Propargylamine derivatives are important materials in organic synthesis, pharmaceutical chemistry and chemical engineering, with a structural motif that is found in many natural products and drug molecules [1, 2, 3, 4]. The synthesis of propargylamines is an important topic in modern synthetic chemistry. Therefore, efforts have been made to develop efficient and green strategies for this preparation. The most efficient, convenient and reliable method for the production of propargylamines is the three component aldehyde-alkyne-amine coupling (A3-coupling) reaction [5]. The catalytic A3-coupling reaction gives water as the only byproduct. Gold salts [6, 7], silver salts [8, 9] and other metal salts [10, 11]have been used as homogeneous catalysts to catalyze the A3-coupling reaction. However, most of these homogeneous catalytic systems suffer from the problems of the difficult separation and recycling of the expensive or hazardous catalysts, and environmental pollution.
In order to overcome these drawbacks, the immobilization of the metal salts on a solid support has been applied to the A3-coupling reaction, which allows the straightforward removal of the catalyst from the reaction mixture. Numerous methods have been developed to immobilize metal salts on a large variety of solid supports such as SiO2 [12],zeolite [13], tungstophosphoric acid [14], polymers [15], and so on [16, 17].
However, the disadvantages of these methods are the high price of the catalyst, tedious and time consuming procedure of catalyst preparation, and sensitivity of the Cu(I) compounds. Thus, the development of an efficient and easily available solid catalyst has been an interesting challenge. One way to improve synthesis efficiency and reduce the cost of the heterogeneous catalyst is to use naturally available wastes as the support. Anumber of recent studies have reported using bio-wastes as the support of catalysts, which would reduce the number of synthesis steps, cost and use of hazardous chemicals in the preparation of heterogeneous catalysts [18].
In Fujian province, an enormous amount of oyster shell wastes has been illegally disposed by oyster farms. Therefore, the recycling of these is desirable. Oyster shell powder (OSP) has been used widely as an additive in construction materials, adsorbent of heavy metal ions in sewage treatment and chicken feed in chicken farms in order to reduce the amount of waste oyster shells [19, 20, 21].In addition, oyster shells have medicinal value and have been used as a calcium source [22]. The main component of oyster shells (>95%) is calcium carbonate.
Although OSPs are already widely used in other fields, their application as support of heterogeneous catalysts is less well understood. In addition, microwave (MW) irradiation has proven to be a highly effective heating source for driving chemical reactions in modern organic chemistry [23, 24]. It was found that MWs can accelerate the A3-coupling reaction[25, 26].
In order to further improve the efficiency and practicability of MW irradiationtechnology [27, 28, 29, 30], we report here a simple, green and scalable process for the synthesis of propargylamines from aldehydes, alkynes and amines catalyzed by a heterogeneous OSP-CuCl2 catalyst under microwave irradiation and solvent-free conditions. OSP-CuCl2 is highly efficient, low cost and easy to make. In addition, the catalyst was easily recovered from the reaction mixture by filtration and was reusable. This work is the first attempt to synthesize propargylamines using a catalyst composed of a bio-waste material support and CuCl2 in a one-pot, three-component and scalable synthesis strategy. It not only produces useful propargylamines at low cost, but also reduces waste and improves environmental conditions.
Waste oyster shells used in this study was obtained from a commercial oyster farm in Jimei district, Xiamen city, Fujian province. All reagents and solvents were obtained from commercial sources and used without further purification. All the A3-coupling reactions were carried out in a commercial microwave reactor (MAS-II) manufactured by Sineo Microwave Chemistry Technology (Shanghai) Co.
FT-IR spectra were recorded using KBr on a Thermo Nicolet iS10 FT-IR spectrometer. OSP-CuCl2 was analyzed by atomic absorption spectrophotometry (AAS) using standard methods with a Varian AA275 atomic absorption spectrophotometer (USA). The crystallinity of OSP-CuCl2 was characterized by XRD on a Bruker D8 Advance (Germany) apparatus using Cu Kα radiation. The thermo gravimetric analyzer (TGA) was a TA instrument (USA) DSC2910/SDT2960, and samples were heated from 25 to 800 ℃ at 10 ℃/min under N2. Scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX) used an Oxford instrument 7021. NMR spectra were acquired in CDCl3 on a Bruker DMX-400 spectrometer at 400 MHz for 1H NMR. The chemical shifts are given in δ values from TMS as an internal standard.
In order to remove seaweeds and sands deposited on the shell surface, the waste oyster shells were washed several times in an ultrasonic cleaner and dried naturally. The oyster shells were roughly crushed using a hammer then ground into powder with a pestle and mortar and passed through a 100 mesh sieve. The OSPs were then dried at 100 ℃ for 2 h and stored in a desiccator.
In a round-bottom flask, OSPs (5.0 g) was mixed with CuCl2 (1.5 g, 0.011 mol) in deionized water (50 mL). The mixture was stirred at room temperature for 8 h. The product was filtered and washed with ethanol, ethyl acetate and water successively. The catalyst was placed in a vacuum oven and dried overnight at 50 ℃. The CaCO3 supported CuCl2 catalyst was prepared by the same procedure as described above. The two kinds of Cu(II) heterogeneous catalysts are denoted as OSP-CuCl2 and CaCO3-CuCl2, respectively.
OSP-CuCl2 and CaCO3-CuCl2 were used for the preparation of propargylamines by the A3-coupling reaction of aldehydes, amines and alkynes. In a typical procedure, to a mixture of aldehyde (3.0 mmol), secondary amine (3.6 mmol) and alkyne (3.6 mmol) was added OSP-CuCl2 or CaCO3-CuCl2 (10 mg) as the catalyst. The mixture was stirred at 90 ℃ under MW irradiation (480 W) for 20 min. After complete conversion of the aldehyde (determined by TLC analysis), the mixture was cooled to room temperature and filtered, extracted with EtOAc, and dried over anhydrous MgSO4. After evaporation of the solvent, the crude product was obtained. Purification was performed by silica gel flash column chromatography with a mixture of petroleum ether/ethyl acetate as eluent to afford the desired propargylamines in good to excellent yields.
After completion of the A3-coupling reaction, OSP-CuCl2 or CaCO3-CuCl2 was separated by simple filtration from the reaction system, and washed with water and ethanol. After drying under vacuum at 60 ℃ for 1 h, the recycled catalyst was used for the next run under the same conditions.
4-(1,3-diphenylprop-2-ynyl)morpholine. IR (KBr, νmax, cm-1): 3059 (m), 2956 (s), 2852 (s), 2750 (m), 2690 (w), 2222 (w), 1680 (w), 1559 (m), 1489 (s), 1450 (s), 1317 (s), 1114 (s), 1001 (s), 758 (s), 696 (s). 1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 7.4 Hz, 2H), 7.57-7.49 (m, 2H), 7.41-7.27 (m, 6H), 4.83 (s, 1H), 3.63-3.87 (m, 4H), 2.62-2.78 (m, 4H).
4-(1-(furan-2-yl)-3-phenylprop-2-ynyl)morpholine. IR (KBr, νmax, cm-1): 3117 (w), 3057 (w), 2956 (s), 2854 (s), 2752 (w), 2690 (w), 2225 (w), 1597 (m), 1494 (m), 1450 (m), 1315 (m), 1112 (s), 1006 (m), 922 (m), 752 (s). 1H NMR (400 MHz, CDCl3): δ = 7.62-7.28 (m, 6H), 6.64-6.31 (m, 2H), 4.91 (s, 1H), 3.89-3.70 (m, 4H), 2.79-2.59 (m, 4H).
4-(1-(4-chlorophenyl)-3-phenylprop-2-ynyl)morpholine. IR (KBr, νmax, cm-1): 3057 (m), 2956 (s), 2854 (s), 2222 (w), 1597 (m), 1487 (s), 1450 (s), 1315 (s), 1114 (s), 1006 (s), 856 (m), 756 (m), 692 (m). 1H NMR (400 MHz, CDCl3): δ = 7.67-7.49 (m, 4H), 7.37 (d, J = 6.4 Hz, 5H), 4.79 (s, 1H), 3.90-3.72 (m, 4H), 2.81-2.62 (m, 4H).
4-(1-(4-methoxyphenyl)-3-phenylprop-2-ynyl)morpholine. IR (KBr, νmax, cm-1): 3055, 2999 (w), 2928 (w), 2820 (w), 1606 (m), 1508 (m), 1319 (m), 1249 (m), 844 (m), 763 (m). 1H NMR (400 MHz, CDCl3): δ = 7.60-7.49 (m, 4H), 7.38-7.32 (m, 3H), 6.93 (d, J = 8.7 Hz, 2H), 4.76 (s, 1H), 3.84 (s, 3H), 3.76 (s, 4H), 2.65 (s, 4H).
4-(3-phenylprop-2-ynyl)morpholine. IR (KBr, νmax, cm-1): 3057 (m), 2958 (s), 2920 (s), 2854 (s), 2814 (s), 2235 (w), 1559 (w), 1489 (m), 1448 (s), 1323 (s), 1118 (s), 1006 (m), 758 (m), 692 (m). 1H NMR (400 MHz, CDCl3): δ = 7.55-7.41 (m, 2H), 7.30 (dd, J = 8.6, 5.0 Hz, 3H), 3.86-3.73 (m, 4H), 3.52 (s, 2H), 2.71-2.60 (m, 4H).
N,N-diethyl-3-phenylprop-2-yn-1-amine. IR (KBr, νmax, cm-1): 3057 (w), 2970 (s), 2818 (m), 2225 (w), 1597 (w), 1487 (m), 1458 (m), 1379 (m), 1321 (m), 1201 (w), 1064 (m), 758 (m), 692 (m). 1H NMR (400 MHz, CDCl3): δ = 7.52-7.39 (m, 2H), 7.36-7.31 (m, 3H), 3.67 (s, 2H), 2.80-2.60 (m, 4H), 1.15-1.13 (2s, 6H).
N-butyl-N-(3-phenylprop-2-ynyl)butan-1-amine. IR (KBr, νmax, cm-1): 3059 (w), 2955 (s), 2866 (m), 2818 (m), 1597 (w), 1462 (m), 1371 (m), 1321 (m), 1089 (m), 947 (m), 754 (m), 692 (m). 1H NMR (400 MHz, CDCl3): δ = 7.50-7.42 (m, 2H), 7.38-7.28 (m, 3H), 3.65 (s, 2H), 2.61-2.51 (m, 4H), 1.55-1.50 (m, 4H), 1.44-1.32 (m, 4H), 1.01-0.97 (2s, 6H).
4-(4-(4-methoxyphenoxy)but-2-ynyl)morpholine. IR (KBr, νmax, cm-1): 3049 (w), 2920 (s), 2854 (s), 2025 (w), 1595 (w), 1506 (s), 1454 (s), 1373 (s), 1290 (m), 1215 (m), 1114 (m), 1010 (s), 827 (m), 711 (m), 524 (w). 1H NMR (400 MHz, CDCl3): δ = 6.89-6.82 (m, 4H), 4.65 (s, 2H), 3.74 (s, 3H), 3.73-3.64 (m, 4H), 3.29 (d, J = 1.6 Hz, 2H), 2.56-2.43 (m, 4H).
N,N-diethyl-4-(4-methoxyphenoxy)but-2-yn-1-amine. IR (KBr, νmax, cm-1): 3049 (w), 2968 (s), 2827 (s), 2256 (w), 1595 (w), 1506 (w), 1458 (m), 1377 (m), 1317 (m), 1213 (s), 1101 (m), 1037 (s), 825 (m), 746 (w). 1H NMR (400 MHz, CDCl3): δ = 6.95-6.89 (m, 2H), 6.87-6.80 (m, 2H), 4.66 (s, 2H), 3.76 (s, 3H), 3.45 (s, 2H), 2.56-2.45 (m, 4H), 1.04-0.98 (2s, 6H).
4-morpholinobut-2-ynyl benzoate. IR (KBr, νmax, cm-1): 3066 (w), 2924 (m), 2856 (m), 2237 (w), 1724 (s), 1595 (m), 1448 (m), 1371 (m), 1267 (m), 1112 (m), 1008 (m), 862 (m), 796 (m), 567 (w). 1H NMR (400 MHz, CDCl3): δ = 8.13-7.98 (m, 2H), 7.59-7.46 (m, 2H), 4.97 (s, 2H), 3.80-3.69 (m, 4H), 3.35 (s, 2H), 2.62-2.52 (m, 4H).
4-(diethylamino)but-2-ynyl benzoate. IR (KBr, νmax, cm-1): 3066 (w), 2970 (w), 2820 (w), 2270 (w), 1726 (s), 1595 (m), 1452 (m), 1375 (m), 1267 (s), 1103 (s), 1020 (m), 952 (m), 709 (s), 609 (w). 1H NMR (400 MHz, CDCl3): δ = 8.09-8.02 (m, 2H), 7.56-7.44 (m, 3H), 4.95 (s, 2H), 3.47 (s, 2H), 2.60-2.50 (m, 4H), 1.06-0.98 (2s, 6H).
FT-IR spectroscopy is a technique that provides valuable information on OSP-CuCl2 and CaCO3-CuCl2. Figure 1 shows the FT-IR spectra of the OSPs, CaCO3, OSP-CuCl2 and CaCO3-CuCl2 samples. As can be seen from Fig. 1, CuCl2deposition onto the OSPsresulted in slight lowering shifts of the characteristic absorption, i.e., the peak at 1429 cm-1was shifted to 1425 cm-1. In addition, the -CO32- bending vibration absorption peaks at 878 and 712 cm-1 were shifted to lower wavenumber at 877 and 711 cm-1 after the complexing of CuCl2 with OSPs. The slight shifts of the peaks of OSP-CuCl2 can be attributed to the chelation of CuCl2 with biological molecules such as chitin and proteins on the surface of OSPs. Compared to OSPs, when CaCO3 was complexed with CuCl2, the -CO32- stretching peak at 1423 cm-1 was shifted to the lower wavenumber at 1421 cm-1. Furthermore, the -CO32- bending vibration peaks at 713 cm-1 were shifted to the lower wave number at 711 cm-1 after the deposition of CuCl2. The lower frequency of the above peak indicated the physical adsorption of CuCl2 by CaCO3.
The crystalline phases of OSP-CuCl2 and CaCO3-CuCl2 were characterized by XRD. The XRD patterns are shown in Fig. 2. The XRD patterns of OSP-CuCl2 and CaCO3-CuCl2 showed characteristic reflections at 2θ = 23.28°, 29.24°, 36.40°, 39.26°, 43.25°, 47.74°, and 48.73° corresponding to the (012), (104), (110), (113), (202), (024), and (116) planes of calcite (JCPDS 72-1652). The XRD patterns also showed the characteristic reflection for CuCl2 at 2θ = 32.2° corresponding to the (201) plane of the cubic CuCl2 crystal. The results indicated that OSP-CuCl2 and CaCO3-CuCl2 catalysts were prepared successfully.
To characterize the thermal behavior of OSP-CuCl2 and CaCO3-CuCl2, TGA was performed under a N2 atmosphere. Figure 3 gives the TGA curves from room temperature to 800 ℃. As can be seen in Fig. 3, calcination of the CaCO3-CuCl2 started at 590 ℃ and was at 730 ℃. The mass of CaCO3-CuCl2 during the calcination under the N2 atmosphere decreased by 37% because of the decomposition of CaCO3 (Fig. 3(1)). OSP-CuCl2 exhibited a slow mass loss at 100 ℃ with 0.4% mass loss, which was attributed to the removal of adsorbed water (Fig. 3(2)). An obvious mass loss (9.2%) from 100 to 590 ℃ was observed, which was assigned to the decomposition of chitin and protein molecules in the OSPs. OSP-CuCl2 did not show any obvious mass loss between room temperature and 200 ℃, which indicated that the OSP-CuCl2 catalyst was thermally stability below 200 ℃.
Cu was detected on OSPs and CaCO3 by SEM/EDX analysis. Figure 4 shows typical SEM/EDX images of the Cu(II) element from OSP-CuCl2 and CaCO3-CuCl2. Fig. 4(a) and (c) showed that CuCl2 was uniformly coated onto the OSPs and CaCO3. Fig. 4(a) and (b) show that the OSP-CuCl2 catalyst can be reused for at least six consecutive runs without any decrease in the CuCl2 on the recycled OSP-CuCl2 catalyst. However, Fig. 4(c) and (d) showed that the CuCl2 of the recycled CaCO3-CuCl2 catalyst after six cycles was obviously lower than on the fresh catalyst. The difference of the Cu element after six cycles between OSP-CuCl2 and CaCO3-CuCl2 can be explained by the biomolecules on the OSP particle surface, such as chitin and proteins, which play an important role in the chelation of CuCl2. Therefore, the OSP-CuCl2 catalyst has better stability.
In order to determine the best catalyst for the A3-coupling reaction, the catalytic activities of different copper salts and supported copper salt catalysts were examined with a model reaction using benzaldehyde, phenylacetylene and morpholine under solvent-free conditions at 90 ℃. The results are summarized in Table 1.
When OSPs was used as the catalyst, the A3-coupling reaction did not give any product (entry 1). When the A3-coupling reaction was carried out using homogeneous copper catalysts such as CuSO4·5H2O, CuBr, and CuCl2 for 20 min at 90 ℃ under MW irradiation, 4-(1,3-diphenylprop-2-ynyl)morpholine was obtained in 87%, 87%, and 83% isolated yield, respectively (entries 2-4). However, these homogeneous copper catalysts could not be reused. In order to recycle the copper salts, supported catalysts such as OSP-CuSO4, OSP-Cu(OAc)2, CaCO3-CuCl2, OSP-CuBr, and OSP-CuCl2 were employed as a heterogeneous catalyst. The results showed that when the reaction was carried out using OSP-CuSO4, OSP-Cu(OAc)2, CaCO3-CuCl2, and OSP-CuBr as the catalyst for 20 min at 90 ℃ under MW irradiation, the desired product was obtained in good to excellent yields of 81%, 89%, 88%, and 92%, respectively (entries 5-8). OSP-CuCl2 was the most effective catalyst in terms of the isolated yield of the corresponding product (96%, entry 9).
Under a conventional heating condition, we investigated the activity of the catalysts for the formation of 4-(1,3- diphenylprop-2-ynyl)morpholine at 90 ℃. After 240 min, when supported CuCl2, CaCO3-CuCl2, and OSP-CuCl2, were used as catalyst, the yields of propargylamines were 86% and 94%, respectively (Table 1). In addition, when OSPs-CuCl2 was used as catalyst, the reaction gave only 11% yield after 20 min under a conventional heating condition. This showed that MW irradiation dramatically accelerated the reaction rate of the A3- coupling reaction.
The solvent plays an important role in the A3-coupling reaction. To check the solvent effect on the outcome of the A3-coupling, the model reaction was performed with OSP-CuCl2 in various solvents such as MeOH, acetonitrile, DMF, toluene, DMSO, and H2O at 100 ℃ (Table 2).
As shown in Table 2, DMF was the best solvent (96%, entry 5), while toluene afforded a lower yield (67%, entry 3). Good yields of the desired propargylamine were obtained when the reaction was performed in acetonitrile and DMSO (80% and 87%, entries 2 and 4) and moderate results were observed when the reaction was carried out in MeOH and H2O (76% and 79%, entries 1 and 6). More important was that the model reaction also occurred efficiently under solvent-free condition, and afforded the product in excellent yield (96%, entry 7). Therefore, the following A3-coupling reactions were carried out under solvent-free condition to avoid the use of a volatile organic solvent to reduce environmental pollution.
To expand the scope of the A3-coupling reaction, various alkynes, aldehydes and amines were used as starting substrate. Under the optimized conditions, the A3-coupling reaction was performed in air under MW irradiation with OSP-CuCl2 as catalyst. The results are summarized in Table 3. Both aromatic and aliphatic aldehydes, including those bearing functional groups such as alkoxy and chloro substitutions, underwent the A3-coupling reaction smoothly to provide the corresponding propargylamines in good to excellent yields (85%-97%, entries 1-11). Different amines also have an effect on the reaction. Excellent yields were observed when a cyclic amine, such as morpholine, was used (entries 1-5, 8, and 10). Lower yields were observed when a chain amine, such as dibutylamine and diethylamine, was used (entries 7 and 11). In addition, we examined the effect of functional alkynes with electron-donating and electron-withdrawing groups, such as 1-methoxy-4-(prop- 2-ynyloxy)benzene and prop-2-ynyl benzoate. As can be seen in Table 3, both electron-donating and electron-withdrawing substituted aromatic alkynes gave good to excellent yields (89%-95%, entries 8-11).
The separation and recovery of a heterogeneous catalyst is an important step in the preparation of fine chemicals. To achieve both environmental and economic benefits, the lifetime of OSP-CuCl2 and its reusability are important considerations for practical applications, especially for the A3-coupling reaction performed on a large scale. To clarify this issue, a set of experiments for the synthesis of 4-(1,3-diphenylprop-2- ynyl)morpholine from benzaldehyde, phenylacetylene and morpholine with OSP-CuCl2 and CaCO3-CuCl2 as catalyst were performed. The results are shown in Fig. 5. The results indicated that there were noticeable drops in the product yields over OSP-CuCl2 after 6 cycles (from 96% to 81%), suggesting that CuCl2 leaching occurred for the heterogeneous OSP-CuCl2 catalyst. Moreover, the A3-coupling reaction catalyzed by CaCO3-CuCl2 gave increasingly low yields (only 68% after 6 cycles). The copper(II) content of the OSP-CuCl2 catalyst after 6 cycles was 6.17% as detected by AAS, which was lower than on the fresh OSP-CuCl2 (9.38%). AAS analysis showed that the copper(II) content in CaCO3-CuCl2 obviously decreased from 10.21% to 2.57% after 6 cycles. An obvious conclusion can be drawn that the obvious difference in catalytic activity after 6 cycles between OSP-CuCl2 and CaCO3-CuCl2 was caused by the chitin and protein mol ecules on the OSP surface, which played an important role in the chelation of CuCl2. Thus, this makes OSP-CuCl2 more stable and the preferred catalyst.
To demonstrate the potential of this method for production purposes, the scale-up synthesis of propargylamines was investigated with N,N-diethyl-3-phenylprop-2-yn-1-amine as a model reaction. The results are summarized in Table 4. The A3-coupling reaction between formaldehyde, phenylacetylene and diethylamine proceeded successfully and the product was obtained in good yields almost comparable to those in the small scale reactions. The results of scale-up experiments showed that when the scale of the reaction was 150 mmol, the yield of purified N,N-diethyl-3-phenylprop-2-yn-1-amine was 87%. Meanwhile, the recovery and reuse of OSP-CuCl2 was also investigated. The recovered catalyst exhibited good activity for up to five consecutive cycles. When the scale of the reaction was 30 mmol, the catalyst can be recycled and reused at least five times and still maintained a moderate yield (70%, entry 8).
On the basis of the above results, a proposed reaction mechanism for the A3 coupling reaction catalyzed by OSP-CuCl2 under microwave-heated conditions is illustrated in Fig. 6. The initial stepis activation of the terminal alkyne by the OSP-CuCl2 catalyst under MW irradiation to afford the corresponding copper-alkylidine complex on the OSPs support. Then, the copper acetylide intermediate reacted with iminium ion (generated in situ from the corresponding aldehyde and amine) to give the desired propargylamine, with the OSP-CuCl2 catalyst being regenerated for a further cycle of reactions.
We successfully developed a bio-waste OSP-based composite with CuCl2 as a heterogeneous catalyst for the scale-upsynthesis of propargylamines by a one-pot three-component A3-coupling reaction of aldehydes, amines and alkynes under MW irradiation. A wide range of functional groups could be tolerated under the reaction conditions. The A3-coupling reaction was carried out at a relatively low temperature, in a shorter reaction time, and in air without a solvent under MW irradiation, and gave good to excellent yields. Propargylamine was obtained in 87% yield when the scale of the A3-coupling reaction was increased to 150 mmol. The OSP-CuCl2 catalyst was easily recovered from the reaction mixture by filtration and could be reused at least six times. The catalyst not only produced useful propargylamines at low cost, but also reduced waste and improvedenvironmental conditions.
2014, Vol. 35 Issue (12): 2006-2013
PDF (677 KB)
2014, Vol. 35 Issue (12): 2006-2013
PDF (677 KB)