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Catalysis Science & Technology
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COMMUNICATION
Journal Name
Flow chemistry methods offer many benefits over the use of
DOI: 10.1039/D0CY01603A
conventional batch reactors, including improvements in organic base full conversion was reached (Table S1, entry 7).
reaction rate and yield, safety, reliability, and energy The base additive was removed by a simple filtration on a silica
efficiency.40,41 During the last decade there has been a gel plug. Conversions were calculated using the relative signal
significant increase in the use of flow chemistry either in intensities of the carboxylic acid starting compound.
laboratory or industrial scale.42-50 Herein we show that the use
In order to find the optimal condition for the flow synthesis,
of carbon disulfide with alumina utilized in continuous flow (CF) the effect of temperature on the outcome of the reaction was
allowed to develop a novel, atom-efficient, green, and tested under conditions established previously. In a reaction
sustainable catalytic method for the direct synthesis of amides. carried out at room temperature no trace of the desired
Thus, the CF approach could offer a possibility to accomplish product was found. The increase of temperature resulted in the
direct amide coupling in new, unique, and efficient way, increase of conversion and a low 9% was reached at 110 °C.
providing amides with high yields and excellent purity in a single Further temperature increases significantly influenced
step.
conversion. The optimal temperature was found to be 200 °C
Reactions were carried out in a home-made continuous- where >99% conversion was obtained. However, reactions at
flow reactor: a solid catalyst was loaded into an HPLC column, even higher temperatures provided inferior results (Figure S1a).
where the reaction takes place and using an organic solution With respect to pressure, tested at 200 °C, the optimal value
transported by an HPLC pump. The system also contained a GC was found to be 50 bar reaching full conversion. Rising the
oven and an in-line back pressure regulator that ensure the pressure higher than 50 bar did not influence the conversion
required temperature and pressure in the reactor zone, (Figure S1b). A similar test about flow rate gave an optimum
respectively. A schematic outline of the reactor used in this value of 0.1 mL min–1. Any increase in the flow rate resulted in
study is shown in Fig. 1.
decreasing conversions (Figure S1c). Analyzing the effect of
concentration on reaction outcome indicated full conversions at
lower concentrations. The use of higher concentrations of the
starting materials, in turn, resulted in lower conversions (Figure
S1d). Finally, the results about changing the quantity of carbon
disulfide show that the optimal amount is 1.5 equiv.: lower
amounts resulted in decreased conversion, whereas higher
amounts did not have any significant effect (Table S4).
Fig. 1 Schematic illustration of the flow system
Inspired by the successful direct amide coupling reaction of
the model substrates, we expanded the scope of the reaction
testing various aromatic and aliphatic substrates (Table 1).
First, a model reaction was selected utilizing benzylamine
and 4-phenylbutyric acid as substrates dissolved in acetonitrile
to provide a 100 mM solution. Second, the optimization of
reaction parameters was carried out. According to our previous
study on the acetylation of amines with acetonitrile, high
temperature and a modest pressure were used.51 The first test
was performed without either any catalyst or reagent at 200 °C
and 50 bar pressure with a flow rate of 0.1 ml min–1 and a
residence time of 27 min. As expected, no trace of the desired
amide product was detected (Table S1, entry 1). A similar result
was found when the reaction was repeated under the same
conditions in the presence of alumina (Table S1, entry 2).
However, a low conversion of 22% was attained when 1.5
equivalent of carbon disulfide was used as an additive along
with numerous by-products (Table S1, entry 3). According to
literature data, Lewis acids were used in direct amidation
reaction as catalysts.52-56 Thus several Lewis acids were tested
too (Table S2). The most promising catalyst was alumina and a
significant increase in conversion of 53% was observed with a
formation of thioure side product (Table S2, entry 4). At this
point the effect of solvent on the reaction outcome was tested.
Several solvents were investigated but acetonitrile was found to
be the most suitable (Table S3). But in favor of even higher
conversion, organic bases, such as triethylamine and pyridine,
in catalytic amount were added to the starting substrate
mixture. However, this afforded only slight improvements
(Table S1, entries 5, 6), although the formation of thiourea side
products was not observed.
Table 1 Substrate scope of amide formation with isolated yield data[a]
Substrates
4-phenylbutyric acid
phenylacetic acid
acetic acid
O
H
N
H
N
N
H
O
O
benzylamine
14
98%
O
3
9
96%
98%
H
N
H
N
HN
O
O
aniline
10
5
15
98%
95%
96%
H
N
H
N
H
N
O
O
O
O
O
O
p-anisidine
piperidine
morpholine
6
94%
11
95%
16
97%
O
N
O
N
O
N
7
96%
12
97%
17
98%
O
O
N
O
N
N
O
O
O
8
97%
13
98%
18
97%
[a]Reaction conditions: CS2, DMAP, Al2O3, 200 °C, 50 bar
Using the optimized protocol (200 °C, 50 bar, 0.1 mL min–1,
27 min residence time), we achieved high yields for 15 different
2 | J. Name., 2012, 00, 1-3
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