Synthesis of Mannich-type derivatives from amides activated by hydrogen bonding with ZnCl2

Article abstract of DOI:10.1039/d0ob01989e

The amide group has one of the most significant functionalities found in many natural products. Herein, low-nucleophilic amides are used in a Mannich-type reaction to synthesize N-acyl-protected amine derivatives. A highly efficient synthetic method utilizing simple aldehydes, N-substituted anilines, and amides as substrates was established through a one-pot amide pathway activated by hydrogen bonding between the ZnCl2 and amide under solvent-free conditions. This strategy can be broadly applied to medicinal chemistry. More importantly, compared with the previous Lewis acid catalyzed reaction, we proposed a new application of zinc chloride. This journal is

Full text of DOI:10.1039/d0ob01989e

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Synthesis of Mannich-type derivatives from amides
activated by hydrogen bonding with ZnCl2†
Cite this: DOI: 10.1039/d0ob01989e
Zhiyu Hu,a,b Zongbo Xie,
*
a,b Zhiqiang Zhu,a,b Bozhen Gong,a,b Guofang Jianga,b
and Zhanggao Le*a,b
The amide group has one of the most significant functionalities found in many natural products. Herein,
low-nucleophilic amides are used in a Mannich-type reaction to synthesize N-acyl-protected amine
derivatives. A highly efficient synthetic method utilizing simple aldehydes, N-substituted anilines, and
amides as substrates was established through a one-pot amide pathway activated by hydrogen bonding
between the ZnCl2 and amide under solvent-free conditions. This strategy can be broadly applied to
medicinal chemistry. More importantly, compared with the previous Lewis acid catalyzed reaction, we
proposed a new application of zinc chloride.
Received 29th September 2020,
Accepted 27th October 2020
DOI: 10.1039/d0ob01989e
rsc.li/obc
Coincidentally, Cao et al. also reported a catalyst-free, three-
component reaction between aldehyde, amine, and indole in
Introduction
The Mannich reaction1 is one of the most important reactions 2014.6 In other instances, this structure was effectively obtained
for C–C and C–N bond formation in organic synthesis.2 This by the reaction between an aldehyde, amine, and unmodified
reaction provides β-amino carbonyl compounds, which are ketone when different kinds of catalyst were used, such as het-
important synthetic intermediates in the production of various eropoly acids and diaryliodonium(III) salts (Scheme 1).7
pharmaceuticals and natural products.3 However, the classical
Over the course of our studies on deep eutectic solvents
Mannich reaction is plagued by several serious challenges, (DES’s) as green media and catalysts in organic transform-
which limit its application. For instance, the classic Mannich ations,8 and our onging green organic chemistry program,9 this
reaction requires the formation of an imine intermediate first, article reports that zinc chloride and acetamideform a clear
and to access aminocarbonyl compounds, activation of the liquid through hydrogen bond interaction. When electron-rich
inherently electrophilic or inert carbonyl β-carbons as nucleo- aromatics and benzaldehyde are added to this mixture, a new
philes is necessary. This situation greatly limits the diversity of Mannich-type derivative is formed after a few hours (Scheme 2).
reaction products.4 Therefore, numerous modified versions of In contrast to the traditional Mannich reaction, ketones or
the Mannich reaction have been developed to overcome the indoles are replaced by electron-rich arenes, which have not
drawbacks of the classical method.
been previously used. Furthermore, it is gratifying to note that
A diverse synthetic route for an asymmetric Mannich reac- amide compounds, which are less nucleophilic, are involved in
tion has been developed. However, in general, the improved the reaction. This reaction is therefore a new breakthrough in
methodology relies on a two-component system using pre- the synthesis of Mannich-type derivatives.
formed electrophiles, such as imines, and stable nucleophiles,
To the best of our knowledge, a wide diversity of amine
such as enolates, enol ethers, and enamines.4 For example, sources, such as aniline and primary and secondary amines,
Kumar et al. described the use of an aldehyde, amine, and
indole in the preparation of 3-amino alkylated indoles under
solvent-free conditions with L-proline as the catalyst in 2012.5
aJiangxi Province Key Laboratory of Synthetic Chemistry, East China University of
Technology, Nanchang 330013, Jiangxi, China. E-mail: zbxie@ecut.edu.cn,
zhgle@ecut.edu.cn
bSchool of Chemistry, Biology and Material Science, East China University of
Technology, Nanchang 330013, Jiangxi, China. E-mail: zbxie@ecut.edu.cn,
zhgle@ecut.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob01989e
Scheme 1 Mannich-type reactions reported in literature.4–7
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Table 1 Optimization of the reaction conditiona
Scheme 2 One-pot three-component reaction in the presence of
ZnCl2.
Temperature Time Yieldb
Entry Solvent
Additive
(°C)
(h)
(%)
have been utilized in nucleophilic reactions with aldehydes.
Nevertheless, because amides have relatively low nucleophili-
city, Mannich-type reactions for the aminoalkylation of alde-
hydes with these compounds are rare.10 In contrast, the amide
group is one of the most significant functionalities found in
many natural products. The catalytic formation of C–N bonds
is highly attractive in organic chemistry, as well as in bulk and
fine chemical industries, for the production of solvents and
pharmaceutical intermediates and synthesis of bioactive com-
pounds such as amino acids.11 Because of the importance of
amide derivatives, there is a need to develop a novel Mannich-
type reaction to synthesize N-acyl-protected amine derivatives.
Hence, we studied the Mannich reaction of aldehydes,
N-substituted anilines, and amides in the presence of ZnCl2
under solvent-free conditions. In this reaction, zinc chloride
not only catalyzed the reaction as Lewis acid, but also pro-
moted the reaction as hydrogen bond acceptor. Meanwhile,
the desired Mannich-type products with an amide group were
formed quickly in excellent yields under mild conditions. This
method is a novel and improved modification of the three-
component Mannich reaction. Moreover, this multicomponent
synthetic strategy is reported for the first time.
1
2
3
4
5
6
7
8
Solvent free ZnCl2 (30%)
80
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
5
6
7
8
58
71
71
36
17
69c
0
0
0
0
0
Solvent free ZnCl2 (0.5 equiv.) 80
Solvent free ZnCl2 (1.0 equiv.) 80
Solvent free ZnCl2 (1.5 equiv.) 80
Solvent free ZnCl2 (2.0 equiv.) 80
Solvent free ZnCl2 (0.5 equiv.) 80
EtOH
MeOH
DMSO
DMF
ZnCl2 (30%)
ZnCl2 (30%)
ZnCl2 (30%)
ZnCl2 (30%)
ZnCl2 (30%)
80
80
80
80
80
80
80
80
80
80
80
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H2O
1,4-Dioxane ZnCl2 (30%)
5
10
0
MeCN
MeCN
MeCN
MeCN
MeCN
ZnCl2 (30%)
L-Proline (30%)
FeCl3 (30%)
HCl (30%)
10
Trace
0
52
40
69
75
82
75
79
NaOH (30%)
Solvent free ZnCl2 (0.5 equiv.) 70
Solvent free ZnCl2 (0.5 equiv.) 60
Solvent free ZnCl2 (0.5 equiv.) 90
Solvent free ZnCl2 (0.5 equiv.) 80
Solvent free ZnCl2 (0.5 equiv.) 80
Solvent free ZnCl2 (0.5 equiv.) 80
Solvent free ZnCl2 (0.5 equiv.) 80
a Unless otherwise noted, the reaction conditions are benzaldehyde
(1a, 0.2 mmol), N,N-dimethylaniline (2a, 0.2 mmol), and acetamide
(3a, 0.4 mmol) in 1 mL solvent. b Isolated yield after silica gel column
chromatography. c Yield in corresponds to the following reaction con-
ditions: 3a (0.4 mmol) and ZnCl2 (0.5 equiv.) heated to 100 °C until the
appearance of a clear colorless liquid.
Results and discussion
was surveyed, and the results are shown in Table 1 (entries
Initially, the three-component Mannich reaction of benz- 7–12). The data indicate that the catalytic activity in the
aldehyde (1a), N,N-dimethylaniline (2a), and acetamide (3a) was Mannich reaction is remarkably influenced by the solvent.
chosen as the model reaction. ZnCl2, as a typical halide salt, can When the reaction was performed in MeOH, EtOH, DMSO,
form a complex with the hydrogen bond donor, acetamide, and DMF, and H2O, the Mannich-type product (4a) was not
their interaction disrupts the crystalline structure of the salt, obtained. In contrast, the yield was extremely low when the
thereby lowering the melting point and generating a liquid at reaction was conducted in 1,4-dioxane. We hypothesize that
room temperature.12 Our preliminary work was performed in the this solvent possibly disrupts the hydrogen bond between
absence of solvent. The ZnCl2 content may affect this reaction ZnCl2 and acetamide.
because the organic salt/hydrogen bond donor molar ratio also
Subsequently, a series of commercially available acids and
has a significant impact on the meltingpoint of DES’s. To bases were screened as catalysts using MeCN as the solvent
confirm the effect of ZnCl2 on this three-component domino (Table 1, entries 13–17). L-Proline did not give the desired
reaction, the addition of 0–2 equiv. of ZnCl2 was investigated product. The best yield (10%) was achieved using 30% ZnCl2
(Table 1, entries 1–6). Encouragingly, 0.5 equiv. of ZnCl2 gave as the catalyst (Table 1, entry 13). The model reaction with
good yields at 80 °C. On the contrary, the reaction performed in other Lewis acids gave lower yields or produced side products
a pretreated DES (ZnCl2: acetamide) gave a yield of 69% (Table 1, (Table 1, entries 14–17). Therefore, ZnCl2 is the optimum cata-
entry 6). Thus, the use of 0.5 equiv. of ZnCl2 without any prepro- lyst for the synthesis of 4a.
cessing was chosen as the optimum reaction condition.
To further optimize the reaction condition, the effect of
The reaction medium is also an important parameter in temperature on the model reaction was investigated (Table 1,
this reaction. Thus, the reaction in different organic solvents entries 18–20). It can be seen that raising the temperature
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increased the yield of the reaction. However, conducting the cantly increase the yield. Generally, theyield increase with reac-
reaction at 90 °C resulted in a slight decline in the yield tion time but only at the early stage; at the later stages, these
(Table 1, entry 20). Moreover, extending the reaction time to values are basically unchangeable.
6 h increased the yield to 82% (Table 1, entry 22), although
Encouraged by the remarkable results obtained under the
continuing this Mannich-type reaction further did not signifi- reaction conditions above, we aimed to show the generality
Table 2 Substrate scope for the reactiona
a All reactions were performed using 1 (0.2 mmol), 2 (0.2 mmol), and 3 (0.4 mmol) at 80 °C under solvent-free conditions. The isolated yield was
determined after silica gel column chromatography.
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and scope of this new protocol using various aldehydes (1), amide (3b) under the same reaction condition. In contrast, in
electron-rich arenes (2), and amides (3). The results are pre- the absence of benzamide (3b), 4,4′-(phenylmethylene)bis(N,N-
sented in Table 2. The reactions with aldehydes containing a dimethylaniline) (5)14 was formed. Finally, no product was
neutral or electron-donating group at the para site R1 gave formed when aniline (6) was reacted with benzaldehyde and
better yields than those containing an electron-withdrawing other aldehydes instead of benzamide (3b) probably because
group (Table 2, 4a–4g). The best yield (87%) was obtained with aniline is not a hydrogen bond donor. These results indicate
the benzaldehyde with R1
=
4-OCH3 (Table 2, 4f). that this reaction does not follow the Mannich or Betti reaction
Subsequently, we continued to investigate the influence of sub- mechanism. Moreover, considering the effect of solvent on the
stituents at the C3 and C2 positions of the benzaldehydes. For reaction, we hypothesize that the hydrogen bonding between
example, 3-nitrobenzaldehyde and 2-nitrobenzaldehyde gave ZnCl2 and acetamide plays an important role in the activation
the desired products 4h (71%) and 4i (32%), respectively. of the C1 amino of acetamide to form the intermediate.
Interestingly, the reaction also worked well with the hetero-
According to an initial investigation, there are two or three
cyclic aldehydes, thiophene 2-carbaldehyde and furfuralde- cheap and safe components that are capable of associating with
hyde, and provided derivatives 4j (60%) and 4k (78%), respect- each other through hydrogen bond interactions to form a eutec-
ively. Unfortunately, the yields obtained with aliphatic alde- tic mixture (i.e., DES).13 In most cases, the DES is obtained by
hydes (4l and 4m) were not as high as those obtained with aro- mixing a quaternary ammonium salt with metal salts or a
matic aldehydes.
hydrogen bond donor that can form a complex with the halide
The scope of our method was extended to other amines. In anion of the quaternary ammonium salt.14 Hydrogen bonds
addition to N,N-dimethylaniline, various substituted arylamines play a key role in many reactions. For instance, in 2014,
were also used as substrates (Table 2, 4n–4q). Interestingly, the Krishnakumar and co-workers discovered a novel and green pro-
electron-rich arene, 1,3,5-trimethoxybenzene (2e), was also toler- tocol for the Michael addition of N-arylhomophthalimides and
ated as a substrate in the transformation (Table 2, 4r). Among chalcones in the low-melting mixture of L-(+)-tartaric acid/
these reactions, the best yield (72%) was obtained from the reac- dimethyl urea.15 The hydrogen bonding in the acidic low-
tion of N,N-diethylaniline (2b). In addition, benzamide (3b) was melting mixture plays an important role in the activation of the
also used as the amide to react with benzaldehyde (1a) and N,N- C3 carbonyl group of N-arylhomophthalimide to form the inter-
dimethylaniline (2a). Excellent yields were obtained with N-acyl- mediate. In contrast, the direct C3 alkenylation/alkylation of
protected amines for a variety of benzamides, including those indoles using the DES, choline chloride/oxalic acid, was
bearing an electron-withdrawing or electron-donating group reported by Sanap and Shankarling.16 In this process, oxalic
(4s–4v). In contrast, the reaction with thiourea resulted in a acid forms a hydrogen bond with ChCl. Similarly, it forms a
moderate yield of 4w.
hydrogen bond with the oxygen atom of the electron-deficient
To explore the mechanism of this reaction, we performed carbonyl of 1,3-dicarbonyl compounds and increases the latter’s
several control experiments (Scheme 3). In the first series of electrophilicity, thereby facilitating the attack of indole. On the
experiments, treatment of benzaldehyde with acetamide (3a) basis of the literature17 and control experiments, we sub-
in the presence of ZnCl2 (0.5 equiv.) without solvent did not sequently concluded that ZnCl2, as a halide salt, can form a
yield a Schiff base. Unfortunately, the imine was also not complex with acetamide by hydrogen bond interaction
formed by the reaction between benzaldehyde (1a) and benz- (Scheme 4).18 ZnCl2 may promote some reactions by forming a
hydrogen bond with amide compounds.
On the basis of the control experiments and previous litera-
ture, we propose a possible mechanism for this relay catalytic
reaction (Scheme 5). First, because imine is not formed in the
presence of ZnCl2 at 80 °C, this reaction is inconsistent with
the classical Mannich reaction. We hypothesize that ZnCl2 acts
as a Lewis acid that promotes the reaction by increasing the
electrophilicity of benzaldehyde (1a) through coordination,
providing a good electrophilic substrate for the nucleophilic
N,N-dimethylaniline. ZnCl2 likely activates the amide com-
pounds through a hydrogen bond interaction. In this case,
Scheme 3 Control experiments.
Scheme 4 Formation of intermolecular hydrogen bonds.19
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Conclusions
In conclusion, we developed a green and efficient, organocata-
lyzed multicomponent reaction of aldehydes, N-substituted
anilines, and amides for the synthesis of N-acyl-protected
amine derivatives under solvent-free conditions. This multi-
component reaction provides simple access to a new family of
compounds containing the N-acyl amine and electron-rich
arene in a single structure. The advantage of our presented
methodology is that it leads to the development of a new
method for the synthesis of N-alkylamides using low-nucleo-
philic amides as the substrates instead of amines.
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
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This project was supported by the National Natural Science
Foundation of China (No. 11765002), the Science and
Technology Projects of Jiangxi (No. 20181BBH80007).
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