Nano-manganese hydrogen sulfate as a novel catalyst for the anti-diastereoselective Mannich reaction in water

Article abstract of DOI:10.1007/s11164-014-1587-8

β-Amino carbonyl compounds are attractive targets for chemical synthesis, because they are widely used as biologically active compounds and are important synthons for a variety of pharmaceuticals. Nano-manganese hydrogen sulfate was prepared and used as a novel nano-catalyst for the named organic transformation, i.e. Mannich-type reaction of benzaldehyde, aniline, and cyclohexanone in water. Mannich products were obtained in high yields, with excellent diastereoselectivity, and short reaction time in the presence of a catalytic system comprising nano-Mn(HSO₄)₂ and a surfactant, for example sodium dodecyl sulfate. Use of mild, environmentally benign reaction conditions, low loading, and ready accessibility are the main features of this new catalyst.

Full text of DOI:10.1007/s11164-014-1587-8

Res Chem Intermed
DOI 10.1007/s11164-014-1587-8
Nano-manganese hydrogen sulfate as a novel catalyst
for the anti-diastereoselective Mannich reaction
in water
H. Eshghi
M. Hosseini
•
M. Rahimizadeh
•
A. Javadian-Saraf
•
Received: 17 November 2013 / Accepted: 5 March 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract b-Amino carbonyl compounds are attractive targets for chemical synthesis,
because they are widely used as biologically active compounds and are important syn-
thons for a variety of pharmaceuticals. Nano-manganese hydrogen sulfate was prepared
and used as a novel nano-catalyst for the named organic transformation, i.e. Mannich-
type reaction of benzaldehyde, aniline, and cyclohexanone in water. Mannich products
were obtained in high yields, with excellent diastereoselectivity, and short reaction time
in the presence of a catalytic system comprising nano-Mn(HSO ) and a surfactant, for
4
2
example sodium dodecyl sulfate. Use of mild, environmentally benign reaction condi-
tions, low loading, and ready accessibility are the main features of this new catalyst.
Keywords Mn(HSO ) ꢀ b-Amino ketone ꢀ Diastereoselective ꢀ Mannich
4
2
reaction ꢀ Micelles ꢀ SDS
Introduction
Nanoparticles have recently attracted much interest because of their many
applications in a variety of disciplines, for example chemistry, materials science,
and the biomedical sciences [1, 2]. Metal nanoparticles are of fundamental interest
because of their unique performance in ultrasensitive chemical and biological
sensors and their selectivity as catalysts in chemical and photochemical reactions
[
3–8]. Because of their high surface-to-volume ratio, metal nanoparticles have more
active sites per unit area than traditional catalysts [9]. Hydrophilic nanoparticles
with high dispersity in environmentally benign solvents are extremely important in
H. Eshghi (&) ꢀ M. Rahimizadeh ꢀ A. Javadian-Saraf ꢀ M. Hosseini
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad,
91775-1436 Mashhad, Iran
e-mail: heshghi@um.ac.ir
123

H. Eshghi et al.
biological applications [10]. These nanoparticles are soluble in water in a pH range
of approximately 5–9 [11].
Diastereoselectively pure b-amino ketones, vital intermediates in the synthesis of
pharmaceuticals [12, 13] and natural products [14, 15], are widely used for
asymmetric synthesis of nitrogen-containing compounds [16–19]. Multicompo-
nent Mannich reactions to produce such compounds have attracted much attention
[
1, 20–29].
Water as a solvent is not only inexpensive and environmentally benign, but can
also lead to unique reactivity and selectivity in organic reactions, which cannot be
achieved in organic solvents [18]. Nevertheless, one major disadvantage of water as
a solvent is the insolubility of organic compounds in water. To solve this problem
one can use a catalyst that solubilizes organic compounds [30]. In this article we
report the development of a new efficient catalyst for environmentally benign
Mannich transformation under mild reaction conditions with high stereoselectivity.
Experimental
General
Chemicals were either prepared in our laboratories or purchased from Merck, Fluka,
and Aldrich. All yields refer to isolated products. The reactions were monitored by
thin-layer chromatography conducted on silica plates. The products were charac-
terized by comparison of their physical or spectral properties with those of authentic
samples. IR spectra were recorded on an Thermo Nicolet Avatar-370 FTIR
1
spectrophotometer. H NMR spectra were recorded on Bruker 100-MHz spectrom-
eter in CDCl as the solvent and with TMS as internal standard.
3
General procedure for synthesis of manganese hydrogen sulfate
MnCl ꢀ2H O (0.1 mol) was placed in a 500-mL flask and concentrated sulfuric acid
2
2
(98 %, 10.8 mL, 0.2 mol) was added dropwise over a period of 30 min at r.t. HCl
gas was evolved immediately. After completion of the addition of H SO , the
2
4
mixture was shaken for 30 min. A pale pink solid was obtained. To eliminate H SO
2
4
contamination, the solid was washed with absolute ethanol, furnishing a white solid
in 86 % yield.
Mn(HSO ) nanostructure characterization
4
2
The XRD pattern of the Mn(HSO ) was recorded in the range 2h = 0°–60° (Fig. 1).
4
2
The prominent peaks were used to calculate the grain size, by use of the Scherrer
equation:
D ¼ Kk=ðb cos hÞ
˚
where k is the wavelength (k = 1.542 A) (CuKa), b is the full width at half
maximum (FWHM) of the line, and h is the diffraction angle [31]. The grain size of
1
23

Nano-manganese hydrogen sulfate as a novel catalyst
4 2
Fig. 1 XRD pattern of Mn(HSO )
the Mn(HSO ) nanostructure was 40 nm, and peaks were observed for the (9.00),
4
2
(
12.64), (12.86), and (13.51) planes.
Results from transmission electronic microscopy (TEM) of Mn(HSO ) nano-
4
2
particles is shown in Fig. 2. It is apparent the average size of nanospheres is 50 nm.
-
1
The FT-IR spectrum of Mn(HSO ) contained characteristic bands at 3,360 cm
4
2
-
–O–H stretching), 1,158 cm (S=O sulfate asymmetric stretching), and 823 cm
1
-1
(
(
-
1
sulfate S–O stretching), and 609–625 cm
(Mn–O stretching). The results
confirmed the desired compound had been successfully synthesized.
General procedure for the Mannich reaction
The aromatic aldehyde (1 mmol), aromatic amine (1 mmol), cyclohexanone
(
(
1.2 mmol), Mn(HSO ) (10 mol%), and SDS (2.5 mol%) were added to water
4 2
0.5 mL). The reaction mixture was stirred at room temperature for the appropriate
time. The progress of reaction was monitored by TLC. After completion of the
reaction, the solid mixture was isolated by filtration to eliminate the catalyst, then
the crude product was extracted with chloroform. The extract was dried over
anhydrous Na SO4 then evaporated to dryness. The residue was purified by
2
recrystallization from ethanol.
2
-((4-(Diethylamino)phenyl)(phenylamino)methyl)cyclohexanone (4)
m.p. 125 °C; IR (KBr) t = 3335, 3047, 2969, 2930, 2851, 1705, 1601, 1520, 1497,
1
1
275, 816, 748, 689; H NMR (CDCl , 100 MHz, d ppm): 1.11 (t, 6H, J = 7.5 Hz),
3
1
.5–2 (m, 6H), 2.2–2.5 (m, 2H), 2.5–2.8 (m, 1H), 3.2–3.4 (q, 4H, J = 7.5 Hz), 4.5
123

H. Eshghi et al.
4 2
Fig. 2 Results from TEM of Mn(HSO )
(
[
[
d, 1H, J = 8.5 Hz, anti), 6.5–6.7 (m, 5H), 6.95–7.25 (m, 4H); EI-MS: m/z 350
?
?
?
?
M] , 349 [M–H] , 257 [M–C H N] , 253 [M–C H O] , 239 [M–C H O] , 93
?
6
6
6
9
7 10
?
M–C H NO] .
1
7 24
2
-((4-Isopropylphenyl)(phenylamino)methyl)cyclohexanone (8)
1
m.p. 83 °C; IR (KBr) t = 3412, 3051, 2931, 2858, 1700, 1600, 1503, 749, 688; H
NMR (CDCl , 100 MHz, d ppm): 1.5–2.1 (m, 6H), 2.3–2.6 (m, 2H), 2.65–2.95 (m,
3
1
J = 10 Hz), 7.1 (d, 2H, J = 10 Hz), 7.2–7.6 (m, 5H); EI–MS: m/z 321 [M] , 319
H), 4.65 (d, 0.65H, J = 7.5 Hz, anti), 4.8 (d, 0.35H, J = 5 Hz, syn), 6.5 (d, 2H,
?
?
?
[
M–2H] , 229 [M–C H N], 223 [M–C H O] .
6 6 6 8
Results and discussion
We have modified an efficient method for preparation of Mannich products, in
water, from aldehydes, aromatic amines, and ketones under very mild conditions by
using manganese hydrogen sulfate and sodium dodecylsulfate (Scheme 1).
Because one or two chiral carbon atoms are formed during the Mannich reaction,
diastereoselectivity and enantioselectivity are the most important features of the
reaction. Initially, the effect of different solvents was examined to achieve the best
diastereoselectivity, lowest reaction time, and high yield (Table 1). Reaction in
ethanol and methanol under catalyst-free conditions proceeded in moderate yield
with low diastereoselectivity, reaction in water failed under the same conditions.
1
23

Nano-manganese hydrogen sulfate as a novel catalyst
Scheme 1 Preparation of Mannich products in water by using manganese hydrogen sulfate and sodium
dodecylsulfate
Table 1 Synthesis of b-amino ketones under catalyst-free conditions
Entry
Solvent
Temp. (°C)
Anti/syn
Time (h)
Yield
a
1
2
3
4
5
6
7
8
a
–
–
25
100
25
–
4
4
NR
b
–
NIL
H
2
O
60/40
60/40
60/40
–
5
10
72
87
EtOH
MeOH
ACN
Py
25
3
25
1
a
25
12
12
12
NR
a
25
–
NR
a
CH
2
Cl
2
25
–
NR
No reaction
b
Aldol condensation occurs; product not isolated
Next, the effect of manganese(II) salts as catalysts of the Mannich reaction was
examined, to gain insight into diastereoselectivity, reaction time, and product yield.
Manganese(II) chloride and acetate do not catalyze this reaction under aqueous
conditions (Table 2, entries 1 and 2).
Mn(HSO ) was prepared, for the first time, from MnCl by addition of two
4
2
2
equivalents of H SO ; the yield was 86 %. Atomic absorption analysis showed the
2
4
Mn content was 22.15 %, is agreement with the formula given. The effect of using
different solvent systems, for example MeOH, EtOH, CH CN, H O, and EtOH–
H O, with manganese hydrogen sulfate as catalyst was examined. Water was found
3
2
2
to be the most suitable solvent with regard to both diastereoselectivity ([99 % anti
isomer) and environmental considerations (Table 2, entries 2–6). Eventually we
chose manganese hydrogen sulfate (10 %) with SDS (2.5 %) as the best catalyst
system (Table 2, entry 11). To the best of our knowledge, this is the first time
Mn(HSO ) has been used as an effective and highly stereoselective catalyst for
4
2
Mannich-type multicomponent one-pot synthesis of b-amino ketones.
123

H. Eshghi et al.
Table 2 Optimization of the conditions used for the Mannich reaction
Entry
Catalyst
Solvent
Time (h)
Yield
Anti/syn
a
1
2
3
4
5
6
7
8
9
MnCl (10 %)
2
H
H
2
O
O
4
4
3
3
1
5
5
5
5
1
1
1
4
NIL
NIL
87
–
a
Mn(OAc) (10 %)
2
2
–
Mn(HSO
Mn(HSO
Mn(HSO
Mn(HSO
Mn(HSO
Mn(HSO
Mn(HSO
Mn(HSO
Mn(HSO
Mn(HSO
Mn(HSO
4
)
2
2
2
2
2
2
2
2
2
2
2
(10 %)
EtOH
75/25
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
(10 %)
EtOH/H
2
O
92
75/25
(10 %)
MeOH
85
[99/\1
–
b
(10 %)
CH
3
CN
NR
75
61
77
90
90
89
77
(10 %)
H
H
H
H
H
H
H
2
O
2
O
2
O
2
O
2
O
2
O
2
O
[99/\1
[99/\1
[99/\1
[99/\1
[99/\1
[99/\1
[99/\ 1
(5 %)
(15 %)
1
1
1
1
a
0
1
2
3
(10 %), SDS(10 %)
(10 %) SDS(5 %)
(10 %) SDS(2.5 %)
(10 %) SDS(1 %)
c
Imine product not isolated
No reaction
b
c
Optimized conditions
Using the optimized reaction conditions, the scope of the reaction was assessed.
Excellent results were obtained when different combinations of aldehydes, amines,
and cyclohexanone were used. The generality of this method can be deduced from
the results summarized in Table 3.
In the reaction of benzaldehyde with most aromatic amines, the anti isomer is
formed exclusively. The presence of weak electron-withdrawing or electron-
donating groups, for example Cl and Me, at the 4-position of benzaldehyde does not
change the diastereoselectivity of the reaction (Table 3, entries 3–5 and 7–9).
However, the presence of a strong electron-withdrawing group, for example NO , at
2
the para or meta position of the benzaldehyde caused precipitation of the
corresponding imine and prevented completion of the reaction (results not shown).
When 4-i-propyl-substituted benzaldehyde is used, anti/syn selectivity is reduced to
6
5:35 (Table 3, entry 8). Furthermore, the presence of a substituent at the ortho
position of benzaldehyde entirely changed the stereoselectivity, leading to the syn
isomer (Table 3, entries 6 and 11). The presence of chloro or methoxy substitution
at the ortho positions of benzaldehyde or aniline changed the diastereoselectivity,
leading to the syn isomer (Table 3, entries 6, 11, 12). The presence of a methoxy
group at the para position of benzaldehyde resulted in formation of the anti isomer
1
23

Nano-manganese hydrogen sulfate as a novel catalyst
4 2
Table 3 Synthesis of b-amino ketones derivatives with anti diastereoselectivity by use of Mn(HSO ) –
SDS under aqueous conditions
a
b
Entry
R
1
R
2
Yield %
Anti/syn
Time (h)
M.p. (°C)/lit.
1
2
3
4
5
6
7
8
9
H
H
90
92
70
72
75
81
73
70
82
70
71
94
[99/\1
[99/\1
[99/\1
[99/\1
[99/\1
\1/[99
[99/\1
65/35
1
6
139–140/139–140 [9]
115/115–116 [32]
123/120–121 [33]
125
3-CH
3
H
H
4-CH
3
1
H
4-N(C
2
H
5
)
2
4
H
4-N(CH
2-OMe
4-OMe
4-i-Pr
H
3
)
2
4
148/160–162 [30]
128/127.8–128 [34]
128/131 [13]
H
8
4-Cl
H
2
7
83
4-Cl
4-Cl
H
[99/\1
[99/\1
\1/[99
45/55
8
139/137–138 [13]
136/137–138 [32]
139/144 [13]
10
11
12
a
4-Cl
10
5
2-Cl
2-Cl
H
6
133/136–137 [13]
Isolated yield
1
Determined by H NMR spectroscopy
b
whereas methoxy at the ortho position gave the syn isomer as major product
(
Table 3, entries 6 and 7).
This phenomenon can mainly be attributed to formation of micelles from the
starting materials and intermediates in the presence of H O and SDS. In other
2
words, the smooth progress of the reaction in the presence of alkyl or halogen
substitution of the aniline or benzaldehyde is the result of the tendency to form
micelles, as a result of the alkyl groups and the lipophilic properties of SDS, with
the result that hydrogen bond formation by halogen and methoxy groups is
disrupted. One possible reaction mechanism (Fig. 3) is that micelle formation is
essential to gather all the components, i.e. ketone, amine, aldehyde, and catalyst. As
expected, the presence of polar groups with nonbonding electron pairs near the
center of the reaction (imine groups) leads to exit of the imine from micelle and into
the aqueous phase. In such circumstances the possibility of isomerization is
increased.
As we expected, only the E enolate of cyclohexanone was formed; this reacted
with the more stable anti imine to produce the anti product under these reaction
conditions. For ortho-chloro or ortho-methoxy-substituted aniline or benzaldehyde,
the syn imine is the more stable isomer. Perhaps interaction of these hydrophilic
groups with the water removes the imine from the micelles, which causes the anti–
123

H. Eshghi et al.
Fig. 3 Possible mechanism of synthesis of b-amino ketones with anti diastereoselectivity by use of
Mn(HSO ) –SDS as catalyst system under aqueous conditions
4 2
syn isomerization possible for the imine intermediate. For para-substituted i-
propylbenzaldehyde, the micelle moves to this side group and lets the imine group
penetrate the water, with increased production of the syn isomer.
1
23

Nano-manganese hydrogen sulfate as a novel catalyst
Table 4 Synthesis of other b-amino ketone derivatives by use of Mn(HSO
4
)
2
–SDS as catalyst system
under aqueous conditions
Entry
R
1
R
2
Yield (%)
Time (h)
M.p. (°C)/Lit
13
14
15
H
H
73
95
70
12
10
10
167/167–168 [35]
3-CH
3
H
135–136/131–134 [36]
136–137/139–140 [37]
H
4-CH
3
To indicate the sufficiency of our catalytic system, the reaction was performed
with other ketones. The reactions were feasible but, because the keto form of
acetophenone is more stable than the enol form, reaction times were increased
(
Table 4). The micelle droplets formed by Mn(HSO ) , SDS, and the substrates
4 2
were, however, sufficiently hydrophobic to reject water molecules, facilitating
formation of the iminium ion. In these reactions, the micelle acts as a nano reactor
by enabling efficient contact between the catalyst and the substrate in its interfacial
area.
In conclusion, we report an environmentally benign, novel, and easy procedure
for diastereoselective synthesis of Mannich products by use of nano-manganese
hydrogen sulfate and SDS in water. The procedure has several advantages, for
example high diastereoselectivity, high yields, mild reaction conditions, use of
inexpensive reagents, low temperature, and very simple work-up procedures. Low
loading and ready accessibility are the main features of the new catalyst.
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