1-and N2-Substituted 2-Amino-5,6-dihydro-4(1H)-pyrimidinones. Monatsh. Chem. 1985, 116, 237–252. [Google Scholar] [CrossRef]
  30. Player, M.R.; Huang, H.; Hutta, D.A. 5-oxo-5,8-dihydro-pyridopyrimidines as Inhibitors of C-FMS Kinase. US Patent 2007/60577 A1, 2007. [Google Scholar]
  31. Sawant, D.P.; Justus, J.; Balasubramanian, V.V.; Ariga, K.; Srinivasu, P.; Velmathi, S.; Halligudi, S.B.; Vinu, A. Heteropoly acid encapsulated SBA-15/TiO2 nanocomposites and their unusual performance in acid-catalysed organic transformations. Chem. Eur. J. 2008, 14, 3200–3212. [Google Scholar] [CrossRef] [PubMed]
  32. Steuneberg, P.; Sijm, M.; Zuilhof, H.; Sanders, J.P.M.; Scott, E.L.; Frannsen, M.C.R. Lipase-catalyzed aza-Michael reaction on acrylate derivatives. J. Org. Chem. 2013, 78, 3802–3813. [Google Scholar] [CrossRef] [PubMed]
  33. Larsen, S.D.; Connell, M.A.; Cudahy, M.M.; Evans, B.R.; May, P.D.; Meglasson, M.D.; Sullivan, T.J.; Schostarez, H.J.; Sih, J.C.; Stevens, F.C.; et al. Synthesis and biological activity of analogues of the antidiabetic/antiobesity agent 3-guanidinopropionic acid: discovery of a novel aminoguanidinoacetic acid antidiabetic agent. J. Med. Chem. 2001, 44, 1217–1230. [Google Scholar] [CrossRef] [PubMed]
  34. Elan Pharmaceuticals, Inc.; Pharmacia and Up John Company. 2-amino and 2-thio-substituted 1,3-diaminopropanes. U.S. Patent WO2005/95326 A2, 12 October 2005. [Google Scholar]
  35. Banno, Y.; Miyamoto, Y.; Sasaki, M.; Oi, S.; Asakawa, T.; Kataoka, O.; Takeuchi, K.; Suzuki, N.; Ikedo, K.; Kosaka, T.; et al. Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: A new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554. Bioorg. Med. Chem. 2011, 19, 4953–4970. [Google Scholar] [CrossRef] [PubMed]
  36. Neogi, S.; Naskar, D. One-pot reductive mono-n-alkylation of aromatic nitro compounds using nitriles as alkylating reagents. Synthetic Commun. 2011, 41, 1901–1915. [Google Scholar] [CrossRef]
  37. Douraki, S.M.; Massah, A.R. The Zeolite ZSM-5-SO3H catalyzed aza-Michael addition of amines and sulphonamides to electron-deficient alkenes under solvent-free conditions. Indian J. Chem. 2015, 54B, 1346–1349. [Google Scholar]
  38. Surrey, A.R. 4-Thiazolidones. IV. The Preparation of Some 3-Alkylaminoalkyl-2-aryl Derivatives. J. Am. Chem. Soc. 1949, 71, 3354–3356. [Google Scholar] [CrossRef]
  39. Zhou, Y.; Porco, J.A.; Snyder, J.K. Synthesis of 5,6,7,8-tetrahydro-1,6-naphthyridines and related heterocycles by cobalt-catalyzed [2 + 2 + 2] cyclizations. Org. Lett. 2007, 9, 393–396. [Google Scholar] [CrossRef] [PubMed]
  40. Biggs, C.; Selley, T. Potential hypotensive compounds: Substituted 3-aminopropionates and 3-aminopropionohydroxamic acids. J. Pharm. Sci. 1972, 61, 1739–1745. [Google Scholar] [CrossRef] [PubMed]
  41. Halimehjani, A.Z.; Saeedeh, T.; Vahid, A.; Behrouz, N.; Mohammed, R.S. Synthesis and characterization of metal dithiocarbamate derivatives of 3-((pyridin-2-yl)methylamino)propanenitrile: Crystal structure of [3-((pyridin-2-yl)methylamino)propanenitrile dithiocarbamato] nickel(II). Polyhedron 2015, 102, 643–648. [Google Scholar] [CrossRef]
  42. Link, N.P.; Diaz, J.E.; Orelli, L.R. An efficient synthesis of N-arylputrescines and cadaverines. Synlett 2009, 5, 751–754. [Google Scholar]
  43. Hoetling, S.; Halberlag, B.; Tamm, M.; Collatz, J.; Mack, P.; Steidle, J.L.M.; Vences, M.; Schulz, S. Identification and synthesis of macrolide pheromones of the grain beetle Oryzaephilus surinamensis and the frog Spinomantis aglavei. Chem. Eur. J. 2014, 20, 3183–3191. [Google Scholar] [CrossRef] [PubMed]
  44. Hebbache, H.; Jerphagnon, T.; Hank, Z.; Bruneau, C.; Renaud, J. Hydrogenation of β-N-substituted enaminoesters in the presence of ruthenium catalysts. J. Organomet. Chem. 2010, 695, 870–874. [Google Scholar] [CrossRef]
  45. Zamora, R.; Delgado, R.M.; Hidalgo, F.J. Model reactions of acrylamide with selected amino compounds. J. Agr. Food Chem. 2010, 58, 1708–1713. [Google Scholar] [CrossRef] [PubMed]
  • Sample Availability: Not available.
Scheme 1. Aza-Michael mono- and bis-addition.
Scheme 1. Aza-Michael mono- and bis-addition.
Molecules 21 00815 sch001
Table 1. Mono-addition of various primary amines 1al to ethyl acrylate (2).Molecules 21 00815 i001
Table 1. Mono-addition of various primary amines 1al to ethyl acrylate (2).Molecules 21 00815 i001
EntryAmine (1)Yield a 3:4 (%)Temperature (°C)Time (h) b
1n-C4H9NH2 (1a)78:3753
2n-C6H13NH2 (1b)76:4703
3NH2CH(CH3)CH2CH2OH (1c)66:0853.5
4c-C5H9NH2 (1d)90:1753
5CH2=CHCH2NH2 (1e)70:8453
6CH CCH2NH2 (1f)93:0753
7 Molecules 21 00815 i004 (1g)10:09068
8PhNH2 (1h)93:01155
9BnNH2 (1i)80:10953
10p-C2H5-C6H4NH2 (1j)89:0904
11p-CH3O-C6H4NH2 (1k)98:0953
12NH2CH(CH3)CH2CH3 (1l)95:2704
a Yields of pure isolated mono- and bis-adducts 3 and 4; b Heating time.
Table 2. Yields and conditions for mono-addition of various primary multi-functional amines with methyl acrylate (5).Molecules 21 00815 i002
Table 2. Yields and conditions for mono-addition of various primary multi-functional amines with methyl acrylate (5).Molecules 21 00815 i002
EntryAmine (1)Yield 6:7 (%) aTemperature (°C)Time (Hours) b
1CH2=CHCH2NH2 (1e)76 : 5453
2CH CCH2NH2 (1f)84 : 8753.5
3p-CH3O -C6H4 CH2NH2 (1m)91 : 0904
a Yields of pure isolated mono- and bis-adducts 6 and 7; b Heating time.
Table 3. Yields and conditions for mono-addition of various amines with different Michael acceptors.Molecules 21 00815 i003
Table 3. Yields and conditions for mono-addition of various amines with different Michael acceptors.Molecules 21 00815 i003
EntryAcceptorAmine (1)Yield a (%) (Mono-Adduct)Temperature (°C)/Time (h) b
1Acrylonitrile (8)n-C6H13NH2 (1b)98 (9b)70/4
28c-C5H9NH2 (1d)92 (9d)65/3.5
38CH CCH2NH2 (1f)83 (9f)75/3.5
48PhNH2 (1h)90 (9h)95/3
58 Molecules 21 00815 i005 (1n)92 (9n)70/4
68p-CH3OPhCH2NH2 (1o)100 (9o)90/4
78CH(CH3)2NH2 (1p)95 (9p)−20/3
8Acrylamide (10)n-C4H9NH2 (1a)95 (11a)75/6
910PhNH2 (1h)90 (11h)95/7
10Methyl methacrylate (12)n-C4H9NH2 (1a)68 (13a)75/5
1112n-C6H13NH2 (1b)78 (13b)90/5
1212n-C5H11NH2 (1q)76 (13q)90/5
13Methyl trans-crotonate (14)n-C4H9NH2 (1a)71 (15a)75/6
14Methyl trans-cinnamate (16)n-C4H9NH2 (1a)43 (17a)70/48
a Yields of pure isolated mono-adducts; b Heating time.
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