Copper-Nanoparticle-Catalyzed A3 Coupling via C–H Activation CMazaahir op er-Nanoparticle-Cat lyzedA3CouplingviaC–HActivation Kidwai,*a Vikas Bansal,a Neeraj Kumar Mishra,a Ajeet Kumar,b Subho Mozumdarb a
Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India Laboratory of Nanobiotechnology, Department of Chemistry, University of Delhi, Delhi 110007, India Fax +91(11)27666235; E-mail: [email protected]
Received 17 March 2007 b
Abstract: Recyclable metal nanoparticles provide an efficient, economic, and novel route for the synthesis of propargylamines via three-component A3 coupling reaction of aromatic aldehyde, amine and alkyne. This method provides a wide range of substrate applicability. This protocol avoids the use of heavy metal, co-catalyst and gives propargylamines in quantitative yield. Key words: metal nanoparticles, propargylamines, heterogeneous catalysis, cyclic secondary amines, one-pot multicomponent reaction
The transition-metal-catalyzed multicomponent reaction is a powerful synthetic tool to access complex structures from simple precursors in one-pot procedures.1 Recently, extensive attention has been paid to the catalytic properties of transition-metal nanoparticles.2 The high surfacearea-to-volume ratio of solid-supported metal nanoparticles is mainly responsible for their catalytic properties.3 Not surprisingly, metal nanoparticles can be employed as heterogeneous catalysts and recycled.4 Metal nanoparticles, in addition to being cheap, require only mild reaction conditions for high yields of the product in short reaction times as compared to traditional catalysts. Propargylamines are frequent skeletons5 and synthetically versatile key intermediates6 for the preparation of many nitrogen-containing biologically active compounds such as b-lactams, oxotremorine analogues, conformationally restricted peptide, isosteres, other natural products, and therapeutic drug molecules.7 Propargylamines can be synthesized by one-pot three-component A3 coupling of aldehydes, alkynes and amines. C–Hsp bond activation of terminal alkynes by transitionmetal catalysts is of fundamental interest in organic synthesis. Several transition-metal systems such as Ag(I) salt,8 Au(I)/Au(III) salt,9 Au(III) salen complexes,10 Cu(I) salt,11 iridium complexes,12 Hg2Cl213 and Cu/Ru14 bimetallic system have been employed under homogeneous conditions. Recently, A3 coupling reaction has been reported through C–H activation in water using Au(I) salts,9 immobilization of Ag salts in ionic liquid,15 and Cu-supported hydroxyapatite,16 although the scope is generally limited for cyclic amines. In addition, alternative energy sources like microwave11,17 and ultrasonic18 radiations have been used in the presence of Cu(I) salt. SYNLETT 2007, No. 10, pp 1581–158418.06207 Advanced online publication: 07.06.2007 DOI: 10.1055/s-2007-980365; Art ID: G08107ST © Georg Thieme Verlag Stuttgart · New York
However, the reagents used in stoichiometric amount are highly moisture-sensitive, and require strictly controlled reaction conditions. In the above-mentioned protocols, reactions are carried out either in toxic solvent like toluene8 or in the presence of expensive solvents such as ionic liquids,19 or require drastic reaction conditions. It is a considerable drawback that an expensive metal catalyst is often lost at the end of the reaction as there were no reports on the recyclability of catalyst. In continuation of our studies on the development of new synthetic methods20 and the role of transition-metal nanoparticles21 in organic transformations, we report herein an efficient recyclable copper-nanoparticle-catalyzed A3 coupling reaction. Initially to optimize the reaction conditions, benzaldehyde and morpholine were chosen as representative aromatic aldehyde and secondary amine, respectively. Thus 1 mmol of phenylacetylene was treated with varying amounts of benzaldehyde and morpholine under nitrogen atmosphere in the presence of 15 mol% of Cu nanoparticles, in THF at 50–60 °C. GC–MS analysis showed that the maximum conversion of phenylacetylene was obtained on treating with 1 mmol of benzaldehyde and 1 mmol morpholine under nitrogen atmosphere (Scheme 1). R2 1
R CHO + R R NH + H 1a–h
nano-M (10 mol%) THF, 70–80 °C, N2, 1 atm
R1 Ph 3a–h
Having optimized the reaction conditions, different metal nanoparticles were employed as heterogeneous catalyst. It was found that the reaction proceed smoothly with Cu, Ag and Au nanoparticles. However, with Ni nanoparticles only 48% conversion of phenylacetylene was found by crude reaction mixture analysis using GC–MS technique (Table 1). Comparable results were obtained with Cu, Ag and Au nanoparticles, and further reactions were carried out using Cu nanoparticles as they are cheap. Increasing the loading of Cu nanoparticles up to 60 mol% gave the desired propargylamine in 95% yield with 98% conversion. Thus an increase in the concentration of catalyst not only promotes the reaction but also increases the yields (Table 2).
1582 Table 1
M. Kidwai et al. A3 Coupling Reaction Using Metal Nanoparticlesa Conversion (%)b
reverse micellar solution containing Cu nanoparticles
Reverse micelle A containing CuSO4 (aq)
extraction of nanoparticles with absolute EtOH
N2 atmosphere 25 °C
nanoparticles + surfactant molecules
Reverse micelle B containing N2H2 (aq)
washing of nanoparticles with absolute EtOH (4–5 times)
Reaction conditions: benzaldehyde (1.0 equiv), morpholine (1.0 equiv), phenylacetylene (1.5 equiv), Cu nanoparticles (18 ± 2 nm; 15 mol%); solvent: MeCN; temperature: 50–60 °C; N2: 1 atm. b Conversion was determined by GC–MS analysis of the crude reaction mixture. c Isolated and unoptimized yields.
Cu nanoparticles free from surfactant
Preparation of Cu nanoparticles22
However, an increase in the concentration of Cu nanoparticles also results in the oxidation of Cu nanoparticles to CuO during recycling of the catalyst and thus decreases the catalytic efficiency in the second and third cycles. In addition, it was found that at higher temperatures (100– 110 °C) Cu nanoparticles showed good catalytic activity, and a 94% yield was obtained. However, at 50–60 °C lower yields were obtained even after longer reaction times. Comparable results were obtained when the reaction was carried out at 100–110 °C with 15 mol% of Cu nanoparticles. Thus to reduce the amount of catalyst, all optimizations were carried out at 100–110 °C with 15 mol% of Cu nanoparticles. Cu nanoparticles were prepared in the aqueous core of reverse micellar droplets (Scheme 2) and their size was confirmed as 18±2 nm through quasielastic light scattering data (QELS) (Figure 1a) and transmission electron microscopy (TEM) (Figure 1b). It is important to stress that the catalyst was recycled and reused for five to seven runs with only a slight drop in catalyst activity (Table 3). An additional starting material was added into the reaction mixture and the reaction proceeded for an additional ten hours and resulted in the formation of 4a (Table 4) in 87% yield. The results in Table 3 show that after every run the yield was excellent while the reaction time was prolonged. Table 2
Optimization of Cu Nanoparticles for A3 Couplinga
Cu (mol%) Time (h)
Conversion (%)b Yield (%)c
Figure 1 (a) QELS data of Cu nanoparticles: plot of population distribution in percentile versus size distribution in nanometer (nm). (b) TEM image of Cu nanoparticles. The scale bar corresponds to 100 nm in the TEM image.
We supposed that this result was induced by the conglomeration of Cu nanoparticles, which was size-dependent. Cu nanoparticles were separated from the reaction mixture by mild centrifugation at 2000–3000 rpm, at 10 °C for five minutes and the QELS data (Figure 2) clearly showed that there was conglomeration of Cu nanoparticles. In addition, the reaction remained very clean without any side product formation. The reaction medium plays an important role in the A3 coupling reaction in the presence of Cu nanoparticles (15 mol%). Among the various solvents investigated such as MeOH, THF, CH2Cl2, benzene and toluene, MeCN was found to the best solvent of choice and no products were obtained when the reaction was carried out in benzene or CH2Cl2. This may be due to the high polarity associated with MeCN, which may result in the stabilization of the alkenyl–Cu intermediate.
After completing the search for the optimized conditions, we chose a variety of structurally diverse aldehydes, and
No. of cycles
Reaction conditions: benzaldehyde (1.0 equiv), morpholine (1.0 equiv), phenylacetylene (1.5 equiv), Cu nanoparticles (18 ± 2 nm); solvent: MeCN; temperature: 50–60 °C; N2: 1 atm. b Conversion was determined by GC–MS analysis of the crude reaction mixture. c Isolated and unoptimized yields.
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© Thieme Stuttgart · New York
Time (h) a
Recycling of Cu Nanoparticlesa
Reaction conditions: benzaldehyde (1.0 equiv), morpholine (1.0 equiv), phenylacetylene (1.5 equiv), Cu nanoparticles (18 ± 2 nm; 15 mol%); solvent: MeCN; temperature: 100–110 °C; N2: 1 atm. b Isolated and unoptimized yields.
Copper-Nanoparticle-Catalyzed A3 Coupling via C–H Activation
nal alkynes. A tentative mechanism (Scheme 3) was proposed involving the activation of the C–H bond of alkyne by Cu nanoparticles. The alkenyl–Cu intermediate thus formed reacted with the iminium ion generated in situ from aldehyde and secondary amine to give the corresponding propargylamine and regenerated the Cu nanoparticles for further reaction. In the literature it was reported that metal nanoparticles act as a redox catalyst via a free radical mechanism and thus the reaction may proceed via a free-radical mechanism.23 R2
Figure 2 QELS data of Cu nanoparticles: plot of population distribution in percentile versus size distribution in nanometer (nm).
R3 N CH
amines possessing a wide range of functional groups to understand the scope and generality of Cu-nanoparticlepromoted A3 coupling reaction. A variety of aromatic aldehydes were coupled with morpholine and phenylacetylene and it was found that the aryl aldehydes possessing an electron-withdrawing group (Table 4, entries 4–6) afforded better yield with good reactivity than those with an electron-donating group (Table 4, entries 2 and 3), which required longer reaction times. The chosen heterocyclic aldehyde (Table 4, entry 7) also displayed high reactivity with good yield. To expand the scope of amine substrate, we used phenylacetylene as model substrate and examined various amines with different aldehydes. The coupling proceeded smoothly with piperidine and pyrrolidine (Table 4, entries 9 and 10), to afford the corresponding propargylamine in good yields under standard conditions. In general, the formation of propargylamine via A3 coupling proceeded smoothly to afford the corresponding propargylamine through Csp–H bond activation of termiTable 4
H2O H Ph
Scheme 3 Tentative mechanism for the Cu-nanoparticle-catalyzed A3 coupling
In conclusion, a novel, facile, and economic practical method for the synthesis of propargylamine via C–H activation has been achieved with Cu nanoparticles as catalyst. The process is simple and a diverse range of propargylamines is obtained in excellent yields. Overall this methodology offers the competitive advantages such
A3 Coupling of Aldehydes, Alkynes and Secondary Amines by Cu Nanoparticles as Catalysta,22 Product
R1CHO + R2R3NH
Reaction conditions: aldehyde (1.0 equiv), secondary cyclic amine: morpholine (1 equiv), phenylacetylene (1.5 equiv), Cu nanoparticles (18 ± 2 nm; 15 mol%); solvent: MeCN; temperature: 100–110 °C; N2: 1 atm. b Conversions were determined by GC–MS analysis of the crude reaction mixture. c Isolated and unoptimized yields. d Pyrolidine was used as the amine substrate. e Piperidine was used as the amine substrate.
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M. Kidwai et al.
as, recyclability of the catalyst without significant loss of catalytic activity, readily available catalyst that can be used or reused without further purification or without using additives or co-factor, lower catalyst loading, broad substrate applicability, high yields in short reaction times, and simple and easy operation.
Acknowledgment S.M. gratefully acknowledges the financial support from the Department of Science and Technology, Government of India for this work.
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(13) Hua, L. P.; Lei, W. Chin. J. Chem. 2005, 23, 1076. (14) Li, C. J.; Wei, C. Chem. Commun. 2002, 268. (15) Zhang, L.; Wei, C.; Varma, R. S.; Li, C. J. Tetrahedron Lett. 2004, 45, 2443. (16) Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Sridhar, B. Tetrahedron Lett. 2004, 45, 7319. (17) Leadbeater, N. E.; Torenius, H. M.; Tye, H. Mol. Diversity 2003, 7, 135. (18) Sreedhar, B.; Reddy, P. S.; Prakash, B. V.; Ravindra, A. Tetrahedron Lett. 2005, 46, 7019. (19) Park, S. B.; Alper, H. Chem. Commun. 2005, 1315. (20) (a) Kidwai, M.; Venkataramanan, R.; Dave, B. Green Chem. 2001, 3, 278. (b) Kidwai, M.; Bansal, V.; Mothsra, P. J. Mol. Catal. A: Chem. 2007, 268, 76. (c) Kidwai, M.; Mothsra, P.; Bansal, V.; Somvanshi, R. K.; Ethayathulla, A. S.; Dey, S.; Singh, T. P. J. Mol. Catal. A: Chem. 2006, 265, 177. (d) Kidwai, M.; Mothsra, P. Tetrahedron Lett. 2006, 47, 5029. (e) Kidwai, M.; Mothsra, P.; Bansal, V.; Goyal, R. Monatsh. Chem. 2006, 137, 1189. (21) (a) Kidwai, M.; Bansal, V.; Saxena, A.; Shankar, R.; Mozumdar, S. Tetrahedron Lett. 2006, 47, 4161. (b) Saxena, A.; Kumar, A.; Mozumdar, S. Appl. Catal. A: Gen. 2007, 317, 210. (22) Preparation of Cu Nanoparticles: A chemical method involving the reduction of Cu2+ ions to Cu(0) in a reverse micellar system was employed to prepare the Cu nanoparticles. Poly(oxyethylene)(tetramethyl)phenyl ether, commercially known as Triton X-100 (TX-100) was used as surfactant in the process. To a reverse micellar solution of CuSO4 (aq), another reverse micellar solution of N2H2 (aq) was added with constant stirring. In the presence of N2 atmosphere the resulting solution was further stirred for 3 h to allow the complete Oswald ripening (particle growth). The Cu nanoparticles were extracted using anhyd EtOH followed by centrifugation. By varying the H2O content parameter Wo (defined as the molar ratio of water to surfactant concentration, Wo = [H2O]/[surfactant]) the size of nanoparticles could be controlled. The nanoparticles prepared were spherical in shape, with an average size of 18 ± 2 nm as confirmed by TEM photograph and QELS data. The metallic nature of the Cu(0) nanoparticles was confirmed by a characteristic UV absorption of the particles dispersed in cyclohexane (580 nm). Typical Procedure A 50-mL round-bottomed flask was charged with aromatic or heterocylic aldehydes 1a–h (1 mmol), secondary amine (1 mmol) and phenylacetylene (1.5 mmol) in MeCN (5 mL) and the contents of the flask were stirred under a nitrogen atmosphere followed by the addition of Cu nanoparticles (15 mol%, 18 ± 2 nm). The resulting solution was refluxed at 100–110 °C for the appropriate time mentioned in Table 4. The extent of reaction was monitored by TLC. After completion of the reaction, the reaction mixture was centrifuged at 2000–3000 rpm, at 10 °C for 5 min. The organic layer was decanted and the remaining Cu nanoparticles were reused for further reactions. The organic layer was dried over anhyd Na2SO4 and the solvent was removed in vacuo. The crude product was subjected to purification by silica gel column chromatography using a mixture of 15% EtOAc, 5% MeOH and 80% PE as eluent to yield the propargylamine 3a–h. The structures of all the products were unambiguously established on the basis of their spectral analysis (IR, 1H NMR, 13C NMR and GC–MS data). All the products are known compounds. (23) Mallick, M.; Witcomp, M.; Scurrell, M. Mater. Chem. Phys. 2006, 97, 283.