Catalytic stereoselective Mannich reaction under solvent-free conditions

Article abstract of DOI:10.1016/j.crci.2011.10.011

Silicon tetrachloride catalyzed one-pot three-component Mannich reaction of cyclic ketones, aromatic aldehydes, and aromatic amine under solvent-free conditions affords the corresponding β-amino ketones with excellent yield and good to excellent anti-selectivity.

Full text of DOI:10.1016/j.crci.2011.10.011

C. R. Chimie 15 (2012) 278–282
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´
Full paper/Memoire
Catalytic stereoselective Mannich reaction under solvent-free conditions
*
Najmadin Azizi , Roya Baghi, Elham Batebi, Seyed Mohammad Bolourtchian
Chemistry and Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
Silicon tetrachloride catalyzed one-pot three-component Mannich reaction of cyclic
ketones, aromatic aldehydes, and aromatic amine under solvent-free conditions affords
Received 11 September 2011
Accepted after revision 24 October 2011
Available online 13 December 2011
the corresponding
selectivity.
b-amino ketones with excellent yield and good to excellent anti-
´
ß 2011 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Keywords:
Amine
Aldehyde
b-amino ketone
Mannich reaction
Solvent-free
Silicon tetrachloride
1. Introduction
Fe(Cp)2PF6[36], DDQ [37], ZnCl2/SiO2 [38], SO42À/TiO2 [39],
TiCl4/PhSiCl3 [40,41], perchloric acid in Triton X10 [42],
The classical Mannich reaction, in which an amino-
methyl group is introduced to the position of a carbonyl
function, provides useful routes for the synthesis of
amino ketones and esters, which are versatile building
blocks for the preparation of many nitrogen-containing
biologically important compounds [1–4].
Recently, a three-component approach for this reaction
using organocatalyst and other catalysts, with in situ
formation of imines, has gained considerable importance
as it allows structural variations. Accordingly, several
recent reports of catalytic Mannich reaction using known
organocatalyses [5–7], proline [8–11], siloxy serine [12],
adenine [13], Trypsin [14], p-dodecyl benzenesulphonic
acid (DBSA) [15,16], ionic liquid [17–20], Zn(OTf)2 [21],
Silica-supported aluminum chloride [22], ZrOCl2Á8H2O
[23], Bismuth Triflate [24–26], cationic organobismuth
complex [27], HCl/SDS [28], boric acid and glycerol [29],
HBF4 [30], Zn(proline)2 [31], ceric ammonium nitrate [32],
heteropoly acid [33], WOx–ZrO2 [34], polyaniline salts [35],
ZnI2 [43], 2-pyrrolidinecarboxylic acid ionic liquid [44],
chiral Brønsted acid [45], are found in the literature.
However, the yields obtained were only moderate, even
with high catalyst loadings and regardless of the immense
importance of this reaction, only a few diastereoselective a-
aminomethylation reactions have been developed (Table 1).
Thus, expanding the scope of Lewis acid catalysis under
a
b
-
solvent-free condition in
a one-pot three-component
Mannich reaction is a useful and challenging objective. In
this context, we wish to report a simple version of an
environmentally benign Mannich reaction with different
aromatic aldehydes, cyclic ketones and aromatic amines for
the synthesis of
b-amino carbonyl compounds under
solvent-free condition in presence of SiCl4 as catalyst with
good yield and excellent selectivity as shown in Scheme 1.
2. Experimental
2.1. General
All chemicals were obtained from commercial suppliers
and used as supplied. NMR spectra were recorded on a
Bruker ACF 500 using CDCl3/CCl4 or CDCl3/DMSO-d6 as
* Corresponding author.
E-mail address: azizi@ccerci.ac.ir (N. Azizi).
1631-0748/$ – see front matter ß 2011 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2011.10.011

N. Azizi et al. / C. R. Chimie 15 (2012) 278–282
279
Table 1
One-pot, three-component Mannich reaction with different catalyst systems.
Entry
Catalyst
Mol %
Solvent
Yields
Anti:syn
Ref.
1
Ln(OTf)3
2
Water
Water
Water
Neat
88
83
91
97
94
90
83
84
84
92
100
92
95
80
95
82
98
97
92:8
[28]
[28]
[28]
[38]
[36]
[34]
[20]
[26]
[33]
[23]
[16]
[42]
[43]
[29]
[13]
[12]
[27]
–
2
HCl/SDS
10
94:6
3
HBF4/SDS
10
97:3
4
ZnCl2/SiO2
Fe(Cp)2PF6
WOx–ZrO2
Ionic liqiud
Bismuth triflate
H3MoW12O40
ZrOCl2Á8H2O
DBSA
1
85:15
76:24
80:20
75:25
86:14
63:37
99:1
5
5
Neat
6
50 (mg)
Neat
7
10
5
Water
Water
Water
Neat
8
9
0.12
15
1
10
11
12
13
14
15
16
17
18
Water
Water
Neat
70:30
76:24
64:36
36:64
83:17
81:19
95:5
HClO4/TX10
ZnI2
10
1
Boric acid
Adenine/H2O2
Siloxy serine
Organobismuth
SiCl4
10
20
20
5
Water
Water
Water
Water
Neat
2
100:00
solvent. Column chromatography was performed on silica
gel, Merck grade 60. Melting points were recorded on
Buchi 535 melting point apparatus and are uncorrected.
Ethyl acetate, hexane, diethyl ether, ethanol and water
were distilled prior to use. Reactions were carried out at
room temperature and all aldehydes, ketones, amines and
catalyst employed are commercially available.
cases with diethyl ether. All compounds were known and
characterized on the basis of their spectroscopic data
(1H NMR, and m.p.) and by comparison with those reported
in the literature.
3. Results and discussion
With the increasing interest in developing environ-
mentally benign reactions, the atom-economic catalytic
process that employs unmodified ketones, aromatic amine,
and aromatic aldehyde would be an ideal Mannich-type
reaction, and is attracting more attention. In continuation
of our studies on the new variants, of one-pot, three-
component Mannich type reaction, and our ongoing
program for developing green organic reactions by using
water as reaction medium or by performing organic
transformations under solvent-free conditions [33,46–
48]. Herein, we report, direct three-component anti-
selective Mannich reactions promoted by silicon tetra-
chloride under solvent-free condition. First, the three-
component Mannich reaction of benzaldehyde, aniline,
and cyclohexanone were selected as a model. As a
preliminary study, reaction temperature and solvents
were screened in the model reaction. The results of
2.2. General procedure
To the mixture of cyclic ketones (cyclohexanone or
cyclohepatone, 3 mmol, and tetrahydro-4H-pyran-4-one,
1.5 mmol), aromatic aldehyde (1 mmol) and aromatic
amine (1 mmol) in the test tube, SiCl4 (2 mol %) was
added. The mixture was stirred at room temperature for
appropriate time until the reaction mixture was solidified.
To the crude product, diethyl ether or ethyl acetate (10 ml)
was added and washed with saturated aqueous sodium
chloride (5 mL) and water (10 mL). The organic layer was
dried over anhydrous Mg2SO4 and solvent was evaporated
under vacuum (rotary evaporator). The oily products were
subjected to column chromatography over silica gel (230–
400) with ethyl acetate:hexane (2:8) as eluent. The solid
products were crystallized directly from ethanol and some
O
O
NHPh
Ph
O
NHPh
Ph
CHO
NH2
SiCl4 (2 mol%)
+
+
+
Solvent
rt, 80 min
4
syn
anti
1
2
3
Solvent Toluene CH3CN THF MeOH Water EtOH Neat
Yield (%)a
anti:syn 92:08 90:10 81:19 75:25 80:20 85:15 100:00
40
70
45
50
10
50
97
[a] reaction conditions: benzaldehyde (1 mmol), aniline (1 mmol) and cyclohexanone (3 mmol)
Scheme 1. Optimization of reaction condition.

280
N. Azizi et al. / C. R. Chimie 15 (2012) 278–282
Table 2
One-pot, three-component direct Mannich reaction catalyzed by SiCl4
O
NHAr'
Ar
O
O
NHAr'
Ar
ArCHO
+
SiCl4 (2 mol%)
Neat, rt, 1-3 h
+
Ar'NH2
syn
z
z
z
anti
Z= O, CH2
Entry
Ar
Ar’
Z
Syn: Anti
Yielda,b (%)
Ref.
1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH2
O
00:100
10:90
00:100
15:85
00:100
10:88
00:100
20:80
13:87
25:75
7:93
97
92
92
82
88
78
86
84
80
70
82
82
85
83
78
95
92
88
80
80
90
72
[33]
[45]
[19]
[39]
[33]
[19]
[34]
[45]
[36]
[34]
[34]
[33]
[35]
[33]
[44]
[45]
[33]
[45]
[33]
[45]
[44]
[19]
2
C6H5
3
4-ClC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
C6H5
CH2
O
4
5
CH2
CH2
CH2
O
6
7
3-CH3C6H4
3-CH3C6H4
2-CH3C6H4
4-ClC6H4
8
C6H5
9
4-BrC6H4
4-ClC6H4
C6H5
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
10
11
12
13
14
15
16
17
18
19
20
21
22
4-OCH3C6H4
C6H5
4-(CH3)2CHC6H4
4-OCH3C6H4
4-BuC6H4
4-BuC6H4
C6H5
21:79
13:87
23:77
15:85
8:92
4-BrC6H4
C6H5
4-ClC6H4
4-CH3C6H4
4-Pyridyl
4-Pyridyl
3-BrC6H4
3-OCH3C6H4
2-Thienyl
2-Thienyl
C6H5
CH2
O
10:90
12:88
14:86
15:85
12:88
20:80
C6H5
C6H5
CH2
O
C6H5
C6H5
CH2
CH2
3-CH3C6H4
a
Isolated yields.
b
Reaction conditions: aromatic aldehyde (1 mmol) and aromatic amine (1 mmol) cyclohexanone, (3 mmol), and tetrahydro-4H-pyran-4-one,
(1.5 mmol), SiCl4 (2 mol %).
Table 3
extensive solvent screening and optimization are shown in
Scheme 1. SiCl4 catalyzed Mannich reactions in organic
solvents such as ether, dichloromethane, methanol, and
ethanol led to recovery of starting material and imines in
addition to small amounts of the desired products 4 in low
yield. Among the screened reaction solvent systems,
solvent-free conditions (neat) was the ideal reaction
media, since in this condition, the Mannich-type reactions
proceed smoothly and afford the desired adducts in
excellent yield and excellent anti-selectivity. Solvent-free
organic reactions would be faster and more selective,
leading to more favorable kinetics. Furthermore, no
Mannich base could be detected when a mixture of
benzaldehyde, aniline and cyclohexanone was stirred for
12 h in the absence of silicon tetrachloride, which
indicated that the catalyst should be absolutely necessary
for the Mannich reaction (Scheme 1).
Direct Mannich reaction of aldehyde, amines and cycloheptanone under
solvent-free condition
O
+
ArNH2
+
Ar'CHO
Neat, rt, 2-4 h
NHAr
SiCl4 (2 mol%)
O
NHAr
Ar'
O
Ar'
+
anti
syn
Then, the scope of the SiCl4 catalyzed Mannich-type
reaction of other aromatic aldehydes (1), aromatic amines
(2) and ketones (3) were investigated under the optimized
reaction conditions (Table 2). In general, the reaction
proceeded smoothly at room temperature to give the
corresponding products in reasonable to good yields ranged
from 70 to 97%. At the beginning, we made a search for the
aryl-aldehyde substrate scope with aniline and cyclohexa-
none as model substrates and the results are shown in
Entry Ar’
Ar
Syn:Anti Yielda,b (%) Ref.
1
2
3
4
5
6
C6H5
C6H5
C6H5
05:95
24:76
19:81
91
82
70
74
86
90
[23]
[23]
[23]
[16]
[39]
[16]
3-CH3C6H4
C6H5
4-ClC6H4
4-ClC6H4
C6H5
4-(CH3)2CHC6H4 24:76
4-MeC6H4
15:85
10:90
4-CH3C6H4 3-ClC6H4
a
Isolated yields.
b
Table 2. Generally, excellent yields of
b-amino ketones
Reaction condition: aromatic aldehyde (1 mmol) and aromatic amine
were obtained under optimized reaction conditions with
(1 mmol), cyclohepatone (3 mmol) and SiCl4 (2 mol%).

N. Azizi et al. / C. R. Chimie 15 (2012) 278–282
281
Table 4
Three component reaction in the presence of HCl
O
NHPh
Ph
NPh
O
NH2
CHO
Catalyst
+
+
+
Neat, rt, 80 min
1 mmol
1 mmol 3 mmol
3
4
Entry
Catalyst
10 l HCl (32%)
Yield (%)a
3
Yield (%) 4
Anti:Syn
1
2
3
4
5
m
40
55
5
50
35
80
35
20
72:18
85:15
–
100 l HCl (32%)
m
2 mL HCl (32%)
1 mL HCl (1 M)
HCl (g)b,c
60
5
85:15
–
a
NMR yields.
b
c
Anilinium chloride (70%) and benzaldehyde were recovered.
HCl gas was prepared by the reaction of concentrated sulfuric acid and sodium chloride.
aromatic aldehydes as well as heterocyclic aldehydes. This
reaction worked well for a variety of aldehydes including
those bearing an electron-withdrawing group, and the
Differentiation between aromatic aldehyde (cross-aldol
condensation) and imine (Mannich reaction) in the
competitive reactions is an important task in organic
synthesis and in fact, only Mannich reaction product was
obtained in this reaction media, which demonstrated that
the reaction catalyzed by silicon mentioned above had a
good chemoselectivity (Scheme 2) [49–51].
The structures of all the synthesized compounds were
established on the basis of their spectroscopic data. The
anti- and syn-isomers were identified by the coupling
constants (J) of the vicinal protons adjacent to C=O and NH
in their 1H NMR spectra. The anti isomer showed a doublet
corresponding b-amino ketones were obtained with excel-
lent yields. Several electron-rich aromatic aldehydes lead to
the desired products in good yields, too. The scope of our
method was extended to other amines. In the case of amines
having an electron-donating group, such as 4-isopropyl
aniline, the corresponding amino alcohols was obtained in
good yields. Furthermore, amines with electron-withdraw-
ing groups, such as 4-chloroaniline and 3,4-dichloroaniline,
gave the desired product in good yields. However, there is
not any relationship between electronic effects and stereo-
selectivity of this reaction.
at
d 4.54 due to CH and the coupling constant J = 7.6 Hz in
the 1H NMR spectrum.
In addition, besides the cyclohexanone, cycloheptanone
and tetrahydro-4H-pyran-4-one could also be employed to
give good yields. However, in case of cycloheptanone as
substrate the anti-selectivity is lower than that of
cyclohexanone and, this procedure could not afford the
corresponding single Mannich base (Table 3).
In summary, silicon tetrachloride was found to be a
highly efficient catalyst for one-pot three-component
Mannich reaction under solvent-free conditions. The
procedure provides several advantages, such as mild
conditions, high yields, and good to excellent stereose-
lectivities, shorter reaction time and clear reaction profile.
In general, the anti-products were invariably formed in
a major scale, dependent of the nature of substituents on
the aldehyde and amines as depicted in Table 2. It is worth
mentioning that the aliphatic aldehydes and aliphatic
amines were inactive and failed to furnish the desired
products with this protocol (Table 4).
Acknowledgment
Financial support of this work by Chemistry and
Chemical Research Center of Iran is gratefully appreciated.
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