Electrochemical: N-acylation synthesis of amides under aqueous conditions

Article abstract of DOI:10.1039/c9gc01391a

An electrochemical N-acylation of carboxylic acids with amines was reported. The sustainable TBAB electrocatalysis proceeded with excellent chemoselectivity and positional selectivity, and with ample scope, allowing electrochemical N-acylation under mild reaction conditions at room temperature in water. Moreover, the synthetic utility of the current method is demonstrated by the synthesis of melatonin.

Full text of DOI:10.1039/c9gc01391a

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DOI: 10.1039/C9GC01391A
Green Chemistry
COMMUNICATION
Electrochemical N-acylation synthesis of amides under aqueous
conditions
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a
a
a
Fang Ke,* Yiwen Xu, Suning Zhu, Xiaoyan Lin, Chen Lin, Sunying Zhou, and Huimin Su
DOI: 10.1039/x0xx00000x
An electrochemical N-acylation of carboxylic acids with amines
was reported. The sustainable TBAB electrocatalysis manifold
proceeded with excllent chemoselecitivity and positional
selectivity, and with ample scope, allowing electrochemical N-
acylation under mild reaction condition at room temperature in
water. Moreover, the synthetic utility of current method is
demonstrated by the synthesis of melatonin.
O
O
MeO
MeO
N
O
NH
NH
OH
NH
O
OMe
F
F
O
F
F
OMe
colchicine
F
paracetamol
diflufenican
Figure 1 Selected amide-containing molecules
(
a) Traditional method of synthesizing amides
Amides are widely prevalent in natural products,
pharmaceuticals, agricultural chemicals, dyes, et al. With
1
O
O
R2
R2
N
R3
respect to pharmaceuticals, amide bonds have merged as
essential components in backbones of various compounds,
A +
NH
R3
A=-Cl,- OCOR1, -OR1
2
such as colchicines, paracetamol and diflufenican (Figure 1).
Traditionally, amides have been usually produced by the (b) Directamidation of carboxylic acids
reaction of carboxylic acid derivatives (acyl halides, anhydrides
O
O
3
and esters) with amines. The shortages of these methods are
R2
R2
N
R3
1. high temperature
2.coupling agents
OH
+
NH
R3
4
mainly due to the limited stability of many acyl halides, the
preparation of dangerous reagents, the release of corrosive
and volatile gases, the difficulty of experimental operation and
the generation of numerous waste. Recently, several new
(
c) This work
O
O
5
Pt
Pt
strategies have been developed to synthesize amides. For
R2
N
R3
R2
OH
+
NH
R3
example, Lange reported the direct synthesis of amide by
thermal condensation of carboxylic acid with amine at high
2
Cs CO , TBAB
3
Scheme 1 Strategies for the synthesis of amides
6
temperature, but the protocols were incompatible with most
functionalized molecules, and suffered from low atom
In the past few years, the renaissance of organic
electrochemistry has provided appealing strategies for
7
8
economy. Various effective N-nucleophiles have also been
9
4
used for the activation of carboxylic acids such as ZrCl ,
1
2
environmentally-benign synthetic methods. The ability of
electrochemistry to reverse the polarity of a functional group
by selective removal or addition of electrons makes it thus
possible to induce reactions of otherwise nonreactive
1
0
11
AlMe
3
,
and Ti(OiPr)
4
in amidations. Although progress has
been made, there are still requirements of catalysts and
removal of by-products. Therefore, the development of a new
N-acylation method for the synthesis of amide bonds without
catalysts is highly desirable.
1
3
molecules. Among the various reactions mediated by
electrocatalysis, the formation of C-N bonds and subsequent
transformation have drawn much attention. For example, Zeng
and co-workers unveiled an efficient paired electrosynthesis
1
4
involving C-N bond formation; Yoshida group developed a C–
N coupling of imidazoles based on electron-oxidative C–H
a. Institute of Materia Medica, School of Pharmacy, Fujian Provincial Key Laboratory
of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350122,
China Tel.: +86-591-22862016; fax: +86-591-22862016; e-mail:
kefang@mail.fjmu.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
1
5
functionalization of aromatic and benzylic compounds;
Nakajima and co-workers developed a method for synthesizing
1
6
amides from esters by electrocatalysis. Encouraged by some
remarkable work in electrochemical C-N bonds, and our
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Journal Name
endeavours to develop environmentally friendly protocols,16 Finally, we studied the effect of different electrVoiedweAsrticolenOntlhinee
herein we envisioned that an electrochemical N-acylation with reaction and found that different electrodDeOsI:h10a.d10l3it9t/lCe9eGfCfe0c13t9o1nA
halogenide salt as the catalyst and electrolyte.
the reaction. (ESI, Scheme S1). Thus, the optimal catalytic
CO (1.0 equiv), TBAB (1.0 equiv), Pt-
Our initial investigations focused on the N-acylation of conditions consist of Cs
2
3
carboxylic acids in the presence of electrocatalysis and bases, wire electrode in water at 40 mA for 30 min at room
in the conditions of which the N-phenylbenzamide was temperature.
obtained when substrates solution in water was stirred with
Having identified the optimized conditions for this
TBAB and Cs CO for 20 min at room temperature. These electrocatalytic N-acylation, we examined the compatibility of
2
3
results are summarized in Table 1. Gratifyingly, screening of this reaction with respect to carboxylic acids and amines (Table
the supporting electrolytes showed that TBAB was the optimal 2). The results showed that most substrates in this reaction,
one giving the product with a 63% yield (table 1, entries 1-4). including aromatic and aliphatic substrates, gave excellent
Interestingly, trace of product was detected when TBAI were yields. The N-acylation of the ammonium hydroxide proceeded
used. The yield was improved to 58 % when KBr was added smoothly and led to the benzamide in 96% yield (table 2, entry
(table 1, entry5). Next, a series of bases were examined. The 1). Primary amines furnished products in good yields whether
results showed that Cs CO exhibited the higher catalytic they were aliphatic amines (table 2, entries 2-3) or aromatic
2
3
activity than others (table 1, entries 1 and 6-10). However, the amines (table 2, entry 5). Interestingly, ethylenediamine can
reaction was carried out in the absence of bases, no desired only undergo N-acylation of one amino group to generate
product was detected. The reaction of 30 min afforded corresponding product in 91 % yield (table 2, entry 3), instead
product in 72 % yield (table 1, entry11). Further, the current of N-acylation of both amino groups. Secondary amine also
had a significant effect on the product yield, it was observed afforded the amides in excellent yield by electrocatalytic N-
that current increase and an increase was found in the yield acylation (table 2, entry 4). Heterocyclic amines (pyridine and
(
table 1, entries 10 and 13-15). When the reaction was thiazole) could also be converted into the corresponding
conducted with high current 40 mA, the yield was further amides in excellent yields (table 2, entries 6-7). Amines
increased to 73% (table 1, entry 12). With these results, we substituted with electron-donating groups (CH and OCH ) and
decided to further explore the scope of this method by electron-withdraw groups (Cl and NO ) could also undergo N-
3
3
2
investigating a dose of catalyst, and it was found that the acylation to the corresponding amides with high yields (table 2,
reaction yield increased with the increase of the amount of entries 8-11). However, the oxidation of the former (table 2,
PTC and Cs CO , which we guessed the reaction was due to the entries 9-10) proceeded much more efficiently than those of
2 3
change of electrical conductivity (table 1, entries 15-20). the latter (table 2 entries 8 and 11).
Table 1 Optimization of the reaction condition for amidesa
O
O
NH2
OH
+
N
H
base, PTC, t
Entry
Base
Cs
Cs
Cs
Cs
Amount of base/mmol
Electrolyte
Amount of Electrolyte/mmol
Time/min
20
20
20
20
20
20
20
20
20
20
30
40
30
30
30
30
Electricity/mA
Yield (%)b
63
1
2
3
4
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
1
1
1
1
1
-
1
1
1
1
1
1
1
1
1
0.4
0.8
1.2
1
TBAB
TBAI
0.2
0.2
0.2
-
30
30
30
30
30
30
30
30
30
30
30
30
20
40
50
40
40
40
40
40
40
trace
trace
-
58
-
53
50
49
55
72
73
48
77
79
36
70
76
TBAPF
-
6
c
5
Cs
TBAI
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.4
0.8
1
6
7
8
9
-
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
KOH
CO
CO
NaOH
K
2
3
Na
2
3
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
0
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
30
30
30
30
85
91
93
1
1
30
aReaction conditions: Undivided cell, benzoic acid(1 mmol), aniline(1 mmol), H
O (2 mL). Isolated yield. 1.0 mmol of KBr was used.
b
c
2
2
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9GC01391A
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COMMUNICATION
Table 2 Synthesis of benzimidazolesa
compounds. To further investigate the synthetic utility and
generality of this reaction, we tested the glycine, under the
optimized reaction conditions resulting in a series of by-
products (table 2, entry 25). And the hydrazine hydrate gave
the desired product with a good yield (table 2, entry 24).
To elucidate the reaction mechanism, cyclic voltammetry
O
O
Pt
Pt
NH2
R2
OH
+
R2
N
R1
0 mA, 30 min R1
H
4
Cs2CO3, TBAB
1
2
3
2
(CV) experiments were performed in H O with TBAB as
O
electrolyte using glassy carbon working electrode, Pt wire
counter electrode and SCE reference electrode with scan rate
at 0.1 V/s (Figure 2). The CV of benzoic acid showed a quasi-
reversible voltammogram, with the oxidation potential being
1.20 V. When one equivalent of benzoic acid was added to the
solution of TBAB, the ipa increased from 45 μA to 1.5 mA.
Meanwhile, the ipc increased from 19 μA to 0.4 mA upon
scanning back in the CV experiment (Figure 2 A and C). The
increasement of ipa associated with the regeneration of
bromide, which suggested that TBAB served as a catalyst
during the reaction. In addition, the increasement of ipc was
attributed to the reduction of the bromine radical to bromide,
O
O
O
OH
NH2
N
NH2
N
N
H
H
O
(
1) 96％
(2) 89％
(3) 91％
(4) 90％
NO2
O
O
O
O
S
N
N
H
N
H
N
N
N
H
H
(
5) 92％
(7) 87％
(8) 88％
(
6) 88％
OCH3
Cl
O
O
O
O
N
H
N
H
N
H
N
H
(12) 91％
(10) 90％
(11) 90％
(
9) 93％
O
O
O
O
N
N
N
N
H
H
H
H
H3CO
O N
HO
Br
2
which clearly indicated that the bromine radical was generated
(
16) 91％
(
15) 93％
(14) 94％
-
(13) 91％
from Br . After the addition of Cs
2
CO
3
, the potential changed
O
O
O
O
from 1.20 V to 1.60 V, and its conductivity changed to a certain
extent (Figure 2 A). We speculated that benzoic acids formed
salts in this reaction and there were electron changes. Benzoic
acid salts exhibited oxidative waves from 1.60 V. By adding
TBAB, the ipa increased from 0.2 mA to 0.5 mA, indicating that
intermediate was formed under basic conditions. Given that
the oxidation potentials of benzoic acid salts and amines are
N
N
H
OH
N
H
N
H
H
NO2
I
NC
(
17) 87％
(18) 87％
(19) 88％
(
20) 89％
O
O
O
O
NH2
O
N
N
N
N
H
H
H
OH
H
N
H
O
NO2
(22) 88％
OH
(23) 90％
NH2
(21) 91％
(24) 84％
(25) 49％
1
.60 V and 0.95 V respectively, benzoic acid salts are much
easier to be electrochemically oxidized to generate radicals
than the amine moiety. The oxidation potential of the amine
was investigated. When Cs CO was added to the strategies,
2 3
aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), Cs
CO
2
O (2 mL), room temperature, 40 mA, 30 min, Pt-wire electrode.
2
3
(1.0 equiv), TABA (1.0
equiv), H
b
Isolated yields.
the potential was increased from 0.95 V to 1.30 V (Figure 2 D),
indicating that the amine changed its electrons after the
addition of Cs CO . These results indicated protons were
2 3
Next, we investigated the scope of carboxylic acids as
substrates in the electrocatalytic N-acylation reaction. The
carboxylic acids moieties which were treated with aniline
under the present reaction condition, also gave excellent
yields. The reaction of acetic acid gave amides in 91 % yield
removed from bases. The potential of the system was
measured to be 1.95 V under the optimal condition of the
reaction, indicating that the reaction system underwent
REDOX reaction. To gain some information of the reaction
mechanism, radical trapping experiments was conducted. With
addition of 2.0 equivalence of TEMPO (2, 2, 6, 6-
tetramethylpiperidin-1-oxyl), the reaction was shut down. The
TEMPO trapping product (4a) was isolated in 40 % yield
(table 2, entry 12). In addition, with a high level of functional
group tolerance, the reaction efficiency was not affected in the
presence of halides, nitro, methoxy and amino groups (table2,
entries 12-17). Furthermore, substituents’ positions of the
aromatic carboxylic acids (meta and para positions) did not
influence the reaction efficiency (table 2, entries 13-17 and 21-
(Scheme 2).
On the basis of the above-mentioned experiments, a
2
3). Moreover, lower yields for ortho-substituted anilines were
plausible reaction mechanism for the generation of N-
phenylbenzamide was proposed, as shown in Scheme 3.
Initially, intermediate A is generated from benzoic acid salts
with the participation of bromide ions, which undergoes base-
relative to the meta and para isomers (table 2, entries 18-20).
It is noteworthy that o-iodobenzoic acid with reactive iodo
group lead to corresponding products (table 2, entry 18) which
could be used for further transformations to heterocyclic
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catalyzed nucleophilic substitution reactions.18 Subsequently,
intermediate A undergoes a homolytic cleavage to afford
intermediate B and bromide radicals. Then, in situ generated
bromide radicals is reduced by the cathodic reaction, giving
bromide ion.19 At the same time, the reaction between
O
View Article Online
O
DOI: 10.1039/C9GC01391A
OCs Cs2CO3
OH
Pt(+)
O
N
H
C
Br-
intermediate B and aniline gives intermediate C. Finally, the
intermediate C is oxidized, giving N-phenylbenzamide.
Furthermore, the scaled-up experiment was also carried
out by using aniline (0.55 g, 5.5 mmol) and benzoic acid (0.61 g,
-e
H
O
Br
OCs
Pt(-)
O
Br-
N
NH2
5
mmol) as substrates, which could be purified by silica gel
H
column in a yield of 81 % (Scheme 3). The scale-up synthesis of
N-phenylbenzamide also highlighted the operational
convenience of this procedure.
O
+
e
A
Br
O
Melatonin is secreted principally by the pineal gland and
mainly at night time. The primary physiological function is to
Br
B
convey information of the daily cycle of light and darkness to Scheme 3 Proposed Mechanisms.
1
8
the body, which is an important health hormone. The
synthesis of melatonin was taken as an example to illustrate
the application of this reaction (scheme 4), which can be
obtained by this method without toxic by-products and harsh
conditions, in a total yield of 85%.
O
O
Pt
Pt
NH2
OH
+
N
4
0 mA, 30 min
H
Cs2CO3, TBAB
81% yield
Scheme 4 Scaled-up experiment.
O
Pt
Pt
O
O
N
O
NH2
OH
+
+
TEMPO
N
+
O
4
0mA, 30min
H
O
NH2
Pt
Pt
(
2.0 equiv)
O
trace
40 ％
+
O
NH
5% yield
CsCO3, TBAB
N
OH
40 mA, 30 min
Cs2CO3, TBAB
Scheme 2 Radical trapping experiments.
H
N
H
8
Scheme 5 Synthesis of melatonin.
Conclusions
In summary, we developed an electrochemical N-acylation
of carboxylic acids with amines. This catalytic protocol avoided
using toxic reagents and showed a broad substrate scope,
providing good yields of amides at room temperature. In
comparison with the classical approaches, we anticipate that
our method should provide a potential alternative.
Conflicts of interest
There are no conflicts to declare
Acknowledgements
This project was supported by Fujian Provincial Foundation
(
Nos. 2016Y9051, 2016Y9052, 2016Y9053, 2017J01574), and
the Research Fund of Fujian Medical University (No.
015MP008, CA18142) for financial support.
2
Figure 2 Cyclic voltammeter studies (scan rate at 0.1 V•s−1)
Notes and references
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