Convenient metal-free direct oxidative amidation of aldehyde using dibromoisocyanuric acid under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2018.08.026

A facile method for the direct synthesis of amides from aldehydes is described. Amide bonds were synthesized by an oxidative amidation in the presence of dibromoisocyanuric acid (DBI). Treatment of aromatic and aliphatic aldehydes with dibromoisocyanuric acid generated acyl bromide intermediates, which were employed to react with a variety of secondary and primary amines to give amides. Through this reaction method, various amides were synthesized directly from aldehydes under mild conditions in high yields and short times. This facile and efficient procedure provides potential strategy for the direct synthesis of amides from aldehydes.

Full text of DOI:10.1016/j.tetlet.2018.08.026

Accepted Manuscript
Convenient Metal-Free Direct Oxidative Amidation of Aldehyde using Dibro-
moisocyanuric Acid under Mild Conditions
Soosung Kang, Minh Thanh La, Hee-Kwon Kim
PII:
S0040-4039(18)31008-6
https://doi.org/10.1016/j.tetlet.2018.08.026
TETL 50201
DOI:
Reference:
Tetrahedron Letters
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6 August 2018
14 August 2018
Please cite this article as: Kang, S., Thanh La, M., Kim, H-K., Convenient Metal-Free Direct Oxidative Amidation
of Aldehyde using Dibromoisocyanuric Acid under Mild Conditions, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.08.026
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Convenient Metal-Free Direct Oxidative
Amidation of Aldehyde using
Dibromoisocyanuric Acid under Mild
Conditions
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Soosung Kang a *, Minh Thanh La b,c, Hee-Kwon Kim b,c
*

1
Tetrahedron Letters
Convenient Metal-Free Direct Oxidative Amidation of Aldehyde using
Dibromoisocyanuric Acid under Mild Conditions
Soosung Kanga , Minh Thanh La b,c and Hee-Kwon Kim b,c 
a College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
b Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Chonbuk National University Medical School and Hospital,
Jeonju, 54907, Republic of Korea
c Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju,
54907, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile method for the direct synthesis of amides from aldehydes is described. Amide bonds
were synthesized by an oxidative amidation in the presence of dibromoisocyanuric acid (DBI).
Treatment of aromatic and aliphatic aldehydes with dibromoisocyanuric acid generated acyl
bromide intermediates, which were employed to react with a variety of secondary and primary
amines to give amides. Through this reaction method, various amides were synthesized directly
from aldehydes under mild conditions in high yields and short times. This facile and efficient
procedure provides potential strategy for the direct synthesis of amides from aldehydes.
Available online
Keywords:
Amidation
2009 Elsevier Ltd. All rights reserved.
Aldehydes
Dibromoisocyanuric acid
Acyl bromide
1. Introduction
Synthesis of amide bond from aldehydes has been considered
one of the more effective and direct procedures to prepare amide
Amides are one of the most important functional units present
in nature. The amide bond constitutes amino acid linkages in
peptides and proteins,1,2 and the amide moiety can be found in
numerous natural products and bioactive materials.3-7
Additionally, 16% of synthetic pharmaceuticals, including
antibiotics, anticancer agents, and enzyme inhibitors, contain
amide bonds.8-12
bonds, and aldehydes have been utilized to prepare amides by
oxidative amidations.23,24 The most commonly known oxidative
amidations of aldehydes are metal-mediated methods. Several
transition metals, including copper, iron, and palladium, have
been employed as metal-catalysts to produce amides from
aldehydes.25-29 Although these metal-mediated methods provide
successful preparation of amides, there are serious weaknesses:
harsh reaction conditions are usually needed to achieve amidation,
and many of the reactions should be carried out in air-protected
conditions. Employment of expensive metal reagents is another
drawback for application on an industrial scale, and utilization of
metal is often considered as not environmentally friendly
chemical protocol. Thus, development of a practical, simple, safe,
and widely applicable efficient procedure for the synthesis of
amides is desirable.
Due to the significance of amides, useful amidation methods
are considered highly valuable, and several procedures for the
synthesis of amides have been developed.13 Condensation of
carboxylic acids with amines is a widely used method for
synthesizing amides.13-15 The condensation reactions are usually
carried out at high temperature to prevent generation of
ammonium salts by the acid-base reaction. Another strategy for
the synthesis of amides is the carbodiimide-mediated
amidation.16-17 However, it suffers from lack of efficiency due to
the urea analogues produced as a co-product. Several other
preparations of amides have been reported, including amidation
from acyl azide and anhydrides, the Staudinger ligation, and the
Schmidt reaction.15-22 However, most of these methods are not
widely applicable for organic synthesis reactions due to
drawbacks such as generation of a large amount of byproduct and
low efficiency.
Acyl halides have been utilized as useful reaction
intermediates in several reactions.30-32 Thus, acyl halides can
potentially be considered part of a successful strategy to prepare
amides from aldehydes. Particularly, we were interested in
discovering novel direct acyl halide-mediated synthesis of
desired amides from aldehydes in high yield. We assumed that, if
acyl bromides can be generated from aldehydes by treatment
with a bromo donor reagent, then target amides could be easily
obtained by the treatment of various amines with prepared acyl
———
 Corresponding author. Tel.: +82 63 250 2768; Fax: +82 63 255 1172; e-mail: hkkim717@jbnu.ac.kr (H. Kim)
 Corresponding author. Tel.: +82 2 3277 6619; Fax: +82 2 3277 2851; e-mail: sskang@ewha.ac.kr (S. Kang)

2
bromides. Cheung reported an oxidation procedure of aldehydes
to acyl bromides using N-bromosuccinimide.33 In addition,
among bromo donor reagents, dibromoisocyanuric acid (DBI)
has been employed as one of the most effective brominating
agents and oxidants in several reactions,34,35 and thus could be
used as a bromo donor reagent for the formation of amide bonds
(Figure 1). To the best of our knowledge, the direct oxidative
amidation of aldehydes using bromo donor reagent has not yet
been reported in the literature. In this study, we describe a DBI-
mediated direct synthetic method to generate various amides
from aldehydes.
of DBI, 1.5 equiv. of amine, and dichloromethane were selected
as optimal reaction conditions for further study.
Table 1. Screening of reaction conditions for synthesis of
amidea
NH2
O
O
O
3a
DBI
H
Et3N
N
Br
H
solvent
rt, 4h
solvent
rt, 10 min
1a
4a
2a
Entry
DBI
Amine
Solvent
Temp. Yieldb
(%)
O
(equiv.) (equiv.)
Br
HN
N
1
0.1.
0.3
0.6
1.0
1.5
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
1.5
1.5
1.5
1.5
2.0
1.0
2.0
3.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
12
51
94
91
90
67
94
93
4
O
N
O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
2
Br
3
Figure 1. Dibromoisocyanuric acid (DBI)
2. Result and Discussion
4
5
Because of the low reactivity of aldehydes to produce their
corresponding acyl halide, aldehyde to acyl halide conversion has
not been extensively studied.36 We expected that, if efficient
reaction conditions for the transformation of aldehyde to acyl
bromide were discovered, direct amidation of aldehydes would
be easily achievable in high yield. We hypothesized that
treatment of a bromo donor reagent with aldehyde could generate
reactive intermediate acyl bromides in situ, which could be
directly used to precede the subsequent reactions to produce
amides in the presence of amines. To test our hypothesis,
benzaldehyde was chosen as the model substrate, and benzyl
amine was used as the amine nucleophile to investigate the
possibility of direct synthesis of amides from aldehydes using
DBI, a bromo donor reagent.
6
7
8
9
10
11
12
13
14
15
toluene
xylene
22
53
2
Et2O
cyclohexene
1,4-dioxane
CH3CN
68
31
67
In the initial study, aldehyde was treated with DBI in
dichloromethane (3 mL) at room temperature. During the
reaction, the disappearance of benzaldehyde 1a and production of
benzoyl bromide 2a and desired amide 3a were monitored by
TLC. First, various reaction ratios of DBI to aldehyde were
examined to optimize reaction conditions for the conversion of
aldehyde to amide. The benzaldehyde starting material was found
to be completely consumed in generating the corresponding
benzoyl bromide 2a after 4 h treatment with 0.6 equiv. or more of
DBI. When the conversion of aldehyde to benzoyl bromide was
complete, benzyl amine was added to the reaction mixture
including in situ prepared benzoyl bromide at room temperature
without isolation. The desired amide was readily obtained in 10
min of reaction with amine. Several amounts of amine were
screened to produce the desired amides with high yield (Table 1).
While the addition of 1 equiv. of amine resulted in synthesis of
the corresponding amide with 67% yield, increasing the amount
of amine in the reaction enhanced the conversion yield from
aldehydes to amides. The corresponding amide was found to be
prepared in 94% yield from treatment with 1.5 equiv. or 2.0
equiv. of amines. However, more than 2 equiv. of amine addition
had no positive effect on enhancing the yield of the desired
amides. Thus, 1.5 equiv. of amine were chosen for subsequent
optimization experiments.
a Reaction conditions: 1a benzaldehyde (2.0 mmol), Et3N (3.0
mmol) and 3 mL of solvent
b Isolated yield after purification (distillation)
To find the optimal reaction conditions for amide synthesis, a
series of commercially available bases were examined for the
reaction with benzyl amine 3a. The results are shown in Table S1.
The reaction of benzylamine without any base provided the
desired product with more than 80% yield. Among the bases,
trimethylamine and NaHCO3 proved effective at providing high
yield synthesis of the desired product (94% for trimethylamine
and 93% for NaHCO3). In addition, the temperature effect was
investigated. However, reactions at the enhanced temperature did
not provide improved synthesis. Thus, room temperature was
chosen as suitable for subsequent reaction studies.
With the optimized experimental conditions determined, the
scope of this direct conversion to amides method was examined
(Table 2). The reactions of aldehydes were performed with
various amines to produce corresponding amides in high yields
of 81–93% without significant side products. First, primary alkyl
amines, including isobutylamine, tert-butyl amine, and
cyclohexylamine, were used to evaluate our synthetic procedure
using benzaldehyde (Table 2, entries 1-4). Besides the reactions
with primary amines having been proven useful for the direct
preparation of the amides, the general secondary amine
dipropylamine was employed for the aldehyde reaction and
successfully produced the corresponding amide in high yield
(Table 2, entry 5). Morpholine, a cyclic secondary amine, was
also used for the reaction of benzaldehyde to assess this DBI-
Solvent effect was also examined to optimize reaction
conditions. The results suggest that solvent influenced the
synthesis of amide significantly. Reactions in tetrahydrofuran
(THF), toluene, diethyl ether (Et2O), and 1,4-dioxane led to low
yield preparations of amide, while dichloromethane generated the
desired product in high yield (Table 1, entry 3). Thus, 0.6 equiv.

3
O
mediated protocol, and the corresponding amide was obtained in
satisfactory yield (Table 2, entry 6). Aniline, an amine of
aromatic ring, was also treated for the reaction of benzaldehyde,
and the desired amide was obtained successfully (Table 2, entry
7). The reaction between benzaldehyde and glycine methyl ester,
an amino ester, was also carried out and provided the
corresponding amide (Table 2, entry 8). The results suggest that
DBI is an important aldehydes-to-amides conversion agent
during the oxidative amidation process.
O
N
O
H
93
12
13
H3C
H3C
4l
1b
O
N
H
H
90
87
89
H3C
H3C
4m
1b
O
O
14
15
16
N
H
Table 2. The scope of oxidative amidation of aromatic
Cl
Cl
aldehydesa,b
1c
4n
O
O
R2
NH
O
N
H
O
O
H
R3
Et3N
3
R2
DBI
H
N
Br
Cl
Cl
R
4o
R
R
R3
1c
CH2Cl2
rt, 3-4h
CH2Cl2
rt, 10 min
1
4
O
2
O
N
Yieldb
(%)
H
Entry
Aldehydes
Product
85
Cl
Cl
Cl
1c
4p
O
H
O
O
O
N
H
94
1
H
N
17
18
81
87
O
1a
O
4a
Cl
1c
4q
O
Br
O
Br
O
H
N
H
4b
2
3
4
92
84
H
H
N
H
1a
1d
O
4r
O
O
O
N
H
H
N
1a
19
20
4c
H
87
O2N
O2N
O2N
4s
O
H
O
1e
O
N
H
O
88
91
N
H
1a
O
4d
84
90
O2N
O
4t
1e
N
5
6
H
O
O
N
1a
4e
H
H
21
22
H
O
O
O
O
4u
1f
H
N
86
82
O
O
O
1a
N
85
4f
H
O
O
O
O
H
O
1g
4v
O
N
H
7
8
a Reaction conditions: aldehyde (2.0 mmol), DBI (1.2 mmol),
amines (3.0 mmol), Et3N (3.0 mmol), and CH2Cl2 (3 mL)
1a
O
4g
O
b
O
Isolated yield after purification by flash column
H
N
87
84
H
chromatography
O
4h
1a
Next, the scope of the optimized reaction procedure using DBI
was extended to aromatic aldehydes with both electron-donating
and electron-withdrawing groups. Even though substituents of
different electronic properties were employed on the aromatic
ring, amidation from aromatic aldehydes was achieved. When
aromatic aldehydes bearing an electron-donating group (p-
O
O
H
N
H
9
H3C
H3C
H3C
4i
1b
O
O
H
N
H
tolualdehyde)
and
electron-withdrawing
groups
(4-
10
11
92
89
chlorobenzaldehyde and 4-nitrobenzaldehyde) were treated with
a variety of amines, the corresponding amides were prepared in
similar yield or high yield (Table 2, entries 9-22). In addition to
reaction with primary amines, reactions of aromatic aldehydes
with various secondary amines, including general secondary
amines (diethylamine and dipropylamine) and cyclic secondary
amines (pyrrolidine and morpholine), also successfully yielded
the desired amides (Table 2, entries 12, 13, 16, 17, and 20). In
4j
H3C
1b
O
O
H
N
H
H3C
H3C
4k
1b

4
O
addition, various aldehydes containing several functional groups
such as 2-bromobenzaldehyde, 4-methoxybenzaldehyde
O
N
H
93
92
4
5
H
H
containing an ether structure, and methyl 4-formylbenzoate
containing an ether structure were also employed for the
oxidative amidation, and the corresponding amides were easily
prepared in high yield (Table 2, entries 18, 21, and 22).
Employing DBI produced acylbromide from aromatic aldehydes
with an electron-donating group within 3 h, and therefore
amidation of these aromatic aldehydes with an electron-donating
group was achieved more rapidly than that of benzaldehyde and
aromatic aldehydes with an electron-withdrawing group.
1i
4z
O
O
N
H
4aa
1i
O
O
6
84
85
87
N
H
H
H
1i
4ab
O
O
To investigate the range of direct conversion of aldehydes to
amides with DBI, reactions of aliphatic aldehydes in the presence
of DBI were carried out to produce amides. Reactions of
aldehydes bearing aliphatic chains with various aliphatic and
aromatic amines successfully provided the corresponding amides
in high yields (84–93%, Table 3, entries 1-6). Especially, the
treatment of aliphatic aldehydes with different aromatic amines
containing electron-donating (methyl) and electron-withdrawing
(cyano) groups under the same reaction protocol resulted in the
synthesis of the desired amides in high yield (Table 3, entries 2
and 3). In addition, dibenzyl amine, which bears two bulky
phenyl groups, was used in the reaction of aliphatic aldehydes,
and the corresponding product was successfully obtained in good
N
H
7
8
1j
4ac
4ad
O
O
N
H
CH3
1j
O
O
H
H
9
N
H
82
1j
4ae
O
O
yield
(Table
3,
entry
6).
The
reaction
of
N
H
10
11
93
88
cyclohexanecarboxaldehyde in the presence of DBI also led to
the successful preparation of the corresponding amides (Table 3,
entries 7-10). These results clearly demonstrate that DBI played a
crucial role during the reaction process in efficient conversion
from aldehydes and various amines to amides. The amidation of
aliphatic aldehydes was completed faster than that of aromatic
aldehydes because acylbromide was generated from aliphatic
1j
4af
O
O
S
S
N
H
H
1k
4ag
aldehydes within
2 h. Furthermore, the scope of this
a Reaction conditions: aldehyde (2.0 mmol), DBI (1.2 mmol),
amines (3.0 mmol), Et3N (3.0 mmol), and CH2Cl2 (3 mL)
methodology using DBI was extended to heterocyclic aldehydes
(Table 3, entry 11). 2-Thiophenecarboxaldehyde was treated with
n-butylamine, and, gratifyingly, the desired amide was
synthesized in 88% yield under the same reaction conditions.
This suggests that amides can be prepared from heterocyclic
aldehydes and amines in the presence of DBI under mild
conditions. Moreover, the reactions of the aliphatic aldehydes
and heterocyclic aldehydes did not produce significant side
products during the reactions we carried out.
b
Isolated yield after purification by flash column
chromatography
Next, a scaled-up oxidative amidation of aldehyde was
performed (Scheme 1) to evaluate application on a large scale.
Benzaldehyde 1a (30.0 mmol, 1.0 equiv., 3.18 g) was treated
with benzyl amine 3a (45.0 mmol, 1.5 equiv.) to give the desired
product 4a in 90% yield under optimized reaction conditions
using DBI. The result suggests that the reaction procedure of
aldehyde is scalable and practical because a gram-scale reaction
was efficiently achieved.
Table 4. Scope of oxidative amidation of aliphatic
aldehydesa,b
R3
NH
O
O
NH2
O
O
O
R4
Et3N
O
3
R1
R1
R1
R3
DBI
DBI
3a
H
N
N
R4
Br
Br
H
H
R2
CH2Cl2
CH2Cl2
rt, 4 h
R2
R2
CH2Cl2
rt, 2 h
CH2Cl2
rt, 10 min
rt, 20 min
1a
4a
2a
2
4
1
5.69 g, 90%
30.0 mmol, 3.18 g
Entry Aldehydes
Product
Yieldb (%)
Scheme 1. The gram-scale reaction of benzaldehyde 1a with
benzyl amine 3a
O
O
N
93
1
H
H
H
H
A proposed reaction pathway for the reaction is suggested in
the supporting information (Figure S1). Introduced DBI can react
with the aldehyde via a radical reaction pathway to produce the
corresponding acyl bromide, which can be then used to react with
amine to afford the desired amides.
1h
4w
CH3
O
O
O
92
2
N
H
4x
1h
CN
O
N
H
3
87
3. Conclusion
4y
1h
A novel practical method for the direct conversion of
aldehydes to amides has been developed. In this study, aromatic

5
and aliphatic aldehydes were treated with DBI to generate
acylbromide intermediates, which are used to react with amines.
The synthetic procedure using DBI demonstrates that the
reactions of aldehydes with various amines, including primary,
secondary and cyclic, readily produce the corresponding amides.
The reaction was easily carried out under mild conditions,
resulting in high yields without any metal catalysts. These
reactions suggest that this novel direct amidation from aldehydes
can help with the synthesis of a variety of amides from aldehydes.
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This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education (2018R1D1A1B07047572)
and by National Research Foundation of Korea (NRF) grant
funded by the Korean government (MSIT) (No.
2018R1A5A202528).
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Conflicts of interest
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Chen A, J. Org. Chem. 2012;77:8007-8015
There are no conflicts to declare.
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37. General procedure for the preparation of amides (4a-4ag): To
a solution of benzaldehyde (1a) (0.212 g, 2.00 mmol) in CH2Cl2
(3 mL) was added dibromoisocyanuric acid (0.344 g, 1.20 mmol).
The mixture was allowed to stir at room temperature for 4 h.
Benzyl amines (0.321 g, 3.00 mmol) and trimethylamine (0.303 g,
3.00 mmol) were added to the reaction mixture. After being
stirred for 10 min at room temperature, the solid was filtered, and
the filtrate was extracted with CH2Cl2 (2 x 30 mL). The organic
layer was dried over sodium sulfate and concentrated under
reduced pressure. The resulting residue was then purified by flash
column chromatography on silica gel with hexane-EtOAc as
eluent to afford the desired product 4a (0.397 g, 94%).
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Highlight

6
-Practical direct preparation of amides from
aldehydes has been reported.
- Dibromoisocyanuric acid was used to produce
amides.
-The oxidative amidations were performed under
mild condition.
-Various amides were obtained in high yield.