A novel and simple transamidation of carboxamides in 1,4-dioxane without a catalyst

Article abstract of DOI:10.1016/j.tetlet.2013.03.049

An easy acylation and formylation of amines has been achieved via transamidation using 1,4-dioxane. The investigation works efficiently without an added catalyst and completes within short time under microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2013.03.049

Tetrahedron Letters 54 (2013) 2553–2555
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A novel and simple transamidation of carboxamides in 1,4-dioxane without
a catalyst
⇑
Rajeshwer Vanjari, Bharat Kumar Allam, Krishna Nand Singh
Department of Chemistry (Centre of Advanced Study), Faculty of Science, Banaras Hindu University, Varanasi 221005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An easy acylation and formylation of amines has been achieved via transamidation using 1,4-dioxane.
The investigation works efficiently without an added catalyst and completes within short time under
microwave irradiation.
Received 14 January 2013
Revised 7 March 2013
Accepted 12 March 2013
Available online 19 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Dioxane
Acylation
Formylation
Transamidation
Formamide
Development of novel and efficient methodologies for the syn-
thesis of carboxamides is a vital task as they are prevalent in living
systems and numerous biologically active compounds including
pharmaceuticals, agrochemicals, and polymers.1 The usual practice
for the synthesis of amides involves the coupling of acid deriva-
tives with amines,2 although the lability of activated carboxylic
acid derivatives remains a major drawback of this approach. To cir-
cumvent this problem, alternative methods for the synthesis of
amides have been developed using amidation of aldehydes with
amines,3 aminocarbonylation of aryl halides4 and alkynes,5 direct
amide synthesis from alcohols and amines,6 direct amidation of
O
O
R2
R2
MW, 1,4-dioxane
30 min
R1
NH2
R1
N
H
NH3
H2N
Scheme 1. Catalyst-free transamidation using 1,4-dioxane.
Table 1
Effect of solvents on transamidationa
NH2
O
O
MW, Solvent
N
H
alcohols with nitroarenes,7 umpolung reaction of amines with
a-
NH2
halo nitro alkanes,8 Beckmann rearrangement,9 and cross coupling
of formamides with alkyl/aryl halides.10
Entry
Solvent
Time (min)
Temp (°C)
Yield (%)
A significant current addition to amide synthesis is ‘transamida-
tion’ which makes the use of cheap and abundant starting materi-
als such as amines and amides. However, due to high inertness of
amide bond, these reactions are generally catalyzed by activating
agents or catalysts which are expensive and/or waste generating.
Recent catalysts explored for transamidation include hydroxyl-
amine hydrochloride, copper, cerium dioxide, boric acid, and bo-
rate esters.11 Although, these methods have their own
advantages, they all invariably suffer from long reaction times
and elevated temperature profile of the reaction. Recently our
group has reported a hypervalent iodine catalyzed mild and effi-
cient transamidation reaction under microwave irradiation.12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Toluene
Xylene
Chlorobenzene
DMSO
DMF
30
30
30
30
30
30
30
30
30
40
30
30
30
30
30
120
120
120
120
120
100
80
100
120
120
130
120
80
20
15
0
0
0
10
0
0
73
73
73
0
H2O
Acetonitrile
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
PEG-600
Isopropanol
THF
0
0
0
70
80
DCE
a
Reaction conditions: aniline (1 mmol), acetamide (1 mmol), solvent (2 ml),
⇑
Corresponding author. Tel.: +91 0542 257 5196; fax: +91 0542 236 8127.
E-mail address: knsingh@bhu.ac.in (K.N. Singh).
Anton Paar Monowave. Yield refers to separated yield after column
chromatography.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.049

2554
R. Vanjari et al. / Tetrahedron Letters 54 (2013) 2553–2555
Table 2
between aniline and acetamide and the results are described in Ta-
1,4-Dioxane mediated transamidationa
ble 1. Out of different solvents tested during the course of optimi-
zation, the solvents such as DMSO, DMF, PEG-600, THF,
isopropanol, dichloroethane, acetonitrile, and chlorobenzene were
found to be completely ineffective (entries 3–5, 7, 12–15). Solvents
such as toluene, xylene, and water could bring about only a little
conversion (entries 1, 2, and 6). However, when the reaction was
carried out in 1,4-dioxane, we were amazed and delighted to ob-
serve a single-handedly magical effect of 1,4-dioxane resulting in
73% isolated product yield at the temperature of 120 °C (entry 9).
It is interesting to note that 1,4-dioxane could not afford any con-
version at 100 °C (entry 8), hence implicating a crucial temperature
effect on the reaction. A 20 °C rise in temperature caused a specta-
cular effect on the reaction.
In order to ensure the generality of this finding, the transamida-
tion of amides with various amines was undertaken and the results
are summarized in Table 2. Various amines having both electron
donating and electron withdrawing groups underwent the reaction
smoothly and gave rise to good to excellent product yields. Func-
tional groups like hydroxyl, chloro, methyl, and methoxy were well
tolerated in the reaction (entries 2, 3, 6–11). Low yield in the case
of ortho substituted reactants is attributed to steric factors (entries
2 and 10). Interestingly the transamidation reaction with phenyl
hydrazine gave excellent yield (entry 12). Transamidation reac-
tions of benzamide, secondary and tertiary amides, however, could
not succeed even at elevated temperatures.
From these results, it could be presumed that 1,4-dioxane
strongly activates the amide linkage perhaps through the hydrogen
bonding of amide group hydrogen atom with oxygen atom of the
solvent,14 thereby facilitating the reaction particularly in the case
of aliphatic amides. Failure of transamidation in the case of benz-
amide, secondary and tertiary amides may be attributed to their
high stability and also due to the failure of 1,4-dioxane to activate
these amides to the desired extent. Thus, coordination or interac-
tion of 1,4-dioxane with amide involving the formation of hydro-
gen bond (Fig. 1) is an underlying cause for the reaction to occur.
Further the applicability of the reaction15,16 was extended to
formamide. As regards the reaction with formamide, various
amines reacted well and resulted in excellent product yields as
listed in Table 3. Aliphatic amines as well as aromatic primary
and secondary amines including N-methyl aniline reacted
smoothly. The reaction was well tolerated by functional groups like
hydroxyl, chloro, methyl, and methoxy, but a little lowering in the
product yield was observed in the case of o-anisidine due to the
steric factor. Heteroaromatic amines such as 2-amino pyridine
and furfuryl amine also reacted smoothly.
O
O
R2
R2
MW, 1,4-dioxane
R1
NH2
Amide
R1
N
H
NH3
H2N
Entry
Product
Time (min)
30
Yield (%)
O
H
N
1
2
76
68
NH2
O
O
O
Cl
H
N
NH2
NH2
30
30
O
O
H
N
3
79
O
O
O
O
O
H
N
4
5
30
30
80
73
NH2
NH2
NH2
O
H
N
O
H
N
6
30
78
O
Cl
O
O
O
H
N
7
8
30
30
74
78
NH2
NH2
NH2
O
H
N
O
H
N
9
30
35
80
70
O
O
O
H
N
NH2
NH2
10
O
O
O
O
H
N
11
12
13
30
30
35
76
78
0
O
HO
H
N
In summary, we have explored an effective 1,4-dioxane medi-
ated transamidation of amides with different amine partners to af-
ford diverse carboxamides in reasonably good to excellent yields.
The reaction proceeds smoothly in the absence of a catalyst or acti-
vating agent and can tolerate a number of functionalities.
NH2
O
N
H
O
O
NH2
N
H
a
Reaction conditions: amine (1 mmol), amide (1 mmol), 1,4-dioxane (2 ml),
Anton Paar Monowave. Yield refers to separated yield after column
chromatography.
O
O
O
As a part of our ongoing program to develop efficient and green
protocols,13 we wish to describe herein an in-depth analysis of the
effect of various solvents on the transamidation reaction. The find-
ings led us to achieve a mild and effective 1,4-dioxane mediated
transamidation approach without the use of any catalyst within
short time under microwave (MW) irradiation (Scheme 1).
H
R
N
H
O
O
To begin with, we examined the effect of different solvents
without the aid of a catalyst on the transamidation model reaction
Figure 1. Proposed H-bond formation.

R. Vanjari et al. / Tetrahedron Letters 54 (2013) 2553–2555
2555
Table 3
287; (c) Opsahl, R. In Encyclopaedia of Chemical Technology; Kroschwitz, J. I., Ed.;
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Ed.; Wiley-Interscience: New York, 1970.
1,4-Dioxane mediated formylation of aminesa
O
O
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R
MW, 1,4-dioxane
R
H2N
H
NH2
NH3
H
N
H
Entry Amine
Product
Time
(min)
Yield
(%)
H
1
2
30
85
O
O
NH2
NH2
N
Cl
Cl
30
70
H
N
O
O
H
N
3
30
30
87
86
O
O
NH2
O
H
N
4
NH2
NH2
O
5
30
30
80
82
N
H
O
NH2
O
6
N
O
O
H
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Cl
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7
30
30
30
81
69
79
Cl
N
O
H
NH2
O
O
8
N
H
O
OH
HO
9
N
H
H2N
O
NH2
10
11
30
30
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78
N
H
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H
N
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15. General experimental: Microwave reactions were performed using an Anton
Paar Monowave 300 mono-mode microwave reactor with a sealed 10-mL vial
containing teflon-coated magnetic stir bar. The microwave system contains a
single magnetron that delivers up to 850 W installed microwave power in an
unpulsed mode over the full power range. The sophisticated software prevents
thermal overshoots and the design of the microwave applicator provides
utmost field density, which allows efficient heating, even of low-absorbing
solvents at any scale. A precisely adjusted IR sensor reflects the internal
reaction temperature up to 300 °C. Pressure control up to 30 bars is provided
by a non-invasive hydraulic piston embedded in the swiveling cover. For
cooling, the cavity is flushed with compressed air automatically after the
programed experiment has been processed.
N
O
O
N
12
NH2
N
N
H
a
Reaction conditions: amine (1 mmol), formamide (1 mmol), 1,4-dioxane (2 ml),
Anton Paar Monowave. Yield refers to separated yield after column
chromatography.
16. General procedure for the 1,4-dioxane mediated transamidation of amides
with an amine under microwave. An oven-dried 10-mL microwave reaction
Acknowledgements
vial containing
carboxamide (1 mmol), amine (1 mmol), and dioxane (2 ml) (undried). The
vessel was sealed with plastic microwave septum, stirred at room
a Teflon-coated magnetic stir bar was charged with
a
We are thankful to the Council of Scientific and Industrial Re-
search (CSIR), New Delhi for providing financial assistance.
temperature for 5 min and then placed into the MW cavity for a specified
temperature and time. After the completion of reaction (TLC), the mixture was
cooled to room temperature; distilled water (10 mL) was added to it and then
extracted with ethyl acetate (3 Â 10 mL). The combined organic phase was
dried over anhydrous Na2SO4, filtered and then concentrated using a rotary
vacuum evaporator. The crude product was purified by column
chromatography using a mixture of ethyl acetate/n-hexane (10–20% of ethyl
acetate depending upon the product) as an eluent.
References and notes
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Ed.; Wiley: New York, 1991; 1, pp 251–266; (b) Lipp, D. In Encyclopaedia of
Chemical Technology; Kroschwitz, J. I., Ed.; Wiley: New York, 1991; 1, pp 266–