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CAN catalyzed synthesis of β-amino carbonyl compounds via Mannich reaction in PEG
Catalysis Communications 9 (2008) 2547–2549
Contents lists available at ScienceDirect
Catalysis Communications journal homepage: www.elsevier.com/locate/catcom
CAN catalyzed synthesis of b-amino carbonyl compounds via Mannich reaction in PEG Mazaahir Kidwai *, Divya Bhatnagar, Neeraj Kumar Mishra, Vikas Bansal Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
a r t i c l e
i n f o
Article history: Received 8 May 2008 Received in revised form 10 July 2008 Accepted 10 July 2008 Available online 16 July 2008
a b s t r a c t Ceric ammonium nitrate (CAN) in PEG was used as an efficient and recyclable solvent system for one pot, three component Mannich reaction of acetophenone with aromatic aldehydes and aromatic amines. This protocol has advantages of high yield, mild reaction conditions, no environmental pollution and simple work up procedure. Ó 2008 Elsevier B.V. All rights reserved.
Keywords: Ceric ammonium nitrate PEG Mannich reaction b-Amino carbonyls
1. Introduction Mannich reaction, since its discovery, has been one of the most important C–C bond forming reactions in organic chemistry for the preparation of secondary and tertiary amine derivatives [1]. The products of Mannich reaction are mainly b-amino carbonyl compounds and its derivatives that are used for the synthesis of amino alcohols, peptides, lactams and precursors to optically active amino acids. The conventional catalysts for classical Mannich reaction of aldehydes, ketones and amines involve mainly organic or mineral acids like proline [2–4], p-dodecyl benzene sulphonic acid [5] and some Lewis acids [6–8]. Various other promoters like Bronsted acid catalysts [9,10] have also been reported to catalyze the Mannich reaction. Other catalysts for Mannich reaction include Yb(OiPr)3 [11], InCl3 [12,13], lanthanide triflate [14] in solvents like dichloromethane and acetonitrile, siloxy serine organocatalysts [15], phosphorodiamidic acid [16] and silica supported AlCl3 [17]. However they often suffer from the drawbacks of long reaction times, harsh reaction conditions, toxicity and difficulty in product separation, which limit their use in the synthesis of complex molecules. Hence development of a synthetic protocol that is nature friendly, simple, efficient and cost effective remains an ever challenging objective. Recently, cerium (IV) ammonium nitrate has emerged as an important reagent for the construction of carbon– carbon and carbon–heteroatom bonds via radical intermediates [18–21]. In addition, many advantages such as excellent solubility
* Corresponding author. Tel./fax: +91 1127666235. E-mail address: [email protected] (M. Kidwai). 1566-7367/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.catcom.2008.07.010
in water, inexpensiveness, eco-friendly nature, uncomplicated handling, high reactivity, fast conversions and convenient work up procedures make CAN a potent catalyst in organic synthesis. Besides this, CAN is able to catalyze various organic transformations not only based on its electron transfer capacity, but also with its Lewis acidic property. It has been explored as powerful catalyst for different reactions, such as oxidation [22], 1,4-addition [23], protection [24], nitration [25], 1,3-dipolar cycloaddition [26], thiocyanation [27], esterification [28], and the Hantsch reaction [29]. The conventional synthetic procedures invariably use organic solvents as media to provide homogeneous phase that allows molecular interactions effectively and bring the reaction to completion. But the organic solvents used are harmful and do not drive the reactions to total completion. The use of water as a solvent is probably the most desirable approach but this is often not possible due to the hydrophobic nature of the reactants. So we decided to use PEG as the reaction media, as it may stand in comparison to other currently favoured systems such as ionic liquids, supercritical carbon dioxide and micellar systems. The important difference between using PEG and other neoteric solvents is that all of the toxicological properties, the short and long term hazards, and the biodegradability, etc., are established and known [30]. The versatility of this reagent and the environmentally benign nature of PEG encouraged us to couple them together and study their utility for three component Mannich reaction. In continuation of our studies on developing cheap and environmentally benign methodologies for organic reactions [31–33], we reveal herein for the first time a CAN catalyzed three component Mannich reaction of acetophenone, aromatic aldehydes and aromatic amines using PEG as the reaction medium (Scheme 1).
2548
M. Kidwai et al. / Catalysis Communications 9 (2008) 2547–2549
R1 CHO
O CH3 +
1
NH2
+ R
R1
2
3
O HN CAN (5 mol%) PEG, 45°C
R
4a-k
Scheme 1. CAN catalysed Mannich reaction of acetophenone, aromatic aldehydes and aromatic amines.
In the beginning, efforts were made towards the catalytic evaluation of CAN towards the synthesis of b-amino ketones. In an initial endeavor, a blank reaction was carried out using 1 equiv. each of acetophenone, benzaldehyde, and aniline. These were stirred at ambient temperature in ethanol. After 42 h only 30% of the expected product 4a was obtained. The same reaction was then carried out using PEG as the reaction medium under similar conditions. Surprisingly a significant improvement was observed and the yield of 4a was dramatically increased to 67% after stirring the mixture for only 16 h. To further improve the yield and to optimize the reaction conditions, the same reaction was carried out in the presence of 2 mol% of CAN under similar conditions. A tremendous improvement was observed and the yield of 4a was dramatically increased up to 93% after stirring the mixture for only 9 h. With this optimistic result in hand, we further investigated the best reaction conditions by using different amounts of CAN. An increase in the quantity of CAN from 2 mol% to 5 mol% not only decreased the reaction time from 9 h to 6 h but also increased the product yield slightly from 93% to 98%. This showed that the catalyst concentration plays a major role in optimization of the product yield. Although the use of 10 mol% of CAN permitted the reaction time to be decreased to 5 h, the yield unexpectedly decreased to 65%. A possible explanation for the low product yields is that the starting material or the product may have been destroyed during the reaction when excess amount (10 mol%) of CAN was used in the reaction and thus 5 mol% CAN is the suitable choice for the optimum yield of b-amino ketones (Table 1). The effect of different solvents on reaction rate as well as yields of products was also investigated. Almost all solvents afforded products in excellent yield with a variation in reaction time. However we used only PEG because it is a cost effective and environmentally benign solvent (Table 2). The effect of temperature was also studied. Faster reactions occurred on increasing the temperature but the product yield decreased at high temperatures possibly because the Mannich base is unstable at elevated temperature and also because one of the reactants (aldehyde) oxidises at high temperature in presence of CAN (Table 3). In order to prove that the use of polyethylene glycol as solvent is also practical, it must be conveniently recycled with minimal loss and decomposition. Since polyethylene glycol is immiscible with solvent ether, the desired product may be extracted with it
Table 1 Catalytic activity evaluation for Mannich reactiona Entry
CAN (mol%)
Time (h)
Yield (%)b
1 2 3 4
0 2 5 10
42 9 8 7
30 93 98 65
a Reaction conditions: aldehyde (1 mmol), acetophenone (1 mmol), aniline (1 mmol); solvent PEG 400; 45 °C. b Isolated and unoptimised yields.
Table 2 CAN catalyzed Mannich reaction in various solventsa Entry
Solvent
Time (h)
Yield (%)b
1 2 3 4 5 6
PEG 200 PEG 400 PEG 600 Ethanol Acetonitrile Toluene
9 9 9 10 10 12
97 98 98 97 95 92
a Reaction conditions: aldehyde (1 mmol), acetophenone (1 mmol), aniline (1 mmol); CAN (5 mol%); temperature 45 °C. b Isolated and unoptimised yields.
Table 3 Effect of temperaturea Entry
Temperature (°C)
Time (h)
Yield (%)b
1 2 3 4
Room temperature 45 60 80
10 6 5 5
98 98 93 72
a Reaction conditions: aldehyde (1 mmol), acetophenone (1 mmol), aromatic amines (1 mmol); CAN (5 mol%); solvent PEG 400. b Isolated and unoptimised yields.
and the retained PEG phase may be reused. The solvent phase was recycled with decrease in reactivity for three cycles, and an approximately 5% weight loss of PEG was observed from cycle to cycle (Table 4). Based on the above observations, we conducted the same reactions using various aldehydes (2) and amines (3) in the presence of 5 mol% CAN under similar conditions. As expected satisfactory results were observed (Table 5). With electron donating substituents in the amine part, increased yield of products were obtained and the effect is reverse with strong electron withdrawing substituents such as –NO2.
Table 4 Recycling yields No. of cyclesa Yield (%) Time/h
b
Fresh
Run 1
Run 2
Run 3
98 9
87 9
83 9
71 9
a Reaction conditions: acetophenone (1 mmol), benzaldehyde (1 mmol) and aniline (1 mmol), CAN (5 mol%); solvent PEG 400; 45 °C. b Isolated and unoptimized yields.
Table 5 Synthesis of various b-amino carbonyls using CANa Entry
R
R0
Product
Time (h)
Yield (%)b
M.P. (°C) (Lit.) [Ref.]
1 2 3 4 5 6 7 8 9 10 11
H H H H 4-CH3 H H H 4-OCH3 4-NO2 4-Br
H 4-CH3 3,4-(CH3)2 4-Cl H 4-OCH3 4-NO2 2-NO2 H H H
4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k
9 8 9 9 8 9 12 12 9 12 10
98 96 91 95 97 90 68 75 90 71 89
169–170 (169–170) [34] 165–166 (165–167) [35] 143–144 (145–146) [34] 168–169 (169–170) [36] 130–131 (131–132) [37] 163–164 (161–162) [36] 183–184 (183–185) [37] 158–162 133–137 (135–137) [38] 103–104 (105–106) [37] 123–127(130–131) [35]
a Reaction conditions: aldehyde (1 mmol), acetophenone (1 mmol), aromatic amines (1 mmol), CAN (5 mol%); solvent PEG 400; 45 °C. b Isolated and unoptimized yields.
M. Kidwai et al. / Catalysis Communications 9 (2008) 2547–2549
In conclusion, we have shown that CAN is a simple, efficient and eco-friendly catalyst for Mannich reaction. The ambient conditions, environmentally benign solvent PEG, high reaction rates, low loading of catalyst, excellent product yields and simple filtration makes this methodology pollution free and safe process.
2549
the spectral analysis. We also thanks to Department of Chemistry, University of Delhi for financial assistance. Appendix A. Supplementary material
2. Experimental
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.catcom.2008.07.010.
2.1. General
References
All chemicals were purchased from Sigma–Aldrich and Lancaster and were used as such. All reactions and purity of b-amino carbonyl compounds (4a–h) were monitored by thin layer chromatography (TLC) using aluminium plates coated with silica gel (Merck) using 15% ethyl acetate, 5% methanol and 80% petroleum ether as an eluent. The isolated products were further purified by column chromatography using silica gel (Sigma–Aldrich 24, 2179,70, 35-70, mesh 40 Ao surface area 675 m2/g) and purified product were recrystallized. IR spectra were recorded on Perkin–Elmer FTIR-1710 spectrophotometer using Nujol film. 1H NMR spectra were recorded on a Bruker Avance Spectrospin 300 (300 MHz) using TMS as internal standard and chemical shift are in d. GC–MS mass spectra were recorded on a Waters LCT Micromass. The temperature of the reaction mixture was measured through a non-contact infrared thermometer (AZ, Mini Gun type, Model 8868).
[1] M. Arend, B. Westerman, N. Risch, Angew. Int. Ed. Engl. 37 (1998) 1044. [2] M.L. Kantam, Ch.V. Rajasekhar, G. Gopikrishna, K.R. Reddy, B.M. Choudary, Tetrahedron Lett. 47 (2006) 5965. [3] A. Sasaoka, Md.I. Uddin, A. Shimomoto, Y. Ichikawa, M. Shiro, H. Kotsuki, Tetrahedron: Asymmetr. 17 (2006) 2963. [4] R. Duthaler, Angew. Int. Ed. Engl. 42 (2003) 975. [5] K. Manabe, Y. Mori, S. Kobayashi, Tetrahedron 57 (2001) 2537. [6] H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 122 (2000) 8180. [7] E. Hagiwara, A. Fujii, M. Sodeoka, J. Am. Chem. Soc. 120 (1998) 2474. [8] P. Desai, K. Schildknegi, K.A. Agrios, C. Mossman, G.L. Milligan, J. Aube, J. Am. Chem. Soc. 122 (2000) 7226. [9] S. Sahoo, T. Joseph, S.B. Halligudi, J. Mol. Catal. A: Chem. 244 (2006) 179. [10] T. Akiyama, J. Takaya, H. Kagoshima, Synlett (1999) 1426. [11] C.T. Qian, F.F. Gao, R.F. Chen, Tetrahedron Lett. 42 (2001) 4673. [12] T.P. Loh, S.B.K.W. Liung, K.L. Tan, L.L. Wei, Tetrahedron 56 (2000) 3227. [13] T.P. Loh, S.C. Chen, Org. Lett. 4 (2002) 3647. [14] S. Kobayashi, H. Ishitani, S. Komiyama, D.C. Oniciv, A.R. Karitzky, Tetrahedron Lett. 37 (1996) 3731. [15] Y.-C. Teo, J.-J. Lau, M.-C. Wu, Tetrahedron: Asymmetr. 19 (2008) 186. [16] M. Terada, K. Sorimachi, D. Uraguchi, Synlett (2006) 133. [17] Z. Li, X. Ma, J. Liu, X. Feng, G. Tian, A. Zhu, J. Mol. Catal. A: Chem. 272 (2007) 132. [18] V. Nair, J. Mathew, P.P. Kanakamma, S.B. Panicker, V. Sheeba, S. Zeena, G.K. Eigendorf, Tetrahedron Lett. 38 (1997) 2191. [19] E. Baciocchi, R. Ruzziconi, J. Org. Chem. 51 (1986) 1645. [20] Y. Zhang, A. J Raines, R.A. Flowers, J. Org. Chem. 69 (2004) 6267. [21] E. Baciocchi, G. Civitarese, R. Ruzziconi, Tetrahedron Lett. 28 (1987) 5357. [22] A.J.M. Vargas, I. Robina, J.G.F. Bolanos, J. Fuentes, Tetrahedron Lett. 39 (2008) 9271. [23] C.-M. Chu, S. Gao, M.N.V. Sastry, C.-W. Kuo, C. Lu, J.-T. Liu, C.-F. Yao, Tetrahedron 63 (2007) 1863. [24] M.J. Comin, E. Elhalem, J.B. Rodriguez, Tetrahedron 60 (2004) 11851. [25] N.C. Ganguly, M. Datta, P. De, R. Chakravarty, Synth. Commun. 33 (2003) 647. [26] T. Sugiyama, S. Mori, K. Komatsu, A. Ohno, Kidorui 32 (1998) 56. [27] A. Kumar, S.R. Pathak, Lett. Org. Chem. 2 (2005) 745. [28] A. Kuttan, S. Nowshudin, M.N.A. Rao, Tetrahedron Lett. 45 (2004) 2663. [29] S. Ko, C.-F. Yao, Tetrahedron 62 (2006) 7293. [30] J. Chen, S.K. Spear, J.G. Huddleston, R.D. Rogers, Green Chem. 7 (2005) 64. [31] M. Kidwai, V. Bansal, P. Mothsra, J. Mol. Catal. A: Chem. 266 (2007) 43. [32] M. Kidwai, P. Mothsra, V. Bansal, R.K. Somvanshi, A.S. Ethayathulla, S. Dey, T.P. Singh, J. Mol. Catal. A: Chem. 265 (2007) 177. [33] M. Kidwai, N.K. Mishra, V. Bansal, A. Kumar, S. Mozumdar, Catal. Commun. 9 (2008) 612. [34] J. Barluenga, H. Cuervo, B. Olano, S. Fustero, V. Gotor, Synthesis (1986) 469. [35] M.A. Bigdeli, F. Nemati, G.H. Mahdavinia, Tetrahedron Lett. 48 (2007) 6801. [36] .R. Wang, B. Li, T. Huang, L. Shi, X. Lu, Tetrahedron Lett. 48 (2007) 2071. [37] W.-B. Yi, C. Cai, J. Fluor. Chem. 127 (2006) 1515. [38] M. Zahouily, B. Mounir, H. Charki, A. Mezdar, B. Bahlaouan, M. Ouammou, ARKIVOC 13 (2006) 178.
2.2. General procedure for the synthesis of b-amino carbonyls In a 50 ml round bottom flask, acetophenone (1 mmol), aromatic aldehydes (1 mmol) and aromatic amines (1 mmol) in PEG 400 (0.2 ml) were mixed and stirred at 45 °C. To this, CAN (ceric ammonium nitrate) was added. The progress of reaction mixture was monitored by TLC. After completion of reaction the reaction mixture was cooled in dry ice-acetone bath to precipitate the PEG 400 and extracted with ether (PEG being insoluble in ether). Ether layer was decanted, dried and concentrated under reduced pressure. The product though seen as a single compound by TLC, was subjected to further purification by silica gel column chromatography using 15% ethyl acetate, 5% methanol and 80% petroleum ether as an eluent to yield the b-amino carbonyls 4a–h. The recovered PEG 400 can be reused for consecutive runs. The structures of all the products were unambiguously established on the basis of their spectral analysis (IR, 1H NMR and GC/MS mass spectral data). All the products are known compounds. Acknowledgement We express our thanks to Director of University Science and Instrumentation Centre, University of Delhi, Delhi for providing
Contents lists available at ScienceDirect
Catalysis Communications journal homepage: www.elsevier.com/locate/catcom
CAN catalyzed synthesis of b-amino carbonyl compounds via Mannich reaction in PEG Mazaahir Kidwai *, Divya Bhatnagar, Neeraj Kumar Mishra, Vikas Bansal Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
a r t i c l e
i n f o
Article history: Received 8 May 2008 Received in revised form 10 July 2008 Accepted 10 July 2008 Available online 16 July 2008
a b s t r a c t Ceric ammonium nitrate (CAN) in PEG was used as an efficient and recyclable solvent system for one pot, three component Mannich reaction of acetophenone with aromatic aldehydes and aromatic amines. This protocol has advantages of high yield, mild reaction conditions, no environmental pollution and simple work up procedure. Ó 2008 Elsevier B.V. All rights reserved.
Keywords: Ceric ammonium nitrate PEG Mannich reaction b-Amino carbonyls
1. Introduction Mannich reaction, since its discovery, has been one of the most important C–C bond forming reactions in organic chemistry for the preparation of secondary and tertiary amine derivatives [1]. The products of Mannich reaction are mainly b-amino carbonyl compounds and its derivatives that are used for the synthesis of amino alcohols, peptides, lactams and precursors to optically active amino acids. The conventional catalysts for classical Mannich reaction of aldehydes, ketones and amines involve mainly organic or mineral acids like proline [2–4], p-dodecyl benzene sulphonic acid [5] and some Lewis acids [6–8]. Various other promoters like Bronsted acid catalysts [9,10] have also been reported to catalyze the Mannich reaction. Other catalysts for Mannich reaction include Yb(OiPr)3 [11], InCl3 [12,13], lanthanide triflate [14] in solvents like dichloromethane and acetonitrile, siloxy serine organocatalysts [15], phosphorodiamidic acid [16] and silica supported AlCl3 [17]. However they often suffer from the drawbacks of long reaction times, harsh reaction conditions, toxicity and difficulty in product separation, which limit their use in the synthesis of complex molecules. Hence development of a synthetic protocol that is nature friendly, simple, efficient and cost effective remains an ever challenging objective. Recently, cerium (IV) ammonium nitrate has emerged as an important reagent for the construction of carbon– carbon and carbon–heteroatom bonds via radical intermediates [18–21]. In addition, many advantages such as excellent solubility
* Corresponding author. Tel./fax: +91 1127666235. E-mail address: [email protected] (M. Kidwai). 1566-7367/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.catcom.2008.07.010
in water, inexpensiveness, eco-friendly nature, uncomplicated handling, high reactivity, fast conversions and convenient work up procedures make CAN a potent catalyst in organic synthesis. Besides this, CAN is able to catalyze various organic transformations not only based on its electron transfer capacity, but also with its Lewis acidic property. It has been explored as powerful catalyst for different reactions, such as oxidation [22], 1,4-addition [23], protection [24], nitration [25], 1,3-dipolar cycloaddition [26], thiocyanation [27], esterification [28], and the Hantsch reaction [29]. The conventional synthetic procedures invariably use organic solvents as media to provide homogeneous phase that allows molecular interactions effectively and bring the reaction to completion. But the organic solvents used are harmful and do not drive the reactions to total completion. The use of water as a solvent is probably the most desirable approach but this is often not possible due to the hydrophobic nature of the reactants. So we decided to use PEG as the reaction media, as it may stand in comparison to other currently favoured systems such as ionic liquids, supercritical carbon dioxide and micellar systems. The important difference between using PEG and other neoteric solvents is that all of the toxicological properties, the short and long term hazards, and the biodegradability, etc., are established and known [30]. The versatility of this reagent and the environmentally benign nature of PEG encouraged us to couple them together and study their utility for three component Mannich reaction. In continuation of our studies on developing cheap and environmentally benign methodologies for organic reactions [31–33], we reveal herein for the first time a CAN catalyzed three component Mannich reaction of acetophenone, aromatic aldehydes and aromatic amines using PEG as the reaction medium (Scheme 1).
2548
M. Kidwai et al. / Catalysis Communications 9 (2008) 2547–2549
R1 CHO
O CH3 +
1
NH2
+ R
R1
2
3
O HN CAN (5 mol%) PEG, 45°C
R
4a-k
Scheme 1. CAN catalysed Mannich reaction of acetophenone, aromatic aldehydes and aromatic amines.
In the beginning, efforts were made towards the catalytic evaluation of CAN towards the synthesis of b-amino ketones. In an initial endeavor, a blank reaction was carried out using 1 equiv. each of acetophenone, benzaldehyde, and aniline. These were stirred at ambient temperature in ethanol. After 42 h only 30% of the expected product 4a was obtained. The same reaction was then carried out using PEG as the reaction medium under similar conditions. Surprisingly a significant improvement was observed and the yield of 4a was dramatically increased to 67% after stirring the mixture for only 16 h. To further improve the yield and to optimize the reaction conditions, the same reaction was carried out in the presence of 2 mol% of CAN under similar conditions. A tremendous improvement was observed and the yield of 4a was dramatically increased up to 93% after stirring the mixture for only 9 h. With this optimistic result in hand, we further investigated the best reaction conditions by using different amounts of CAN. An increase in the quantity of CAN from 2 mol% to 5 mol% not only decreased the reaction time from 9 h to 6 h but also increased the product yield slightly from 93% to 98%. This showed that the catalyst concentration plays a major role in optimization of the product yield. Although the use of 10 mol% of CAN permitted the reaction time to be decreased to 5 h, the yield unexpectedly decreased to 65%. A possible explanation for the low product yields is that the starting material or the product may have been destroyed during the reaction when excess amount (10 mol%) of CAN was used in the reaction and thus 5 mol% CAN is the suitable choice for the optimum yield of b-amino ketones (Table 1). The effect of different solvents on reaction rate as well as yields of products was also investigated. Almost all solvents afforded products in excellent yield with a variation in reaction time. However we used only PEG because it is a cost effective and environmentally benign solvent (Table 2). The effect of temperature was also studied. Faster reactions occurred on increasing the temperature but the product yield decreased at high temperatures possibly because the Mannich base is unstable at elevated temperature and also because one of the reactants (aldehyde) oxidises at high temperature in presence of CAN (Table 3). In order to prove that the use of polyethylene glycol as solvent is also practical, it must be conveniently recycled with minimal loss and decomposition. Since polyethylene glycol is immiscible with solvent ether, the desired product may be extracted with it
Table 1 Catalytic activity evaluation for Mannich reactiona Entry
CAN (mol%)
Time (h)
Yield (%)b
1 2 3 4
0 2 5 10
42 9 8 7
30 93 98 65
a Reaction conditions: aldehyde (1 mmol), acetophenone (1 mmol), aniline (1 mmol); solvent PEG 400; 45 °C. b Isolated and unoptimised yields.
Table 2 CAN catalyzed Mannich reaction in various solventsa Entry
Solvent
Time (h)
Yield (%)b
1 2 3 4 5 6
PEG 200 PEG 400 PEG 600 Ethanol Acetonitrile Toluene
9 9 9 10 10 12
97 98 98 97 95 92
a Reaction conditions: aldehyde (1 mmol), acetophenone (1 mmol), aniline (1 mmol); CAN (5 mol%); temperature 45 °C. b Isolated and unoptimised yields.
Table 3 Effect of temperaturea Entry
Temperature (°C)
Time (h)
Yield (%)b
1 2 3 4
Room temperature 45 60 80
10 6 5 5
98 98 93 72
a Reaction conditions: aldehyde (1 mmol), acetophenone (1 mmol), aromatic amines (1 mmol); CAN (5 mol%); solvent PEG 400. b Isolated and unoptimised yields.
and the retained PEG phase may be reused. The solvent phase was recycled with decrease in reactivity for three cycles, and an approximately 5% weight loss of PEG was observed from cycle to cycle (Table 4). Based on the above observations, we conducted the same reactions using various aldehydes (2) and amines (3) in the presence of 5 mol% CAN under similar conditions. As expected satisfactory results were observed (Table 5). With electron donating substituents in the amine part, increased yield of products were obtained and the effect is reverse with strong electron withdrawing substituents such as –NO2.
Table 4 Recycling yields No. of cyclesa Yield (%) Time/h
b
Fresh
Run 1
Run 2
Run 3
98 9
87 9
83 9
71 9
a Reaction conditions: acetophenone (1 mmol), benzaldehyde (1 mmol) and aniline (1 mmol), CAN (5 mol%); solvent PEG 400; 45 °C. b Isolated and unoptimized yields.
Table 5 Synthesis of various b-amino carbonyls using CANa Entry
R
R0
Product
Time (h)
Yield (%)b
M.P. (°C) (Lit.) [Ref.]
1 2 3 4 5 6 7 8 9 10 11
H H H H 4-CH3 H H H 4-OCH3 4-NO2 4-Br
H 4-CH3 3,4-(CH3)2 4-Cl H 4-OCH3 4-NO2 2-NO2 H H H
4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k
9 8 9 9 8 9 12 12 9 12 10
98 96 91 95 97 90 68 75 90 71 89
169–170 (169–170) [34] 165–166 (165–167) [35] 143–144 (145–146) [34] 168–169 (169–170) [36] 130–131 (131–132) [37] 163–164 (161–162) [36] 183–184 (183–185) [37] 158–162 133–137 (135–137) [38] 103–104 (105–106) [37] 123–127(130–131) [35]
a Reaction conditions: aldehyde (1 mmol), acetophenone (1 mmol), aromatic amines (1 mmol), CAN (5 mol%); solvent PEG 400; 45 °C. b Isolated and unoptimized yields.
M. Kidwai et al. / Catalysis Communications 9 (2008) 2547–2549
In conclusion, we have shown that CAN is a simple, efficient and eco-friendly catalyst for Mannich reaction. The ambient conditions, environmentally benign solvent PEG, high reaction rates, low loading of catalyst, excellent product yields and simple filtration makes this methodology pollution free and safe process.
2549
the spectral analysis. We also thanks to Department of Chemistry, University of Delhi for financial assistance. Appendix A. Supplementary material
2. Experimental
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.catcom.2008.07.010.
2.1. General
References
All chemicals were purchased from Sigma–Aldrich and Lancaster and were used as such. All reactions and purity of b-amino carbonyl compounds (4a–h) were monitored by thin layer chromatography (TLC) using aluminium plates coated with silica gel (Merck) using 15% ethyl acetate, 5% methanol and 80% petroleum ether as an eluent. The isolated products were further purified by column chromatography using silica gel (Sigma–Aldrich 24, 2179,70, 35-70, mesh 40 Ao surface area 675 m2/g) and purified product were recrystallized. IR spectra were recorded on Perkin–Elmer FTIR-1710 spectrophotometer using Nujol film. 1H NMR spectra were recorded on a Bruker Avance Spectrospin 300 (300 MHz) using TMS as internal standard and chemical shift are in d. GC–MS mass spectra were recorded on a Waters LCT Micromass. The temperature of the reaction mixture was measured through a non-contact infrared thermometer (AZ, Mini Gun type, Model 8868).
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2.2. General procedure for the synthesis of b-amino carbonyls In a 50 ml round bottom flask, acetophenone (1 mmol), aromatic aldehydes (1 mmol) and aromatic amines (1 mmol) in PEG 400 (0.2 ml) were mixed and stirred at 45 °C. To this, CAN (ceric ammonium nitrate) was added. The progress of reaction mixture was monitored by TLC. After completion of reaction the reaction mixture was cooled in dry ice-acetone bath to precipitate the PEG 400 and extracted with ether (PEG being insoluble in ether). Ether layer was decanted, dried and concentrated under reduced pressure. The product though seen as a single compound by TLC, was subjected to further purification by silica gel column chromatography using 15% ethyl acetate, 5% methanol and 80% petroleum ether as an eluent to yield the b-amino carbonyls 4a–h. The recovered PEG 400 can be reused for consecutive runs. The structures of all the products were unambiguously established on the basis of their spectral analysis (IR, 1H NMR and GC/MS mass spectral data). All the products are known compounds. Acknowledgement We express our thanks to Director of University Science and Instrumentation Centre, University of Delhi, Delhi for providing