Novel one-pot Cu-nanoparticles-catalyzed Mannich reaction

Article abstract of DOI:10.1016/j.tetlet.2009.01.031

Recyclable heterogeneous Cu-nanoparticles efficiently catalyzed the one-pot three-component Mannich reaction of ketones, aromatic aldehydes and amines in methanol. This method provides a novel and improved method for obtaining β-amino carbonyl compounds in terms of good yield with little catalyst loading.

Full text of DOI:10.1016/j.tetlet.2009.01.031

Tetrahedron Letters 50 (2009) 1355–1358
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel one-pot Cu-nanoparticles-catalyzed Mannich reaction
a
a
b
b
Mazaahir Kidwai a, , Neeraj Kumar Mishra , Vikas Bansal , Ajeet Kumar , Subho Mozumdar
*
a Green Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
b Laboratory of Nanobiotechnology, Department of Chemistry, University of Delhi, Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Recyclable heterogeneous Cu-nanoparticles efficiently catalyzed the one-pot three-component Mannich
reaction of ketones, aromatic aldehydes and amines in methanol. This method provides a novel and
improved method for obtaining b-amino carbonyl compounds in terms of good yield with little catalyst
loading.
Received 3 September 2008
Revised 5 January 2009
Accepted 10 January 2009
Available online 14 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cu-nanoparticles
Mannich reaction
Recyclability
b-Amino carbonyl compounds
The vast majority of nature’s molecules including proteins, nu-
cleic acids and most biologically active compounds contain nitro-
gen. Consequently, developing new synthetic methods for the
construction of nitrogenous molecules1 has defined the frontiers
of organic synthesis since its very beginning. The Mannich reaction
is a very useful platform for the development of several mole-
cules.2 Originally, this reaction produces b-amino carbonyl com-
pounds from three components such as an amine, aldehyde and
ketone. The products of the Mannich reaction are used for the syn-
thesis of amino alcohols, peptides and lactams and as precursors to
synthesize amino acids. Moreover, three-component coupling
Mannich reactions are the most important in organic synthesis3
and are conventionally used for making synthetic intermediates,
as several elements can be introduced in a single step into a mol-
ecule. The Mannich reaction relies on two as well as three compo-
nent systems, but the preferable route is the use of a one-pot three-
component setup rather than a two step.4
it worthwhile to perform a controlled reaction condition for the
Mannich reaction using nanoparticles.
Nanoparticles are core base materials for implementing nano-
technology and have attracted researchers in the field of chemistry
because of their current promising applications in organic synthe-
sis.20–24 Metal-nanoparticles have a characteristic high surface-to-
volume ratio that translates into more active sites per unit area
compared to standard catalysts. Cu-nanoparticles, in particular,
are cheap and easy to make and require mild reaction conditions
for high yield products in comparison to traditional catalysts.25,26
Cu-nanoparticles in comparison to homogeneous copper catalysts
have the advantage of recyclability with greater ease of reaction
selectivity, and thus behave as efficient heterogeneous catalysts.
In continuation of our efforts towards the development of newer
synthetic methodologies27 for organic transformations using tran-
sition metal nanoparticles,25,26,28 we report herein an efficient and
recyclable Cu-nanoparticle (Cu-nps)-catalyzed one pot three-com-
ponent Mannich reaction using aldehydes, ketones and amines.
To examine the catalytic behaviour of Cu-nanoparticles in the
Mannich reaction, benzaldehyde (1 mmol), aniline (1 mmol) and
acetophenone (1 mmol) in methanol (5 ml) were stirred under a
nitrogen atmosphere at room temperature in the presence of
10 mol % of Cu-nanoparticles for 8–12 h (Scheme 1),29 and the
reaction yielded 98% b-amino ketone. The structure was elucidated
on the basis of spectral data.
Numerous versions of the Mannich reaction have been devel-
oped5 in the past. Conventional catalysts for the classical Mannich
reaction6 of aldehydes, ketone and amines involve mainly Lewis
acids,7–9 Bronsted acids10–12 and Lewis base catalysis.13 However,
sodium tetrakis (3,5-trifluoromethylphenyl)borate,14 scandium
tris (dodecanesulfonate),15 organometalic,16 ionic liquids17,18 and
19
recently NbCl5 have also been found to catalyze this reaction.
These catalysts suffer mainly from the drawbacks of long reaction
time, toxicity and their usage in stoichiometric amounts. While
searching for economical, cheap and better catalysts, we thought
O
NHR2
R1
O
10 mol% Cu-np (18 2) nm
methanol, r.t., N2
+
R2NH2
R1CHO
+
R
R
CH3
* Corresponding author. Tel./fax: +91 11 27666235.
Scheme 1. Cu-nanoparticles-catalyzed Mannich reaction of acetophenone, benzal-
E-mail address: kidwai.chemistry@gmail.com (M. Kidwai).
dehyde and aniline.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.031

1356
M. Kidwai et al. / Tetrahedron Letters 50 (2009) 1355–1358
R2
R1
We chose various metal nanoparticles, namely, Cu, Au and Ni-
O
HN
O
np to optimize catalytic activity under similar reaction conditions
in the Mannich reaction, and on the basis of product formation
we found that Cu-np was efficacious in comparison to Au or Ni-
np in the Mannich reaction.
10 mol% Cu-np (18 2) nm
R1CHO
R2NH2
+
+
methanol, r.t, N2
A control experiment was conducted in the absence of Cu-np.
The reaction did not proceed and the substrate remained un-
changed. Mechanistically, the reaction proceeds typically via imine
formation through the condensation of aldehyde and amine, fol-
lowed by the attack of an enol form of ketone on imine to afford
the desired product in good yield.
Scheme 2. Cu-nanoparticle-catalyzed Mannich reaction of cyclohexanone, benzal-
dehyde and aniline.
Table 2
Optimization of the concentration of Cu-nanoparticles in the Mannich reactiona
Entry
Cu-np (18 2 nm)/mol %
Time/h
Yieldb (%)
Encouraged by these remarkable results, we screened a variety
of aromatic aldehydes and amines including electron-withdrawing
and electron-donating groups. When ortho-substituted anilines
were used as substrates, the reaction gave no product due to the
steric hindrance of ortho-substituents. In the investigation of vari-
ous benzaldehydes, it was found that p-methylbenzaldehyde is
most active in the reaction (Table 1, entry 5). This is because the
substituents on benzaldehyde have a remarkable influence on
the stability of intermediate ‘RC6H4C+HNHC6H5’ derived from the
aldehyde and the amine. The rich electron-donating substituents
such as ‘–OCH3’ result in low stability of the intermediate (Table
1, entries 9, 12 and 18). However, electron-withdrawing groups
such as ‘–NO2’ degrade the activity of the intermediate and result
in a very low amount of yield (Table 1, entries 7 and 10). In addi-
tion, aliphatic aldehydes, such as isobutyaldehyde, do not favour
the formation of the desired product due to enamine formation.
In order to ascertain the scope and limitation of this Cu-nano-
particle-catalyzed Mannich reaction, we extended the use of the
catalytic systems to the reaction of cyclohexanone with various
aldehydes and amines (Scheme 2, Table 1). Better results were ob-
tained for the formation of b-amino ketones.29
In addition, to compare the catalytic activity of Cu-nanoparti-
cles, the reaction was also tried with copper salts (such as CuCl2
and CuSO4) and was found to be unsuccessful under similar
conditions.
Catalyst concentration plays a major role in the optimization of
the product yield. By increasing the molar concentration of Cu-np
(18 2) nm from 10 to 50 mol %, it was observed that increased
loading of the catalyst from 10 to 50 mol % gave almost the same
yield of the product (Table 2). It appears that a concentration of
10 mol % of Cu-nanoparticles is the suitable choice for an optimum
yield of b-amino ketones.
1
2
3
4
0
42
8
8
0
10
30
50
93
96
97
8
a
Reaction conditions: acetophenone (1 mmol), benzaldehyde (1 mmol) and
aniline (1 mmol), Â mol % Cu-np (18 2) nm; solvent methanol; rt, N2 atmosphere.
b
Isolated and unoptimized yields.
In addition, an increase in the concentration of Cu-nanoparticles
also resulted in the oxidation of Cu-nanoparticles to CuO during
the recycling of the catalyst. We surmised that the oxidized CuO
underwent conglomeration, thus reducing the surface area of the
nanoparticles and hence resulting in a decrease in catalytic activity
during recycling.
Cu-nanoparticles were prepared by the reverse micellar drop-
lets method28d,30 and the size was confirmed as 10–80 nm through
quasi-elastic light scattering data (QELS) (Fig. 1a) and transmission
electron microscopy (TEM) (Fig. 1b).
The study shows that the catalytic effect of nanoparticles is
dependent on the size of nanoparticles (Table 3). The maximum
reaction rate has been observed for an average particle of diameter
of about 20 nm. Particles below this size tended to show a decrease
in reaction rate with a decrease in particle size, while those above
this diameter showed a steady decline in the reaction rate with
increasing size. It has been postulated that in the case of particles
with a size less than 20 nm, a downward shift of the Fermi level
takes place with a consequent increase of band gap energy.31 As
a result, the particles require more energy to pump electrons to
the adsorbed ions in the electron transfer reaction. This leads to
a reduction in reaction rate when catalyzed by smaller particles.
Table 1
One-pot three component Mannich reaction of ketones, aromatic aldehydes and aromatic aminesa
Entry
Ketone
R1
R2
Time (h)
Yieldb (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
Acetophenone
p-methylacetophenone
p-nitroacetophenone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Ph
Ph
Ph
Ph
Ph
8
9
10.5
9
8
10
12
9
93
97
92
95
97
91
73
89
91
74
91
76
85
87
88
90
91
83
169–171
170–171
145–146
172–173
129–130
163–164
185–186
168–170
150–152
105–106
117–118
173–175
137–138
146–147
139–140
118–119
137–138
132–133
4-CH3C6H4
3,4-(CH3)2C6H3
4-ClC6H4
Ph
4-OCH3C6H4
4-NO2C6H4
4-IC6H4
Ph
Ph
Ph
4-IC6H4
Ph
Ph
4-CH3C6H4
Ph
Ph
Ph
4-OCH3C6H4
4-NO2C6H4
4-ClC6H4
4-OCH3C6H4
Ph
Ph
Ph
Ph
9
12
12
9.5
10
10
9
11
12
12
Ph
4-CH3C6H4
4-ClC6H4
Ph
Ph
4-OCH3C6H4
a Reaction conditions: acetophenone (1 mmol)/cyclohexanone, aromatic aldehydes (1 mmol) and aromatic amines (1 mmol), 10 mol % Cu-np (18 2) nm; solvent methanol;
rt, N2 atmosphere.
b
Isolated and unoptimized yields.

M. Kidwai et al. / Tetrahedron Letters 50 (2009) 1355–1358
1357
Figure 1. (a) QELS data of Cu-nanoparticles: Plot of population distribution in percentile versus size distribution in nanometres (nm); (b) TEM image of Cu-nanoparticles.
Table 3
Size screening of Cu-nanoparticles on three-component Mannich reactiona
Entry
Particle size ( 2) nm
Time (h)
Yieldb (%)
1
2
3
4
5
10
20
30
50
70
8
8
8
8
8
87
95
84
71
65
a
Reaction conditions: acetophenone (1 mmol), benzaldehyde (1 mmol) and
aniline (1 mmol), 10 mol % Cu-np ( 2) nm; solvent methanol; rt, N2 atmosphere.
Table 4
Recycling yields
No. of cyclesa
Fresh
Run 1
Run 2
Run 3
Run 4
Figure 2. QELS data of recycled Cu-nanoparticles: plot of population distribution in
percentile versus size distribution in nanometres (nm).
Yield (%)b
Time (h)
93
8
85
8
80
8
71
8
62
8
a
Reaction conditions: acetophenone (1 mmol), benzaldehyde (1 mmol) and
catalytic activity decreases with a decrease in the surface area of
the particles. It was observed that when the number of cycles of
the reaction increased, the catalytic activity of the Cu-nanoparticle
decreased (Table 4). Another explanation is that catalyst recycling
is not as efficient as anticipated because of the slow oxidation of
the Cu-nanoparticles.
Overall, this methodology offers the competitive advantages of
recyclability of the catalyst which could be used without further
purification and without any additives. It also requires less loading
of the catalyst and has broad substrate applicability with ease and
improved yields.
In conclusion, we have successfully developed a novel, easy, eco-
nomic and practical method for the synthesis of b-amino ketones.
The catalyst can be recovered and reused, thus making this proce-
dure more environmentally acceptable. In addition, our method
does not use expensive reagents or high temperatures. Further
investigations on the synthetic applications of various metal-nano-
particles are in progress and will be reported in due course.
aniline (1 mmol), 10 mol % Cu-np (18 2) nm; solvent methanol; rt, N2 atmosphere.
b
Isolated and unoptimized yields.
On the other hand, for nanoparticles with diameters above 20 nm,
the change of the Fermi level is not significant. As these particles
exhibit less surface area for adsorption with increased particle size,
a decrease in catalytic efficiency results.
The nature of reaction media has an important role in the three-
component Mannich reaction in the presence of Cu-nanoparticles
(10 mol %). Here, initially, we chose water as a solvent that had
been conventionally reported but we found that the Cu-nanoparti-
cles are easily oxidized in the water and are not recyclable. We
thus chose methanol as a solvent which gives excellent results
and in which Cu-nanoparticles are recyclable.
We found that the Cu-nanoparticles could be recycled and re-
used three to four times by separating them from the reaction mix-
ture through centrifugation at 2000–3000 rpm at 10 °C for 5–8 min
and by frequent washing with THF. They could be reused as cata-
lysts and this results in the formation of 1 (Table 1) from 85% to
62% yield (Table 4, run 1–3). The change in their catalytic activity
was monitored. The relation between the number of cycles of the
reaction and the catalytic activity in terms of yields is presented
in Figure 2. The data shows a gradual loss of the activity of the cat-
alyst used in the experiment with an increasing number of cycles.
Only a mild decrease in reaction yields in the second cycle was ob-
served, but there was a gradual decrease in the yield of the product
after the third and fourth cycle. One explanation could be that the
active catalyst is efficiently recycled but is of limited stability. This
causes the size of the particles to increases dramatically and hence
Acknowledgements
M. Kidwai and S. Mozumdar gratefully acknowledge the Dean,
Research, University of Delhi and the Department of Science and
Technology, Govt. of India, for financial assistance.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.031.

1358
M. Kidwai et al. / Tetrahedron Letters 50 (2009) 1355–1358
19. Wang, R.; Li, B.; Huang, T. K.; Shi, L.; Lu, X. X. Tetrahedron Lett. 2007, 48,
References and notes
2071.
20. Astruc, D.; Lu, F.; Aranzaes, J. R. Angew. Chem., Int. Ed. 2005, 44, 7852.
21. Praharaj, S.; Nath, S.; Ghosh, S.; Kundu, S.; Pal, T. Langmuir 2004, 20, 9889.
22. Bonnemann, H.; Richards, R. M. Eur. J. Inorg. Chem. 2001, 2455.
23. Dyakonov, A. J. Appl. Catal. B 2003, 45, 257.
24. Martinez, S.; Vallribera, A.; Cotet, C. L.; Popovici, M.; Martin, L.; Roig, A.;
Moreno-Manas, M.; Molins, E. New J. Chem. 2005, 29, 1342.
1. Wohler’s synthesis of (nitrogenous) urea is generally considered the birth of
organic synthesis: (a) Wohler, F. Ann. Phys. Chem. 1828, 12, 253; (b) Ishimaru,
K.; Kojima, T. Tetrahedron Lett. 2003, 44, 5441.
2. Mannich, C.; Krosche, W. Arch. Pharm. (Weinheim, Ger.) 1912, 250, 647;
Reviews: (a) Denmark, S. E.; Nicaise, O. J.-C.. In Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Comprehensive Asymmetric Catalysis; Springer:
Heidelberg, 1999; pp 923–961; (b) Kleinmann, E. F.. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 2,. Chapter
4.1.
25. Kidwai, M.; Bansal, V.; Saxena, A.; Aerry, S.; Mozumdar, S. Tetrahedron Lett.
2006, 47, 8049.
26. Kidwai, M.; Bansal, V.; Kumar, A.; Mozumdar, S. Green Chem. 2007, 9, 742.
27. (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, 266, 43; (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.
28. (a) Kidwai, M.; Bansal, V.; Saxena, A.; Shankar, R.; Mozumdar, S. Tetrahedron
Lett. 2006, 47, 4161; (b) Kidwai, M.; Bansal, V.; Mishra, N. K.; Kumar, A.;
Mozumdar, S. Synlett 2007, 1581; (c) Kidwai, M.; Mishra, N. K.; Bansal, V.;
Kumar, A.; Mozumdar, S. Catal. Commun. 2008, 9, 612; (d) Kidwai, M.; Mishra,
N. K.; Bansal, V.; Kumar, A.; Mozumdar, S. Tetrahedron Lett. 2007, 48, 8883.
29. General procedure for the preparation of b-amino carbonyls: In a 50 ml round
bottom flask, acetophenone (1 mmol)/cyclohexanone, aromatic aldehydes
(1 mmol) and aromatic amines (1 mmol) in methanol (4 ml) were mixed and
3. (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044;
(b) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
4. (a) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338; (b) Matsunaga, S.;
Kumagai, N.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 4712; (c) Juhl,
K.; Gathergood, N.; Jorgensen, K. A. Angew. Chem. 2001, 113, 3083; (d) Cordova,
A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F. J. Am. Chem. Soc. 2002, 124,
5640.
5. For reviews see: (a) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.;
Houk, K. N. Acc. Chem. Res. 2004, 37, 558; (b) Hayashi, Y.; Tsuboi, W.; Ashimine,
I.; Urushima, T.; Shoji, M.; Sakai, K. Angew. Chem., Ind. Ed. 2003, 42, 3677; (c)
Zhang, C. X.; Dong, J. C.; Cheng, T. M.; Li, R. T. Tetrahedron Lett. 2001, 42, 461; (d)
Qian, C. T.; Gao, F. F.; Chen, R. F. Tetrahedron Lett. 2001, 42, 4673.
6. (a) Kobayashi, M.; Araki, M.; Yasuda, M. Tetrahedron Lett. 1995, 36, 5773; (b)
Manabe, K.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 3773.
7. (a) Badorrey, R.; Cativiela, C.; Diaz-de-Villegas, M. D.; Ga’lvez, J. A. Tetrahedron
Lett. 2003, 44, 9189; (b) Periasamy, M.; Suresh, S.; Ganesan, S. S. Tetrahedron
Lett. 2005, 46, 5521; (c) Pandey, G.; Singh, R. P.; Garg, A.; Singh, V. K.
Tetrahedron Lett. 2005, 46, 2137.
8. Loh, T. P.; Wei, L. L. Tetrahedron Lett. 1998, 39, 323.
9. Prukala, D. Tetrahedron Lett. 2006, 47, 9045.
stirred under
a nitrogen atmosphere at room temperature. To this, Cu-
nanoparticle (10 mol % 18 2 nm) were added. On completion of the reaction
(as monitored by TLC using Petrolium Ether/AcOEt = 80:20 as an eluent), the
solid product was filtered and washed with methanol. The precipitate was
dissolved in chloroform to isolate the Cu-nanoparticle via centrifugation at
2000–3000 rpm, at 10 °C for 5 min. The chloroform was removed under
reduced pressure. The crude product was subjected to purification by
recrystallization using Ethanol or flash chromatography using 15% ethyl
acetate, 5% methanol and 80% petroleum ether as an eluent to yield the b-
amino carbonyls 1–18. The structures of all the products were unambiguously
established on the basis of their spectral analysis (IR, 1H NMR, 13C NMR and
GC–MS mass spectral data). All the products are known compounds (see
Supplementary data).
10. Akiyama, T.; Takaya, J.; Kagashima, H. Synlett 1999, 1426.
11. Akiyama, T.; Matsuda, K.; Fuchibe, K. Synlett 2005, 322.
12. Sahoo, S.; Joseph, T.; Halligudi, S. B. J. Mol. Catal. A: Chem. 2006, 244, 179.
13. Takahashi, E.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2004, 33, 936.
14. Chang, C. T.; Liao, B. S.; Liu, S. T. Tetrahedron Lett. 2006, 47, 9257.
15. Kobayashi, S.; Busujima, T.; Nagayama, S. Synlett 1999, 545.
16. Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III Tetrahedron Lett. 2001,
42, 199.
30. Petit, C.; Lixon, P.; Pileni, M. P. J. Phys. Chem. 1993, 97, 12974.
31. (a) Sharma, R. K.; Sharma, P.; Maitra, A. N. J. Colloid Interface Sci. 2003, 265, 134;
(b) Sharma, P.; Brown, S.; Walter, G.; Santra, S.; Moudgil, B. Adv. Colloid Interface
Sci. 2006, 123–126, 471;(c) Samim, M.; Kaushik, N. K.; Maitra, A. N. Bull. Mater. Sci.
2007, 30, 535; (d) Sugunan, A.; Dutta, J. J. Phy. Sci. Idea 2004, 4. 1 and 2.
17. Akiyama, T.; Suzuki, A.; Fuchibe, K. Synlett 2005, 1024.
18. Liu, B. Y.; Zhao, D. S.; Xu, D. Q.; Xu, Z. Y. Chem. Res. Chin. U 2007, 23, 163.