Tartaric acid-zinc nitrate as an efficient brnsted acid-assisted lewis acid catalyst for the mannich reaction

Article abstract of DOI:10.3184/174751918X15355426661373

Tartaric acid-zinc nitrate has been found to be an efficient Brnsted acid-assisted Lewis acid catalytic system for the facile synthesis of β-amino carbonyl compounds through the one-pot Mannich reaction of aldehydes, aromatic amines and ketones in ethanol at room temperature. Remarkable enhancement of reactivity by tartaric acid (Br?nsted acid) was observed in these reactions in the presence of anhydrous zinc nitrate (Lewis acid), due to coordination of the tartaric acid ligand to zinc ions increasing the acidity of the system. This procedure shows some advantages such as mild reaction conditions, short reaction times and high yields.

Full text of DOI:10.3184/174751918X15355426661373

JOURNAL OF CHEMICAL RESEARCH 2018
VOL. 42 SEPTEMBER, 463–466
RESEARCH PAPER 463
Tartaric acid–zinc nitrate as an efficient Brønsted acid-assisted Lewis acid
catalyst for the Mannich reaction
a
a
a
b
Hao Dong , Qing Liu *, Yuanyu Tian and Yingyun Qiao
a
Key Laboratory of Low Carbon Energy and Chemical Engineering, College of Chemical and Environmental Engineering, Shandong University of Science and
Technology, Qingdao Shandong 266590, P.R. China
State Key Laboratory of Heavy Oil Processing, China University of Petroleum (East China), Qingdao Shandong 266580, P.R. China
b
Tartaric acid–zinc nitrate has been found to be an efficient Brønsted acid-assisted Lewis acid catalytic system for the facile synthesis
of β-amino carbonyl compounds through the one-pot Mannich reaction of aldehydes, aromatic amines and ketones in ethanol at room
temperature. Remarkable enhancement of reactivity by tartaric acid (Brønsted acid) was observed in these reactions in the presence of
anhydrous zinc nitrate (Lewis acid), due to coordination of the tartaric acid ligand to zinc ions increasing the acidity of the system. This
procedure shows some advantages such as mild reaction conditions, short reaction times and high yields.
Keywords: Mannich reaction, anhydrous zinc nitrate, tartaric acid, Lewis acid catalysis
Multicomponent reactions represent a very interesting organic
synthetic methodology due to their advantages, such as one-pot
and easy operating conditions, atom economy, high chemical
yields and cheap substrates. β-Amino carbonyl compounds
are important intermediates for various pharmaceuticals and
Results and discussion
In multicomponent condensation reactions, three or more
reactants come together in a single reaction vessel to form the
products containing portions of all the components. However,
the sequence of additions sometimes plays an important role
1
natural products, and are usually synthesised via the one-pot
22
in these reactions. In this work, the reaction of benzaldehyde,
1,2
three-component Mannich reaction. This reaction can be
aniline and acetophenone was selected as a model to investigate
the effect of the addition sequence. As shown in Table 1
3,4
catalysed by many acidic catalysts, such as ionic liquids,
Lewis acids, Brønsted acids, heteropolyacids, supported acids
(entries 2 and 3), the sequence has an obvious effect on the
5
as well as copper nanotubes or nanoparticles. Also, Zetchi et
catalytic activity for the Mannich reaction. The reaction time
was long with low yield when three components were added
simultaneously. However, if acetophenone and the catalyst
al. reported that the Mannich reaction can be carried out in high
yields within shorter reaction times using PEG-600 as a safer
6
catalyst under solvent-free conditions at room temperature.
(tartaric acid–zinc nitrate) were added 10 min after the addition
Most of the above strategies suffer from several shortcomings,
of benzaldehyde and aniline, the reaction proceeded smoothly
in a short time with high yield. Hence, the ketones were treated
with aldehydes and aromatic amines with the latter method in
the following tests.
7
including the high cost of catalyst, low activities, long reaction
4
times or the use of environmentally unfriendly solvents. Thus,
there is high interest in developing a new readily available and
efficient catalyst for the Mannich reaction.
Furthermore, several different catalysts were examined
for the model reaction. When tartaric acid was used alone as
the catalyst, no product was obtained even after 24 h (Table
1, entry 1). Similarly, the catalytic activities of metal nitrates
alone were inferior (Table 1, entries 2–6). However, the yields
were improved markedly when tartaric acid was used together
with metal nitrates. Among them, tartaric acid–zinc nitrate
was the best with a yield of 92% after 6 h (Table 1, entry 2).
In addition, several different zinc salts were also investigated
for this Mannich reaction (Table 1, entries 7–9). Whether they
were used alone or combined with tartaric acid, the activities
were poorer than that of tartaric acid–zinc nitrate. In short, in
view of the excellent catalytic activity and low cost, tartaric
acid–zinc nitrate was found to be the best catalytic system for
this Mannich reaction.
The effect of the molar ratio of the tartaric acid–zinc nitrate
catalyst system on the Mannich reaction was investigated, and
the results are shown in Table 2. First, the amount of Zn(NO3)2
was fixed at 10 mol%, and a significant enhancement was
observed when the amount of tartaric acid was increased from
1 to 10 mol% (Table 2, entries 1–3), while, an excess amount
of tartaric acid (15 mol%) did not lead to further improvement
of the yield (Table 2, entry 4). However, when the amount of
zinc nitrate was increased, there was no increment in the yield
(Table 2, entries 5–7). Therefore, the optimum molar ratio of
tartaric acid–zinc nitrate was 1:1, and the selective amounts of
them were both 10 mol%. In addition, the molar ratio of the
tartaric acid–zinc nitrate can affect the coordination modes of
Brønsted acid-assisted Lewis acid (BLA) catalytic systems
can be formed by mixing an inactive metal salt and an
organic acid inactive towards a specific reaction, which
8
becomes active via the enhancement of the Brønsted acidity.
Recently, much attention has been focused on BLA catalytic
systems, which have been used as the combined catalyst in
9
10
reactions such as the Fries rearrangement, aldol reactions,
11
12
13
the Diels–Alder reaction, allylation, diacetylation and
tetrahydropyranylation. The discovery and development of
new BLAs is therefore in demand.
14
Tartaric acid is a common natural product that is found
in many plants, particularly grapes. It can be used as a juice
15
additive and antioxidant, and is also an important chiral ligand.
Tartaric acid contains six oxygen atoms, and binds easily with
16,17
metal atoms as a mono-, bi- or tridentate ligand. As a result,
dimeric or polymeric structures can be formed via the interaction
of the hydroxyl and carboxyl groups of the ligand with different
18
metal atoms. Thus, we decided to examine the feasibility of
the mixture of tartaric acid and metal salts as a promising BLA
catalyst. Furthermore, Eshghi et al. reported that enantioselective
ring opening by using Zn(NO ) /(+)-tartaric acid was an efficient
3
2
alternative short route with simple work up and high enantiomeric
19
excess for the synthesis of (S)-propranolol. Following our
2
0,21
research work on catalysis,
the mixture of zinc nitrate and
tartaric acid as a new BLA catalytic system for the Mannich
reaction is investigated in this work. We find it exhibits enhanced
catalytic activity with short reaction times and a high yield.
*
Correspondent. E-mail: qliu@sdust.edu.cn; sdsslq@163.com

4
64 JOURNAL OF CHEMICAL RESEARCH 2018
a
Table 1 Screening of catalysts for the Mannich reaction
O
NH
O
HN
CHO
2
CH3
catalyst
+
+
b
Yield (%)
Entry
MXn
Time (h)
Catalyst: MXn
Catalyst: MX + TA
n
c
1
2
3
4
5
6
7
8
9
–
24
24
6
8
24
6
24
20
30
16
–
–
0
c
d
Zn(NO3)2
Zn(NO3)2
Cu(NO ) ·3H O
Fe(NO ) ·9H O
Ni(NO ) ·6H O
Co(NO ) ·6H O
ZnCl2
ZnSO ·7H O
62
92
e
37
52
39
21
43
0
87
70
65
78
86
3
3
2
3
3
2
3
2
2
3
2
2
0
0
24
Trace
4
2
10
Zn(OAc) ·2H O
2
2
a
b
c
d
e
Reaction conditions: 20 mmol benzaldehyde, 20 mmol aniline, 20 mmol acetophenone, 2 mmol tartaric acid, 2 mmol metal salt, 5 mL ethanol, room temperature.
Isolated yield.
Not done in this work.
Addition sequence: benzaldehyde, aniline and acetophenone were added simultaneously.
Addition sequence: benzaldehyde and aniline reacted for 10 min, after that acetophenone was added to the above mixture for the further reaction.
Table 2 Effect of molar ratio of zinc nitrate and tartaric acid on the
O
O
O
O
a
Mannich reaction
Amount (mol%)
b
Zn
Entry
Yield (%)
Zn(NO3)2
Tartaric acid
HO
O
1
2
3
4
5
6
7
10
10
10
10
20
30
40
1
5
42
75
92
92
92
92
91
Zn
HO
HO
10
15
10
10
10
O
O
HO
O
a
a
b
Reaction conditions: 20 mmol benzaldehyde, 20 mmol aniline, 20 mmol acetophenone,
mL ethanol, room temperature, 6 h.
Isolated yield.
5
Fig. 1 Two possible coordination modes of the tartaric acid ligand and
zinc ions with a molar ratio of 1:1.
b
2
3
ligand tartaric acid and metal ions. Lin et al. have reported
that Zn ions had a six-coordinate distorted octahedron geometry
with tartaric acid adopted via two different coordinated
modes in {[Zn(C H O )(H O)] ·3H O} when the molar ratio
ortho-substituted aniline was used as substrate, the reaction
time is very long, possibly because of the steric hindrance of
para- or ortho-substituent, or other factors (Table 3, entries
6–7). Furthermore, cyclohexanone was also used under
these conditions (Table 3, entries 8–10). Compared with
acetophenone, cyclohexanone showed higher activity, which
may be because its enol formation was much faster than that
of acetophenone. Moreover, the great efficiency of tartaric
acid–zinc nitrate catalyst system as a novel catalyst compared
with data reported in the literature for the Mannich reaction
is shown in Table 4. As can be seen, the tartaric acid–zinc
nitrate catalyst system shows high activity, short reaction time,
high purity, simple work-up and green solvent, which further
indicates that this catalytic system is an efficient catalyst for the
Mannich reaction.
4
4
6
2
2
2
n
2
4
of tartaric acid and zinc ions is 2:1. In this work, the molar
ratio of tartaric acid and zinc ion was 1:1, and two possible
coordination modes are shown in Fig. 1. As can be seen, the
2
+
Lewis acid Zn coordinated with two hydroxyl groups and two
H were released, which increases the acidity of the system. In
+
all, the above results clearly showed that tartaric acid-assisted
zinc nitrate formed a new BLA synergistic catalytic system that
catalysed the Mannich reaction efficiently.
Encouraged by the above results, a variety of aromatic
aldehydes, amines and ketones were also examined, and the
results are shown in Table 3. In the investigation of various
aldehydes, both electron-withdrawing and electron-donating
substituents resulted in excellent yields, indicating the high
generality of the aldehydes in this reaction (Table 3, entries
Conclusions
We have shown tartaric acid–zinc nitrate as a new Brønsted
acid-assisted Lewis acid catalytic system for the Mannich
reaction in ethanol at room temperature. The combined catalyst
is highly efficient because the coordination of ligand tartaric
1
–4). However, aliphatic aldehydes, such as butyraldehyde,
did not favour the formation of the desired product, because
the enamine was formed (Table 3, entry 5). When para- or
2
5

JOURNAL OF CHEMICAL RESEARCH 2018 465
a
Table 3 Catalytic activities of tartaric acid and zinc nitrate for the Mannich reaction
R2
NH
O
O
L-tartaric acid-Zn(NO3)2
ethanol, rt
R CHO + R
2
NH
2
+ R
3
R1
R4
1
R4
R =Ph
R3
R =aryl R =aryl
R =H
3
1
2
4
-(CH2)4-
alkyl
o
Aldehyde
R1
Amine
R2
Ketone
Mp ( C)
b
Entry
Time (h)
Yield (%)
Ref.
R3
R4
Found
Reported
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
4-CH C H
2-CH C H
Ph
Ph
4-CH C H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6
8
6
92
97
96
99
0
95
0
93
94
90
167–169
131–132
128–130
148–149
–
170–171
–
138–140
118–120
118–120
167–169
130–132
129–130
148–150
–
170–171
–
137–139
117–118
118–119
26
26
5
26
–
27
–
26
5
4-ClC6H4
4-CH C H
6 4
4-CH OC H
6 4
3
7
3
CH CH CH
24
12
24
1
6
10
3
2
2
Ph
Ph
Ph
4-ClC6H4
Ph
3
6
4
3
6
4
–(CH ) –
2
4
–(CH ) –
2 4
10
–(CH ) –
27
3
6
4
2 4
a
b
Reaction conditions: 20 mmol aldehyde, 20 mmol aromatic amine, 20 mmol ketone, 2 mmol tartaric acid, 2 mmol zinc nitrate, 5 mL ethanol, room temperature.
Isolated yield.
Table 4 Comparison of different catalytic systems used for the Mannich reaction in literature
O
NH
O
HN
CHO
2
CH3
catalyst
+
+
Entry
Catalyst
Tartaric acid–zinc nitrate
[bmim][OH] ionic liquid
Amount of catalyst (mol%)
Solvent
EtOH
EtOH
H2O
Time (h)
6
10
6
12
8
24
12
20
12
11
24
12
7
5 (60 °C)
Yield (%)
92
85
90
83
93
99
69
95
95
95
93
92
84
95
Ref.
This work
1
2
3
4
5
6
7
8
9
10
10
10
2.5 g
10
5
10
5
10
5
28
29
3
5
30
7
4
31
8
32
33
34
35
[DDPA][HSO ] ionic liquid
4
+
‒
[Hmim] Tfa ionic liquid
Cu nanoparticles
IL
MeOH
Neat
H2O
BMI.NTf2
EtOH
EtOH
Neat
H2O
Benzenedisulfonimide
Dodecylbenzene–sulfonic acid
MSI PW
3
NbCl5
BiCl3
1
0
1
1
Ph IOTF
10
7.5
5
2
1
2
Polyacrylic acid
Bi(OTf)3
HNMPCl/ZnCl /SBA-15
1
3
H2O
EtOH
14
30 mg
2
acid and zinc ions can increase the acidity of the system, which
is crucial for this reaction. This work sheds light on the design
of catalysts for acid-catalysed organic synthesis.
China). The Fourier-transform infrared spectra (FTIR) were taken on
a Nicolet 380 Fourier Transform-Infrared spectrophotometer (Thermo
Electron Corporation, USA) in the range of 400–4000 cm . H NMR
spectra were taken on an EFT-60 NMR spectrometer (Anasazi
–1 1
Experimental
Instruments, USA) using CDCl as solvent and TMS as the internal
3
standard. All products are known compounds and identified by m.p.,
All the chemicals with analytical grade were purchased from
Sinopharm Chemical Reagent Co. Ltd, China, and used without
further treatment. All reagents were purchased and used without
further purification. Melting points were determined by using XT-4
micromelting point apparatus (Beijing Taike Instrument Company,
1
IR and H NMR with those reported in the literature.
General procedure for Mannich reaction
Aldehyde (20 mmol) and aromatic amine (20 mmol) in anhydrous
ethanol (5 mL) were added and stirred in a 50 mL round-bottomed

4
66 JOURNAL OF CHEMICAL RESEARCH 2018
flask at room temperature for 10 min. Then, acetophenone or
cyclohexanone (20 mmol), tartaric acid (2 mmol) and anhydrous zinc
nitrate (2 mmol) were added successively, and the reaction mixture was
further stirred for the specified time (see Table 3). After completion of
9
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Acknowledgements
16
The authors gratefully acknowledge the support from National
Natural Science Foundation of China (No. 21606146), Natural
Science Foundation of Shandong Province (No. ZR2016BB17),
and Scientific Research Foundation of Shandong University
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Received 18 July 2018; accepted 22 August 2018
Paper 1805534
https://doi.org/10.3184/174751918X15355426661373
Published online: 31 August 2018
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