Graphene oxide (GO) catalyzed transamidation of aliphatic amides: An efficient metal-free procedure

Article abstract of DOI:10.1016/j.tetlet.2018.01.060

Transamidation involves direct interconversion of an amide with amine, and represents an alternative to the common method of amide formation from the reaction of carboxylic acid with an amine. While the carboxamides have huge potential in biological systems and polymer industries, their formation from carboxylic acids requires activation by a suitable catalyst. A metal-free transamidation of aliphatic amide with aromatic amine catalyzed by graphene oxide (GO) has been developed and established as a general, synthetically useful and selective procedure. Graphene oxide bearing several carboxylic acids on the edges and having large surface area acts as an efficient and recyclable catalyst for transamidation.

Full text of DOI:10.1016/j.tetlet.2018.01.060

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Graphene oxide (GO) catalyzed transamidation of aliphatic amides:
An efficient metal-free procedure
⇑
Suchandra Bhattacharya, Pranab Ghosh, Basudeb Basu
Department of Chemistry, North Bengal University, Darjeeling 734013, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Transamidation involves direct interconversion of an amide with amine, and represents an alternative to
the common method of amide formation from the reaction of carboxylic acid with an amine. While the
carboxamides have huge potential in biological systems and polymer industries, their formation from
carboxylic acids requires activation by a suitable catalyst. A metal-free transamidation of aliphatic amide
with aromatic amine catalyzed by graphene oxide (GO) has been developed and established as a general,
synthetically useful and selective procedure. Graphene oxide bearing several carboxylic acids on the
edges and having large surface area acts as an efficient and recyclable catalyst for transamidation.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 17 November 2017
Revised 11 January 2018
Accepted 21 January 2018
Available online xxxx
Keywords:
Amide
Amine
Graphene oxide
Metal-free
Transamidation
Introduction
Cu(OAc)
2 2 2 2
, CeO and Cp ZrCl showed better activation of the amide
1
6–20
group to undergo transamidation.
The carboxamide function is present in numerous molecules of
proteins, pharmaceuticals, polymers and small organic molecules.
Harnessing the catalytic efficiency of sustainable nanomaterials
like graphene oxide (GO) in diverse synthetic reactions is an
1
2
1,22
Synthesis of amides is therefore an extremely important organic
reaction. The condensation of carboxylic acid with an amine is con-
intriguing area of research.
GO possesses a rich oxygenated
chemical functionality, is somewhat acidic (pH 4.5 at 0.1 mg
2
,3
À1
23
sidered by far as the most common synthetic procedure. Since
amide formation results in the generation of one molecule of
water, a suitable catalyst is required to activate the carboxylic acid
mL in aqueous suspension), and is recognized as having strong
2
4
oxidizing properties.
In connection with our interests in utilizing catalytic function of
4
23,25
function. Without the presence of any catalyst, the acid and the
GO,
we disclose herein our studies on the transamidation reac-
tion under solvent-free conditions, which finally constitute a com-
plete metal-free, general and useful protocol to prepare a variety of
carboxamides (Scheme 1).
amine usually undergo salt formation or require high tempera-
5
ture. As a result, several metal-based catalytic systems have been
developed to achieve this reaction.6 Another alternative strategy
avoiding direct use of carboxylic function is the interconversion
of amides, commonly known as transamidation.3 Although
transamidation is relatively uncommon due to the fact that the
amide function is a poor electrophile, suitable catalytic systems
,7
,7
Results and discussion
We began our experiment taking aniline and acetamide
(equimolar and 1 mmol scale) with GO (50 mg) in toluene. Moni-
toring the reaction by TLC reveal multiple spots and after isolation
by chromatography, a moderate yield of the desired amide is
obtained (Table 1, entry 1). Changing the reaction medium with
more polar and low to high-boiling solvents like acetonitrile,
DMSO or even water gave moderate to poor yields of the acetani-
lide (entries 2–4). Considering that solvent might not have much
desired influence towards improving the yield, we perform the
reaction under solvent–less i.e., in neat conditions at varying tem-
peratures (80–150 °C). In Table 1, entries 5–7 show that the best
results are obtained when we take a mixture of aniline, acetamide
could activate and exchange with amines resulting in the forma-
tion of new carboxamide derivatives.8 The catalytic system and
reaction conditions remain the key factors for transamidation of
primary, secondary or tertiary amides to establish a synthetically
useful procedure. Among different catalytic systems, metal-free
catalysts like boronic acid,9
,10
hypervalent iodosobenzene
1
1
12
13
14
diacetate, hydroxylamine hydrochloride,
L
-proline, Et
3
N,
1
5
2 2 8
and K S O
are noteworthy, while metal-based catalysts like
⇑
Corresponding author.
E-mail address: basu_nbu@hotmail.com (B. Basu).
https://doi.org/10.1016/j.tetlet.2018.01.060
040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
0
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2
S. Bhattacharya et al. / Tetrahedron Letters xxx (2018) xxx–xxx
R'
N
O
compound, which can be attributed to the presence of a halogen
Graphene Oxide
R
R'
Ar NH
2
+
in ortho position (Table 2, entry 7). N-Substituted aliphatic amides
like N-methylacetamide, N,N-dimethylacetamide also worked effi-
ciently affording the desired products (Table 2, entries 8–10). In
the case of aromatic amides (Table 2, entries 11 and 12) however
no product was formed. This could be attributed to the additional
conjugation of the amide carbonyl with the benzene ring, which
also reduces the electrophilicity of the centre. We have performed
one reaction using a long carbon chain amide (Table 2, entry 13)
and obtained the corresponding carboxamide in 70% isolated yield.
On the other hand, aliphatic amine (Table 2, entry 18) in spite of
being more nucleophilic in nature no reaction was observed. This
R''
Neat, 150 oC, 24 h
HN
Ar
R
+
NH
R''
O
Ar = C
CH -C
OCH
6
6
H
5
H
, 2-CH
3
-C
6
6
H
H
4
4
,
, 4-
4-
R = H, CH
R', R'' = H, CH
3 2 3
, (CH )10CH
3
4
H
,
2-Cl-C
3
3
-C
6
4
,
4-Br-C
6
H
4
,
4
-COOH-C
6
4
H , 2-naphthyl
Scheme 1. Transamidation reaction using graphene oxide (GO) as a heterogeneous
catalyst.
and GO and heated at 150 °C affording the desired amide in 76%
yield after purification (entry 7). Further optimization of reaction
is conducted by varying the catalyst (GO) quantity, as shown in
entries 7–9. While doubling the catalyst quantity does not have
significant effect (entry 8), lowering its (GO) quantity afforded con-
siderably poor yield (entry 9). In the absence of GO, there was no
conversion indicating that GO has definite role in catalyzing the
process (Table 1, entry 10). We also performed two experiments
taking reacting partners in 1:2 ratios (entries 11 and 12), which
however did not give any significant increase in yield of the
transamidation product. In order to check any effect of atmo-
could be attributed to possible attachment of aliphatic amines on
27,28
the surface of graphene oxide, as reported previously,
discussed in the mechanism section.
and also
Mechanism
The carbonyl carbon of amide is unreactive and should be acti-
vated for further reaction. It is believed that the –COOH groups
present on the edges of GO initially form H-bonding with the
amide and the epoxide oxygen with the amine hydrogen (1) as
shown in the Scheme 2. Then the nucleophile, the –NH2 function
attacks at the carbonyl centre to form the intermediate 2. Finally
elimination of the primary/secondary amine (deamination) gener-
ates the product 3 (Scheme 2). Activation of the amide group is
important for the transamidation, which is corroborated by the fact
that aromatic amide bond being sufficiently stable through conju-
gation could not be activated by the GO (Table 2, entries 11 and
12). From the literature reports, the reason behind unreactive nat-
ure of aliphatic amines in the presence of GO is assumed to be (a)
amine forms H-bond with the oxygen functionalities present on
GO, (b) it may attack the epoxide ring before it attacks the amide
carbonyl, (c) some sort of ionic bonding is also described by
2
spheric air, we conducted the reaction under blanket of N and
ended up with 70% isolated yield (Table 1, entry 13). Hence, it
can be concluded that there is no such effect of the atmospheric
oxygen in the reaction. We therefore considered the optimized
reaction condition as in entry 7, i.e.: amine (1 mmol), amide (1
mmol), GO (50 mg), 150 °C, 24 h.
After optimization, we extended the method for various amine
components and amides (Table 2). Diverse functionalities on the
amine moiety including electron donating and withdrawing
3 3
groups e.g., CH , OCH , Cl, Br, COOH and also naphthyl system gave
products in the range of 60–79% yields. Changing the amide from
acetamide to formamide produced N-formylated products (Table 2,
entries 4–7). In these cases, a mixture of rotamers was achieved as
evident from NMR data and also supported by literature
1
3,26
À +
27,28
reports.
However, 2-chloroaniline afforded the single
3
forming –COO NH R.
Table 1
Optimization of reaction conditions.
Entry
Catalyst amount (mg)
Solvent
Temperature (°C)
Yield (%)a
1
2
3
4
5
6
7
8
9
50
50
50
50
50
50
50
100
20
–
Toluene
DMSO
CH CN
3
100
120
80
90
80
120
150
150
150
150
150
150
150
55
Trace
43
Trace
50
64
76
78
39
NR
77
Water
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
b
1
1
1
1
0
1
2
3
c
50
50
50
d
e
70
70
a
b
c
Isolated yield of product by column chromatography.
Optimized condition.
Aniline (1 mmol), acetamide (2 mmol).
Aniline (2 mmol), acetamide (1 mmol).
d
e
2
Reaction was done under N in a sealed tube. All reactions were carried out up to 24 h and 1 mmol of each reactant were used unless mentioned.
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S. Bhattacharya et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 2
a
Transamidation of various amides using amines
Entry
1
Amine
Amide
Product
Yield (%)b
76
NH2
3
H C
NH2
NH2
NHCOCH3
O
2
NH2
3
H C
NHCOCH3
75
O
CH
3
CH3
3
4
NH2
CH3
H C
NH2
NHCOCH3
CH
65
69
3
O
3
NH2
NH2
H
O
N(CH3)2
N(CH3)2
NHCHO
5
H
O
NHCHO
61
CH
3
CH3
6
7
8
NH2
H
O
N(CH3)2
N(CH3)2
NHCHO
CH
70
60
67
CH3
NH2
3
H
O
NHCHO
Cl
Cl
NH2
NH2
H C
3
N(CH3)2
NHCOCH3
O
O
9
H C
N(CH3)2
NHCH3
NHCOCH3
60
3
CH
3
CH3
1
1
0
NH2
3
H C
NHCOCH3
60
–
O
1c
NR
NH2
CONH2
CONH2
CH
NH2
3
1
2c
NR
–
CH
3
NO2
1
3
4
NH2
O
C
NHCO(CH ) CH3
70
72
2 10
CH (CH )
3
2 10
NH
2
1
NH2
H C
NH2
NHCOCH3
3
O
OCH3
NH2
OCH
3
1
1
5
6
H C
NH2
NH2
NHCOCH3
75
79
3
O
O
Br
Br
NH2
3
H C
NHCOCH3
(
continued on next page)
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S. Bhattacharya et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Table 2 (continued)
Entry
Amine
Amide
Product
Yield (%)b
71
1
7
NH2
3
H C
NH2
NH2
NHCOCH3
O
COOH
Ph
COOH
NR
1
8
3
H C
–
O
N
H
a
b
c
Reaction condition: amine (1 mmol), amide (1 mmol), GO (50 mg), neat condition, 150 °C, 24 h.
Isolated yield after purification by column chromatography.
No reaction.
Scheme 2. Possible mechanism of transamidation using GO.
Table 3
on the edges of GO nanosheets play as the active acidic sites to
activate the poorly electrophilic amide group and facilitate further
attack of the amine nucleophile via hydrogen bonding. The reac-
tion proceeds under solvent-less conditions and the catalyst can
be recovered and reused for three more runs. The present protocol
could be useful to the synthetic and pharmaceutical chemists.
Experimental: Representative procedure for transamidation: In a
typical procedure, a mixture of amine (1 mmol), amide (1 mmol)
and 50 mg GO was taken in a round-bottom flask (50 mL) and stir-
red the mixture using a magnetic stirring bar under open air at
Recyclability test of the catalyst.
No. of run
Yield (%)
st
1
76
75
72
70
nd
2
rd
3
th
4
Recyclability of the catalyst
1
50 °C for 24 h. After the reaction was completed, ethyl acetate
The main advantage of using a heterogeneous catalyst is the
ease of separation along with its reusability. To test the reusability,
we set up a reaction using aniline (2 mmol), acetamide (2 mmol)
and GO (100 mg) at the optimized condition. After completion of
the reaction, ethyl acetate was added to the reaction mixture and
the catalyst was filtered off. Then the catalyst was washed with
ethyl acetate and finally with water and acetone, dried under vac-
uum and used in the next runs in the same manner. No significant
drop in the isolated yield was observed up to four consecutive runs
(5 mL) was added to the reaction mixture and the catalyst was fil-
tered off. The filtered catalyst was further washed with ethyl acet-
ate and the combined organic layer was evaporated to afford
nearly pure product. The residue was further purified by passing
through a silica gel column and eluting with ethyl acetate–petro-
leum ether mixture.
Acknowledgments
(
Table 3).
Conclusion
In summary, we have demonstrated that GO acts as an effective
Financial support under the SERB – India project (No.
EMR/2015/000549) is gratefully acknowledged. SB is thankful to
CSIR – India, India for awarding JRF-NET fellowship.
A. Supplementary data
heterogeneous catalyst for the transamidation of aliphatic amides
with aromatic amines. Graphene-based sustainable nanomaterials
provide a clean and practical procedure for the formation of amides
in good yields. Aliphatic amines however do not react under the
condition and offers the selectivity. The carboxylic groups present
Supplementary data (experimental procedure, catalyst prepara-
1
13
tion, characterization data of products and scanned spectra ( H,
C
NMR)) associated with this article can be found, in the online ver-
sion, at https://doi.org/10.1016/j.tetlet.2018.01.060.
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