One-pot three-component Mannich-type reaction catalyzed by trifluoromethanesulfonic acid in water

Article abstract of DOI:10.1134/S0023158411010113

One-pot three-component Mannich-type reaction of ketones, aldehydes and amines was efficiently catalyzed by liquid trifluoromethanesulfonic acid in water at ambient temperature. The high yield of corresponding β-amino ketones compounds were achieved. The proposed method is mild, green, simple and efficient.

Full text of DOI:10.1134/S0023158411010113

ISSN 0023ꢀ1584, Kinetics and Catalysis, 2011, Vol. 52, No. 1, pp. 89–93. © Pleiades Publishing, Ltd., 2011.
OneꢀPot ThreeꢀComponent MannichꢀType Reaction Catalyzed
by Trifluoromethanesulfonic Acid in Water1
Li Gang, Wu Hankui, Wang Zhiyong, and Wang Xianli
College of Chemistry and Chemical Engineering, Anyang Normal University, People’s Republic of China
eꢀmail: lgorgchem@126.com
Received May 2, 2010
Abstract—Oneꢀpot threeꢀcomponent Mannichꢀtype reaction of ketones, aldehydes and amines was effiꢀ
ciently catalyzed by liquid trifluoromethanesulfonic acid in water at ambient temperature. The high yield of
corresponding
efficient.
β
ꢀamino ketones compounds were achieved. The proposed method is mild, green, simple and
Ar
O
O
Ar
NH
Ar
CH
Ar
3
10 mol % CF3SO3H
3 mL H2O, r t
Ar–CHO + Ar–NH2 +
Ar
O
O
Ar
N
H
10 mmol
10 mmol
10 mmol
up to 98%
DOI: 10.1134/S0023158411010113
1
Organic reactions using water as a medium instead nent Mannichꢀtype reactions of aldehydes, amines
of noxious organic solvents are a hot study field in the
recent years for several reasons [1–5]. First, in comꢀ
parison with organic solvents often used in organic
chemical reaction, water is a green, safe and economꢀ
ical solvent. Second, generally, water’s unique physical
and chemical properties lead to special reactivity and
selectivity of organic reaction, which cannot be
attained in organic solvents. Third, organic reactions
in water do not require to use expensive anhydrous
reactants and reagents. Finally, the workꢀup procedure
is simple. The organic products which are insoluble in
water can be obtained by simple filtration or separaꢀ
tory funnel.
and ketones are carried out in organic solvents. One
of the most conspicuous disadvantages of these
methods is to use large number of noxious organic
solvents, which pollute the environment and augꢀ
ment operation hazard. To overcome these disadvanꢀ
tages, the threeꢀcomponent Mannichꢀtype reactions
in water or aqueous solvent have been developed in
the recent years [19–24].
Trifluoromethanesulfonic acid (TfOH) is an
important liquid superacid, which has been used to
catalyze many organic reactions [25–31]. Ishimaru
and Kojima reported TfOHꢀcatalyzed Mannichꢀtype
reaction of silyloxydiene in ether [32, 33], but the
preparation of nucleophilic silylenolate used in the litꢀ
erature was troublesome. To our knowledge, TfOHꢀ
catalyzed oneꢀpot threeꢀcomponent Mannichꢀtype
reaction of ketones, aldehydes and amines in water has
not yet been reported in the open literature. In this
paper, we report that such reactions under mild condiꢀ
tion were efficiently catalyzed by TfOH to give the
The Mannichꢀtype reaction is one of the most
essential and fundamental carbon–carbon bondꢀ
forming organic reactions because product ꢀamino
β
carbonyl compounds are crucial intermediates in
numerous pharmaceuticals and natural products
synthesis [6–9]. Mannichꢀtype reactions have been
widely applied in organic chemical industry over the
past decades. Up to now, many protocols of Manꢀ
nichꢀtype reaction have been reported in a number of
publications [10–18]. Conventional threeꢀcompoꢀ
corresponding
βꢀamino ketones compounds in good
1
The article is published in the original.
to excellent yields.
89

90
LI GANG et al.
Table 1. Direct threeꢀcomponent Mannich reaction catalyzed by different Br
ø
nsted acid
O
CHO
NH2
Ph
10 mol % cat
3 mL solvent,
r t
NH
O
CH3
+
+
Ph
Ph
10 mmol
10 mmol
10 mmol
Entry
Catalyst
Solvent
Time, h
Yield, %
1
2
3
4
5
6
7
CF3SO3H
H2SO4
H2O
18
24
24
18
18
18
18
93
0
H2O
CH3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
H2O
11
85
72
EtOH
DCE*
H2O
84 (first recycle)
H2O
57 (second recycle)
* Dichlorethane.
EXPERIMENT
uct in an excellent yield 93% (entry 1). However, comꢀ
mon Br nsted acid H2SO4 and CH3SO3H were hardly
ø
Materials and Methods
active for the Mannich reaction in water under the
same condition (entries 2, 3). The Mannich reaction
catalyzed by TfOH was also carried out in organic solꢀ
vents, such as alcohol and dichlorethane, but its catalꢀ
ysis activity in organic solvent was less than that in
water (entries 4, 5). Notwithstanding the solubility of
substrates and TfOH are completely different, the
Mannich reaction in water can be still catalyzed effiꢀ
ciently by TfOH at room temperature. The reaction
should happen at the interface of organic substratesꢀ
water in the heterogeneous system because the experꢀ
iment results indicated that vigorous stirring was
imperative for the smooth progress of the reactions.
The recycling performance of TfOHꢀcatalyzed Manꢀ
nich reaction was also investigated under the same
condition. After the separation of the crude products
by simple filtration, the catalystꢀcontaining filtrate
was reused in the next run without further treatment.
The results show that the yield of product gradually
decreases in recycling process (entries 6, 7) and the
phenomenon should attribute to the loss of catalyst
All the chemicals and reagents used are of analytiꢀ
cal grade and were used without further purification.
The structure and syn/anti ratio of products were
1
determined by IR and H NMR. IR spectra were
recorded on a Bruker AMꢀ400 spectrometer using
KBr discs. 1H NMR spectra were obtained from soluꢀ
tion in CDCl3 with TMS as internal standard using a
Varian Scimitar Series 800 (400 MHz) spectrometer.
General Procedure for the TfOHꢀCatalyzed
Mannich Reaction in Water
Aldehyde (10 mmol), amine (10 mmol) and ketone
(10 mmol) were added usualy to a solution of TfOH
(10 mmol) in water (3 mL) placed in a 50 mL oneꢀ
necked roundꢀbottom flask. Then, the reaction mixꢀ
ture was stirred vigorously (400 rpm) with a magnetic
stirrer at room temperature (rt) for the mentioned
time. After reaction completion, the crude mixture is
either purified by silica gel chromatography (ethyl
acetate/petroleum ether mixtures) or recrystallization
from ethanol or ethanol–acetone (v/v = 1 : 1) to
afford the corresponding compounds.
because of adsorption of TfOH to alkalic product (
β
ꢀ
amino ketones).
To explore the generality and scope of the TfOHꢀ
catalyzed oneꢀpot threeꢀcomponent Mannichꢀtype
reaction in water, the reaction was examined with a
series of various ketones, aldehydes and amines under
the same condition as shown in Table 2. These Manꢀ
nichꢀtype reactions of various substrates catalyzed by
TfOH reveal the following characteristics.
RESULTS AND DISCUSSION
Initially, we selected the reaction of an equal
amount of benzaldehyde, aniline, and acetophenone
as a typical Mannich reaction to investigate the influꢀ
ence of various catalysts and solvents on the reaction
(1) TfOH can catalyze Mannichꢀreactions of equal
as shown in Table 1. To our surprise, among Brønsted mole amount of ketones, aldehydes and amines in
acid catalysts used, liquid superacid TfOH can more water. For Mannich reactions of cyclohexanone,
efficiently catalyze the Mannich reaction in water at 2ꢀpentone with aldehydes and amines, polyamiꢀ
ambient temperature to give the corresponding prodꢀ noalkylations were not found in products.
KINETICS AND CATALYSIS Vol. 52
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ONEꢀPOT THREEꢀCOMPONENT MANNICHꢀTYPE REACTION CATALYZED
91
Table 2. Oneꢀpot threeꢀcomponent Mannichꢀtype reaction catalyzed by TfOH in water
b
Entry
Aldehydes
Amines
Ketones
Time, h Yielda, % (syn
/
anti
)
O
1
18
18
16
93
73
98
CHO
NH2
CH3
O
2
3
CH3O
CHO
NH2
CH3
O
CHO
CHO
CH3
NH2
CH3
O
NH2
4
16
94
CH3
O
NO2
5
6
18
18
18
8
93
72
68
84
61
70
CHO
CHO
CH3O
NH2
CH3
O
H3C
H3C
H3C
H3C
H3C
NH2
NH2
CH3
O
7
CH3O
CH3O
CHO
CHO
CH3
O
8
CHO
CH3
CH3
NO2
NH2
NH2
NH2
CH3
O
9
18
18
CH3
O
10
CHO
CHO
CHO
CHO
CH3
O
NH2
H3C
11
12
13
8
17
1
81
CH3
O
NO2
H3C
O
53
CH3O
NH2
CH3
92c
48 : 52
49 : 51
39 : 61
NH2
NH2
O
O
14
15
14
8
85
96
CH3O
CHO
CHO
Cl
NH2
KINETICS AND CATALYSIS Vol. 52
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2011

92
LI GANG et al.
Table 2. (Contd.)
b
Entry
16
Aldehydes
Amines
Ketones
Time, h Yielda, % (syn
/anti)
O
O
1.5
84
97
47 : 53
50 : 50
Cl
Cl
NH2
NH2
CH3O
CHO
17
7
3
Cl
CHO
O
O
O
O
O
O
18
19
20
21
22
23
85
34
40
70
91
56
53 : 47
51 : 49
52 : 48
53 : 47
52 : 48
51 : 49
CHO
NH2
19
Cl
NH2
CH3O
CHO
9
18
18
18
CHO
CHO
CHO
CH3O
CH3
Cl
NH2
NH2
NH2
NH2
Cl
Cl
CHO
OH
OH
24
25
24
24
88
71
CHO
CHO
NH2
CH3
NH2
Note: Reaction conditions: aldehyde⎯10 mmol, amine⎯10 mmol, ketones⎯10 mmol, catalyst⎯10 mol %, water⎯3 mL, room temperaꢀ
ture.
a
b
c
Isolated yields.
1
anti/syn ratio was determined by H NMR spectroscopy analysis of the crude reaction mixture.
1 mol % TfOH.
KINETICS AND CATALYSIS Vol. 52
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ONEꢀPOT THREEꢀCOMPONENT MANNICHꢀTYPE REACTION CATALYZED
93
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groups, including nitroaniline bearing strong elecꢀ
tronꢀwithdrawing group NO2, the reaction can hapꢀ
pen and give the corresponding
β
ꢀamino ketones
compounds in moderate to excellent yields (entries 4,
10, 11).
(3) Though activity of anisaldehyde bearing strong
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benzaldehyde, good yields of
also obtained.
β
ꢀamino ketones can be
(4) For Mannich reaction of aliphatic ketone, reacꢀ
tivity of open alkyl chain 2ꢀpentone is less than that of
cyclic ketone cyclohexanone because the opening of
alkyl chain increases steric effect in the reaction
course (entries 13–23).
(5) Only 1 mol % of TfOH is enough to catalyze the
Mannich reaction of benzaldehyde, aniline and cycloꢀ
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reaction of
β
ꢀnaphthol in water in good yields
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2007, vol. 8, p. 2217.
,
(entries 24, 25).
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1
pentone and cyclohexanone was determined by H
NMR spectroscopy and comparison with the known
compounds reported in the literatures. For the reacꢀ
tions using cyclohexanone as the substrate, anti
amino ketone isomer is the major product. For the
reactions employing 2ꢀpentone as the substrate, syn
ꢀamino ketone isomer is the major product.
So, oneꢀpot threeꢀcomponent Mannichꢀtype
ꢀβꢀ
ꢀ
19. Manabe, K. and Kobayashi, S., Org. Lett., 1999, vol. 1,
β
p. 1965.
20. Hayashi, Y., Urushima, T., Aratake, S., Okano, T., and
reactions of equal molar amounts of aldehydes,
amines and ketones can be efficiently catalyzed by
TfOH at ambient temperature. The method is applicaꢀ
ble to various structural aromatic aldehydes, aromatic
amines, aromatic ketones, aliphatic ketones and
Obi, K., Org. Lett., 2008, vol. 10, p. 21.
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β
ꢀnaphthol. The Mannichꢀtype reaction catalyzed by
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cient route to obtain ꢀamino ketones compounds.
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2005, vol. 2, p. 322.
,
β
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26. George, A.O., Ramaiah, P., Wang, Q., and Surya, G.K.P.,
ACKNOWLEDGMENTS
The authors thank Natural Science Foundation of
Anyang Normal University for financial support.
J. Org. Chem., 1993, vol. 58, p. 6900.
The authors can provide supplementing supporting
information (NMR spectra of the studied comꢀ
pounds) on request to eꢀmail address:
lgorgchem@126.com.
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KINETICS AND CATALYSIS Vol. 52
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2011