One-pot three-component Mannich reaction catalyzed by iodine under solvent-free conditions

Article abstract of DOI:10.1134/S0023158411030062

One-pot three-component Mannich reactions of ketones with aromatic aldehydes and aromatic amines are effectively catalyzed by molecular iodine at room temperature under solvent-free conditions to afford the corresponding β-amino carbonyl compounds with moderate to excellent yields. The method has the following advantages: no use of solvent, mild condition, high reaction speed and small quantity of catalyst.

Full text of DOI:10.1134/S0023158411030062

ISSN 0023ꢀ1584, Kinetics and Catalysis, 2011, Vol. 52, No. 3, pp. 397–400. © Pleiades Publishing, Ltd., 2011.
OneꢀPot ThreeꢀComponent Mannich Reaction Catalyzed
by Iodine under SolventꢀFree Conditions1
Li Ganga, Long Ruilingb, and Yang Jianglia
a College of Chemistry and Chemical Engineering, Anyang Normal University, China
b Department of Life Science and Technology, Xinxiang Medical University, China
eꢀmail: lgorgchem@126.com
Received October 18, 2009
Abstract—Oneꢀpot threeꢀcomponent Mannich reactions of ketones with aromatic aldehydes and aromatic
amines are effectively catalyzed by molecular iodine at room temperature under solventꢀfree conditions to
afford the corresponding ꢀamino carbonyl compounds with moderate to excellent yields. The method has
β
the following advantages: no use of solvent, mild condition, high reaction speed and small quantity of catalyst.
DOI: 10.1134/S0023158411030062
The threeꢀcomponent Mannich reaction is one of the ration, expensive reagents or catalysts, the use of large
most important carbon–carbon bond forming reactions in
organic synthesis and one of the most fundamental and
convenient methods for preparation of ꢀamino carbonyl
amount of catalysts, pollution of water or use of toxicity
organic solvent.
β
Iodine as a mild and efficient catalyst has been used
to promote various organic reactions [18–23]. Phukan
and coꢀworkers reported that 10 mol % iodine cataꢀ
lyzed Mannich reaction of benzyl carbamate with aroꢀ
matic aldehyde and 1.5 equivalents of aromatic ketone
in acetonitrile for 24 h. However, the method not only
used noxious acetonitrile as solvent, but also needed
long reaction time (24 h) [24].
compounds, which are essential synthetic intermediates
for many pharmaceuticals and natural products [1, 2].
Recently, the threeꢀcomponent Mannich reactions have
gained increasing popularity for versatile application of
its products— ꢀamino carbonyl compounds—in drugs
β
and natural products. Numerous versions of the Manꢀ
nich reaction have been developed in the past. Generally,
threeꢀcomponent Mannich reactions of aldehydes,
ketones and amines are carried out using Brønsted acids
[3–6], Lewis acids [7–10], Lewis bases [11–13] or small
organic molecules as catalysts in organic solvent or water
[14–17]. Moreover, most of these methods often suffer
from some serious drawbacks such as long reaction time,
In this work, we describe a mild, convenient, efficient
and oneꢀpot method for preparation of ꢀamino carboꢀ
β
nyl compounds from ketones with aromatic aldehydes
and aromatic amines using molecular iodine as catalyst
harsh reaction condition, and difficulty in product sepaꢀ under solventꢀfree conditions (Scheme).
R1
O
CH3
O
R2
N
H
NH2
CHO
3
I
2
r.t.
5
+
+
O
R1
R2
R1
R2
O
1
2
CH
4
N
H
6
Scheme
.
1
The article is published in the original.
397

398
GANG et al.
Table 1. Synthesis of
βꢀamino ketones under different conditions*
Entry
Ketone
Aldehyde
Amine
Amount of catalyst, mol %
Time, h
Yield**, %
1
2
3
4
5
PhCOCH
PhCOCH
PhCOCH
PhCOCH
PhCOCH
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhNH
PhNH
PhNH
PhNH
PhNH
3
5
8
5
5
5
5
5
8
3
83
92
94
93
87
3
3
3
3
3
2
2
2
2
2
O
O
O
O
O
6
7
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhNH
PhNH
PhNH
PhNH
PhNH
0.5
1
1
90
96
97
86
97
2
2
2
2
2
1
8
2
1
9
1
0.5
2
10
1
*Reaction conditions: 1 equiv of ketone, 1 equiv of aldehyde, 1 equiv of amine; room temperature.
** Isolated yield.
EXPERIMENTAL
iodine and time of reaction on Mannich reaction of
acetophenone and cyclohexanone with benzaldehyde
and aniline as typical substrates, respectively. The
Materials and Methods
All the chemicals and reagents used are of analytical
grade and are used without further purification. The
structure and syn/anti ratio of products were determined
yields of ꢀamino carbonyl compounds under differꢀ
β
ent reaction conditions are shown in Table 1. For
Mannich reaction of acetophenone with benzaldeꢀ
hyde and aniline, appropriate reaction condition are
5 mol % iodine catalyst and 5 h reaction time at room
temperature (entry 2). Iodine is highly efficient cataꢀ
lyst to Mannich reaction of acetophenone with benꢀ
zaldehyde and aniline at room temperature. An excellent
yield can be obtained within 1 h only using 1 mol %
iodine as catalyst (entry 7). Furthermore, without
making one of the reactants excess, solventꢀfree threeꢀ
component Mannich reaction catalyzed by iodine can
be smoothly carried out. Iodine should be used as a
Lewis acid to catalyze Mannich reaction.
by IR, 1H NMR, and physical data (melting points) with
those reported in the literatures. IR spectra are recorded
on a Bruker AMꢀ400 spectrometer using KBr discs.
1H NMR spectra are obtained from solution in CDCl3 or
acetone with TMS as internal standard using a Varian
Scimitar Series 800 (400 MHz) spectrometer.
General Procedure for the IodineꢀCatalyzed
Mannich Reaction
Equal molecular quantities of aldehyde, amine, ketones
and 5 mol % iodine were added to a 50 ml oneꢀnecked
roundꢀbottom flask. The reaction mixture was stirred vigꢀ
Substrate Scope of IodineꢀCatalyzed
Mannich Reaction
orously with a magnetic stirrer at room temperature (r.t.
)
for the mentioned time. After reaction completion, the
crude mixture was either purified by silica gel–chromatogꢀ
raphy (ethyl acetate–petroleum ether mixtures) or recrysꢀ
tallized from ethanol or ethanol–acetone mixture (1 : 1,
v/v) to afford the corresponding compounds.
Next, to explore the generality and scope of iodineꢀ
catalyzed threeꢀcomponent Mannich reaction under
solventꢀfree conditions, the Mannich reactions of aceꢀ
tophenone with various aromatic aldehyde and aroꢀ
matic aniline were carried out under the same condiꢀ
tions. As shown in Table 2, these Mannich reactions of
various substrates catalyzed by iodine present the folꢀ
lowing peculiarities: (1) for nitroaniline bearing strong
electronꢀwithdrawing –NO2 group that deceases
nucleophilicity of –NH2 group, the reaction can
RESULTS AND DISCUSSION
Screening of Conditions for IodineꢀCatalyzed Mannich
Reaction under SolventꢀFree Conditions
To optimize condition of the Mannich reaction
catalyzed by iodine, we examined effect of amount of smoothly take place and give the corresponding
βꢀamino
KINETICS AND CATALYSIS Vol. 52
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2011

ONEꢀPOT THREEꢀCOMPONENT MANNICH REACTION CATALYZED
399
Table 2. Solventꢀfree threeꢀcomponent Mannich reaction of acetophenone catalyzed by iodine*
R1
NH2
O
CHO
O
5 mol % I
r.t.
CH3
2
R2
+
+
N
H
R2
R1
1
2
3
5
Entry
Temperature,
°
C
R
R
Product
5
Yield**, %
1
2
1
2
3
4
5
6
7
8
9
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
50
50
r.t.
r.t.
H
H
H
5a
5b
5c
5d
5e
5e
5f
92
4ꢀCl
H
56
4ꢀCl
4ꢀCl
H
88
4ꢀCH O
52
3
4ꢀCH O
44
3
4ꢀCH O
H
83***
46
3
4ꢀCH O
4ꢀCH
4ꢀCH
3
3
H
5g
5h
5i
86
3
H
3ꢀNO
4ꢀCl
78
2
10
4ꢀCl
4ꢀCl
4ꢀCl
82
11
12
13
14
4ꢀCH
5j
90
3
4ꢀNO
3ꢀNO
4ꢀNO
5k
5l
41
2
2
2
4ꢀCH O
28
3
H
5m
43
Notes: * Reaction conditions: 1 equiv of ketone, 1 equiv of aldehyde, 1 equiv of amine, 5 h.
** Isolated yield.
*** 24 h.
ketones compounds in good yields (entries 9, 12–14); hexanone is better than that of acetophenone is elecꢀ
(2) activity of anisaldehyde bearing strong electronꢀ
donating CH3O– group is lower than that of benzaldeꢀ
hyde, but a good yield of corresponding product can
be obtained by prolonging reaction time from 5 to 24 h
(entries 4–7, 13); (3) amines and aldehydes with –CH3
and –Cl groups gave the corresponding amino ketones
in good yields (entries 2, 3, 8, 10, 11).
tronꢀwithdrawing inductive effect of alkylcarbonyl
which is stronger than that of benzoyl. For aldehydes
and amines with substitution group, even nitroaniline
with strong electronꢀwithdrawing groups and 4ꢀmethꢀ
oxybenzaldehyde with strong electronꢀdonating
groups, the desired product was also obtained in a
good yield within 3 h (entries 5, 7–10).
Further, iodineꢀcatalyzed threeꢀcomponent Manꢀ
nich reactions of cyclohexanone with various aromatic
aldehydes and aromatic anilines are also researched
under solventꢀfree conditions as shown in Table 3. We
This study demonstrates that molecule iodine is a
convenient, efficient catalyst for the solventꢀfree oneꢀ
pot threeꢀcomponent Mannich reactions of ketones
find out that activity of cyclohexanone is evidently with aromatic aldehydes and aromatic amines under
better than that of acetophenone in the Mannich reacꢀ
tion catalyzed by iodine. By comparison with that of
acetophenone, the Mannich reaction of cyclohexꢀ
anone can give the desired product in a good to excelꢀ
lent yield only using 1 mol % iodine as catalyst within
3 h. To our surprise, the Mannich reaction of cycloꢀ
hexanone with benzaldehyde and aniline is very rapid,
and a 96% yield can be obtained within 1 h (entry 1).
mild conditions. It is worth mentioning that iodine
can highly efficiently catalyze Mannich reaction of
cyclohexanone with benzaldehyde and aniline, and a
96% yield can be obtained in the present of only 1 mol %
iodine within 1 h. The solventꢀfree Mannich reactions
catalyzed by iodine have the following advantages: (1)
no need any solvent, (2) a low amount of catalyst used,
We consider that the reason why reactivity of cycloꢀ (3) a short reaction time.
KINETICS AND CATALYSIS Vol. 52
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2011

400
GANG et al.
Table 3. Solventꢀfree threeꢀcomponent Mannich reaction of cyclohexanone catalyzed by iodine*
NH2
R2
R1
CHO
O
O
NH
CH
1 mol % I
r.t.
2
+
+
R2
R1
1
2
4
6
Entry
R
R
Time, h
Temperature,
°C
Product
6
Yield**, %
1
2
1
2
3
4
5
6
7
8
9
H
H
H
H
1
3
3
3
3
3
3
3
3
3
r.t.
r.t.
r.t.
50
r.t.
r.t.
r.t.
r.t.
r.t.
50
6a
6b
6c
6d
6e
6f
6g
6h
6i
96
92
80
85
78
84
80
79
74
81
4ꢀCl
4ꢀCH
4ꢀCl
4ꢀCl
H
4ꢀCH
H
3ꢀNO
3ꢀNO
3
4ꢀCl
4ꢀCH O
4ꢀCl
4ꢀCH O
4ꢀCH O
3
4ꢀCH O
4ꢀCl
3
3
3
3
2
2
10
6j
*Reaction conditions: 1 equiv of ketone, 1 equiv of aldehyde, 1 equiv of amine, room temperature.
** Isolated yield.
12. Takahashi, E., Fujisawa, H., and Mukaiyama, T.,
ACKNOWLEDGMENTS
Chem. Lett., 2005, vol. 34, p. 468.
We are grateful to the Nature Science Foundation
of Anyang Normal University for financial support.
13. Fujisawa, H., Takahashi, E., and Mukaiyama, T.,
Chem. Eur. J., 2006, vol. 12, p. 5082.
14. List, B., Pojarliev, P., William, T.B., and Harry, J.M.,
J. Am. Chem. Soc., 2002, vol. 124, p. 827.
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2011