Highly efficient one-pot three-component Mannich reaction in water catalyzed by heteropoly acids

Article abstract of DOI:10.1021/ol060498v

Heteropoly acids efficiently catalyzed the one-pot, three-component Mannich reaction of ketones with aromatic aldehydes and different amines in water at ambient temperature and afforded the corresponding β-amino carbonyl compounds in good to excellent yields and with moderate diastereoselectivity. This method provides a novel and improved modification of the three-component Mannich reaction in terms of mild reaction conditions and clean reaction profiles, using very a small quantity of catalyst and a simple workup procedure.

Full text of DOI:10.1021/ol060498v

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2079-2082
Highly Efficient One-Pot
Three-Component Mannich Reaction in
Water Catalyzed by Heteropoly Acids
Najmodin Azizi, Lalleh Torkiyan, and Mohammad R. Saidi*
Department of Chemistry, Sharif UniVersity of Technology, P.O. Box 11465-9516,
Tehran 11365, Iran
saidi@sharif.edu
Received February 28, 2006
ABSTRACT
Heteropoly acids efficiently catalyzed the one-pot, three-component Mannich reaction of ketones with aromatic aldehydes and different amines
in water at ambient temperature and afforded the corresponding â˜-amino carbonyl compounds in good to excellent yields and with moderate
diastereoselectivity. This method provides a novel and improved modification of the three-component Mannich reaction in terms of mild
reaction conditions and clean reaction profiles, using very a small quantity of catalyst and a simple workup procedure.
Carrying out organic reactions in water has become highly
desirable in recent years to meet environmental consider-
ations.1 The use of water as a sole medium for organic
reactions would greatly contribute to the development of
environmentally friendly processes. Indeed, industry prefers
to use water as a solvent rather than toxic organic solvents.
In this context, in recent years, much attention has been
focused on Lewis acid catalyzed organic reactions in water.
Heteropoly acids (HPAs) are environmentally benign and
economically feasible solid catalysts that offer several
advantages.2 Therefore, organic reactions that exploit het-
eropoly acid catalysts in water could prove ideal for industrial
synthetic organic chemistry applications, provided that the
catalysts show high catalytic activity in water.
provide â-amino carbonyl compounds, which are important
synthetic intermediates for various pharmaceuticals and
natural products.4 The increasing popularity of the Mannich
reaction has been fueled by the ubiquitous nature of nitrogen-
containing compounds in drugs and natural products.5
However, the classical Mannich reaction is plagued by a
number of serious disadvantages and has limited applications.
Therefore, numerous modern versions of the Mannich
reaction have been developed to overcome the drawbacks
of the classical method. In general, the improved methodol-
ogy relies on the two-component system using preformed
electrophiles, such as imines, and stable nucleophiles, such
as enolates, enol ethers, and enamines.6 But the preferable
route is the use of a one-pot three-component strategy that
allows for a wide range of structural variations. In this
context, recent developments of asymmetric synthesis, using
Mannich reactions are among the most important carbon-
carbon bond forming reactions in organic synthesis.3 They
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9624 and references cited there in.
10.1021/ol060498v CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/20/2006

a three-component protocol, have made the Mannich reaction
very valuable.7 However, despite the diverse synthetic routes
so far developed for the asymmetric Mannich reaction, only
a few one-pot procedures on the use of unmodified aldehydes
or ketones in water have been reported in the literature.
Furthermore, most of the reported Mannich reactions in water
have been carried out in the presence of surfactants such as
SDS. Unfortunately, normal-phase separation is difficult
during workup due to the formation of emulsions because
of the SDS.8
Scheme 1. Direct Mannich Reaction Catalyzed by Heteropoly
Acids in Different Solvents
in a table in the Supporting Information. Heteropoly acids
(HPAs) catalyze Mannich reactions in organic solvents such
as acetonitrile, 1,2-dichloroethane, methanol, ethanol, toluene
and mixtures of toluene/water and gave the desired products
in low yield with the foramtion of aldol side products.
Among the screened solvent systems, water was the solvent
of choice, since in this solvent the Mannich-type reactions
proceeded smoothly and afforded the desired adducts in high
yields at room temperature. Consequently, we conclude that
the HPAs are much more reactive in water than in other
organic solvents. At room temperature, the Mannich reaction
proceeded to completion affording the Mannich adduct in
good to excellent yield and relatively good diastereoselec-
tivity. Addition of surfactants such as sodium dodecyl sulfate
(SDS) or cetyltrimethylammonium bromide (CTAB) was not
effective, and they did not improve diastereoselectivity. The
reaction in pure water without using any catalyst gave a low
yield of the product. Furthermore, we were excited to find
that only 0.12 mol % of the catalyst gave good yields at
room temperature. In the some cases, even 0.06 mol % of
HPA was sufficient for the completion of the reaction.
Furthermore, simple workup in water opened the route for
an entirely green highly efficient one-pot Mannich reaction
in water. In addition, H3PMo12O40 has been compared with
H3PW12O40, and we found the same results for both het-
eropoly acids in this reaction in water.
Encouraged by the remarkable results obtained with the
above reaction conditions, and in order to show the generality
and scope of this new protocol, we used various aldehydes
and amines and the results. Table 2 clearly demonstrates that
HPAs are excellent catalysts for Mannich reactions in water.
Thus, a variety of aromatic aldehydes, including electron-
withdrawing and electron-donating groups, were tested using
our new method in water in the presence of H3PW12O40 or
H3PMo12O40. The results are shown in Table 2. Generally,
excellent yields of R-amino ketones were obtained for a
variety of aldehydes including those bearing an electron-
withdrawing group. Furthermore, several electron-rich aro-
matic aldehydes led to the desired products in good yield.
However, under the same reaction conditions aliphatic
aldehydes, such as isobutyaldehyde, gave a mixture, due to
enamine formation; the desired product was obtained in low
yield (Table 2, entry 22). The scope of our method was
extended to other amines. In the case of amines having an
electron-donating group, such as 4-isopropylaniline, the
corresponding amino ketones were obtained in good yields.
Furthermore, amines with electron-withdrawing groups, such
as 4-chloroaniline and 3,4-dichloroaniline, gave the desired
product in good yields.
There is increasing interest in developing environmentally
benign reactions and atom-economic catalytic processes that
employ unmodified ketones, amines, and aldehydes for
Mannich-type reaction in recent years. In continuation of our
studies on the new variants, of one-pot, three-component
Mannich-type reactions for aminoalkylation of aldehydes
with different nucleophiles,9 and our ongoing green organic
chemistry program that uses water as a reaction medium,
performs organic transformations under solvent-free condi-
tions,10 herein we describe a mild, convenient, and simple
procedure for effecting the one-pot, three-component reaction
of an aldehyde, an amine, and a ketone for the preparation
of â-amino carbonyl compounds in water using a heteropoly
acid catalyst.
Initially, the three-component Mannich reaction of 4-chlo-
robenzaldehyde (3.0 mmol), aniline (3.1 mmol), and the
cyclohexanone (5 mmol) was examined (Scheme 1).
As a preliminary study, several Lewis acids and solvents
were screened in the model reaction. The results of extensive
Lewis acid and solvent screening and optimization are shown
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Am. Chem. Soc. 2005, 127, 11256. (c) Ollevier, T.; Nadeau, E. J. Org.
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Am. Chem. Soc. 2004, 126, 15942. (e) Xu, L.-W.; Xia, C.-G.; Li, L. J.
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102. (k) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 4712. (l) Kobayashi, S.; Hamada, T.; Manabe, K. J.
Am. Chem. Soc. 2002, 124, 5640. (m) Curdova, A. Chem. Eur. J. 2004, 10,
1987. (n) Chowdari, N. S.; Suri, J. T.; Barbas C. F. Org. Lett. 2004, 6,
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Soc. 2003, 125, 11208. (p) Josephsohn, N. S.; Carswell, E. L.; Snapper, M.
L.; Hoveyda, A. H. Org. Lett. 2005, 7, 2711.
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Matsuda, K.; Fuchibe, K. Synlett 2005, 322. (d) Akiyama, T.; Takaya, J.;
Kagoshima, H. Synlett 1999, 1045.
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M. R.; Azizi, N. Synlett 2002, 1347. (c) Azizi, N.; Saidi, M. R. Tetrahedron
Lett. 2002, 43, 305.
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M. R. Org. Lett. 2005, 7, 3649.
2080
Org. Lett., Vol. 8, No. 10, 2006

The high yield, simple reaction protocol, and originality
of this novel process prompted us to use other ketones under
these conditions (Table 1). Thus, the three-component
Table 2. One-Pot, Three-Component Direct Mannich Reactiona
Table 1. HPA-Catalyzed Three-Component Mannich Reactiona
yieldsc
(%)
entry
R1
R2
catalyst anti/synb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
A
B
A
B
A
B
B
A
B
A
B
A
B
A
B
B
B
B
B
B
B
B
B
B
63:37
62:38
63:37
64:35
64:36
65:35
47:53
46:54
58:42
55:45
56:44
57:43
41:59
39:61
66:34
68:32
65:33
54:46
50:50
72:28
62:38
-
81
80
84
80
84
83
95
95
90
94
90
88
80
93
80
83
60
70
72
88
80
25
85
87
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
4-ClC6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2,4-Cl2C6H3
2,4-Cl2C6H3
2,4-Cl2C6H3
2,4-Cl2C6H3
2-MeOC6H4
4-MeOC6H4
4-OMeC6H4
Ph
4-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
3,4- Cl2C6H3
4-ClC6H4
Ph
Ph
4-ClC6H4
4-ClC6H4
4-MeO2CC6H4 Ph
a Reaction conditions: aldehyde (3 mmol), amine (3.1 mmol), 2-butanone
(5 mmol), acetophenone (3 mmol), and H3PW12O40 (0.02 g). b Yield of
isolated products. c Syn/anti ratio. d Syn/anti ratio was determined by 1H
NMR analysis of crude products.
4-ClC6H4
(CH3)2CH
2-naphthyl
2-thienyl
4-(i-Pr)C6H4
Ph
4-ClC6H4
4-ClC6H4
43:57
62:38
a Reaction conditions: aldehyde (3 mmol), amine (3.1 mmol), and
cyclohexanone (5 mmol) were successively added to a solution of catalyst
(10 mg) in water (5 mL) placed in a test tube, and the reaction mixture was
vigorous stirred at room temperature for 3-16 h. b Yields of isolated
products. c Diastereomeric ratio mearsured by 1H NMR spectroscopy
analysis of the crude reaction mixture.
coupling reactions were carried out with acyclic ketones such
as 2-butanone and acetophenone. The expected products were
obtained in moderate yields under these conditions. Acyclic
ketones were less reactive than cyclohexanone and needed
much more catalyst to afford the desired products (Table
1).
The regioselectivity was determined by 1H and 13C NMR
spectroscopy and by comparison with known compounds
reported in the literature.8 In general, anti selectivity was
observed in the reaction of cyclohexanone and 2-butanone.
Another characteristic feature of the present protocol is
the high chemoselectivity of cyclohexanone toward aldi-
mines, prepared in situ from the reaction of aldehydes and
amines, in preference to aldehydes as shown in Scheme 2.
Despite of the low solubility of aldehydes, ketones, and
amines in water, the heteropoly acid-catalyzed Mannich
reactions still proceed efficiently at ambient temperature. The
reaction might take place at the interface of organic materials
with water in the heterogeneous system. It was found that
vigorous stirring was required for the success of these
reactions.
Scheme 2. Aldole and Mannich Reaction in Water
The possibility of recycling the catalyst was examined.
For this reason, the reaction of 4-chlorobenzaldehyde, aniline
and cyclohexanone in water at room temperature in the
presence of H3PW12O40 was studied. When the reaction was
complete, ethyl acetate was added and organic materials were
extracted and the aqueous solution was saved for the next
reaction. When the same reaction was carried out in this
solution, containing the used catalyst, low yields (ca. 60%)
of the product were obtained.
Although conventional Lewis acids activate aldehydes
preferentially, in this media, aldehydes do not undergo aldol
reaction by means of HPAs in water. The high chemoselec-
tivity is rationalized by considering the higher basicity of
nitrogen over oxygen. A related phenomenon was recently
reported in the reactivity between aldimines and aldehydes
by the use of proline, HBF4, and dibutyltin dimethoxide.11
Org. Lett., Vol. 8, No. 10, 2006
2081

In conclusion, this procedure offers several advantages
including low loading of catalyst, improved yields, clean
reaction, use of unmodified ketones, which make it a useful
and attractive strategy for the multicomponent reactions of
combinational chemistry. In addition, a very easy workup
has been realized that does not require organic solvents.
When the products are solid and insoluble in water, the pure
products can be obtained directly by filtration and washing
the filtrate with water and by crystallization from ethanol or
diethyl ether. No extraction or separation by column chro-
matography is necessary in some cases. Current efforts in
our research group are attempting to expand the application
of heteropoly acids in water for other reactions.
Acknowledgment. We are grateful to the Research
Council of Sharif University of Technology for financial
support. We thank “Volkswagen-Stiftung, Federal Republic
of Germany” for financial support toward the purchase of
chemicals. We also thank Professor J. Ipaktschi (University
of Giessen) for his valuable advice and suggestions.
Supporting Information Available: General experimen-
tal procedure and copies of 1H NMR and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Hayashi, Y.; Urushima, T.; Shoji, M.; Uchimaru, T.; Shiinac, I.
AdV. Synth. Catal. 2005, 347, 1595. (b) Akiyama, T.; Takaya, J.; Kagoshima,
H. AdV. Synth. Catal. 2002, 344, 338. (c) Yanagisawa, A.; Saito, H.; Harada,
M.; Araia, T. AdV. Synth. Catal. 2005, 347, 1517.
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Org. Lett., Vol. 8, No. 10, 2006