Communication
RSC Advances
Table 1 Results of optimisation studiesa
effective for transamidation. However, their major drawbacks are
the long reaction times and difficulties in recovery and recycling.
To exploit the advantages of ease of separation, the heterogeneous
catalysts HfCl4 supported on KSF polyDMAP,14 and cerium oxide15
have been developed. Unfortunately these methods suffer from
drawbacks such as need of a strong base, and a limited substrate
scope because the reactions were unsuccessful with aliphatic
amines. Therefore there is a clear need for better methods for
transamidation.
Recently, our group has introduced sulfated tungstate, a mild
solid acid, as a heterogeneous catalyst and has shown its
usefulness in bringing about a variety of transformations,
including amidation, by condensations between carboxylic acids
and amines,16 the Ritter reaction17 and N-formylation;18 the
Biginelli,19 Kindler,20Willgerodt–Kindler21 and Strecker reac-
tions;22 and N-alkylations.23 To further realise its potential, we
investigated the transamidation reaction and the details are
presented in this paper.
Sulfated tungstate
(wt%)
Entry Solvent
T (uC) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
—
1
5
10
20
20
20
20
Reflux 24
Reflux 12
Reflux 12
Reflux 12
Reflux 12
Nil
13
41
85
96
Nil
29
66
rt
24
12
12
60
80
9
10
11
Acetonitrile 20
Reflux 24
69
DMF
Nil
20
20
120
100
24
24
,5
87c
a
Reaction conditions: benzamide (1 g, 9.52 mmol) and benzylamine
b
c
(1.02 g, 9.52 mmol) at different temperatures. Isolated yield. Neat
reaction.
lethylamine, and morpholine giving the corresponding
amides in very good yields (Table 2, entries 1–7). The reaction
was found to be comparatively slow in the case of the reaction
between benzamide and morpholine, requiring 18 h and
giving an 84% yield (Table 2, entry 4). Similarly, the reaction
was also found to be slow between p-nitrobenzamide, carrying
an electron-withdrawing group, and benzylamine, giving a
yield of 78% in 24 h (Table 2, entry 7). Furthermore, it was
found that 2-furamide, an acid labile heterocyclic amide,
which is difficult to transamidate under homogenous
catalysis, reacted smoothly with benzylamine and gave a very
good yield (Table 2, entry 8). Cinnamide could also undergo
smooth transamidation, giving a high yield ranging between
82% to 91% (Table 2, entries 9–12). Similarly, phenylaceta-
mides were transamidated using aniline, substituted anilines,
benzylamine, cyclohexyl amine, and morpholine; in all cases,
the reaction was smooth and the yield ranged between 84% to
90% (Table 2, entries 13–18). Acetamide could be transami-
dated with different amines to give the corresponding amides
in high yield but the reaction with p-nitroaniline, as expected
due to its decreased nucleophilicity, was very slow and gave a
yield of 74% in 24 h (Table 2, entries 19–24). In general, it was
observed that reactions with highly basic amines were
comparatively slower, and this behavior is attributed to the
stronger binding of the amines to sulfated tungstate. As an
example of a higher aliphatic amide, n-hexanamide was
transamidated successfully with benzylamine, giving a 77%
yield in 24 h (Table 2, entry 25).
Initial studies were performed using benzamide and
benzylamine as building blocks (Scheme 1) and toluene as
the solvent, under various reaction conditions and the results
are depicted in Table 1. To ensure its catalytic role, a control
experiment was performed in the absence of sulfated
tungstate and, as expected, there was no reaction even after
a prolonged reaction time of 24 h (Table 1, entry 1). Next,
experiments were conducted to optimize the quantity of
sulfated tungstate and it was found that the use of just 20
wt% is sufficient to give a yield of 96% of the product
N-benzylbezamide in 12 h (Table 1, entries 2–5). To find the
optimum temperature, reactions were conducted at progres-
sively lower temperatures of 80 uC, 60 uC and rt. Reactions
were found to be progressively slower giving yields of 66%
and 29% at 80 uC, and 60 uC respectively in 12 h whereas no
reaction occurred at rt (Table 1, entries 6–8). Reactions were
performed in different solvents (toluene, acetonitrile and
DMF) and under solvent free conditions. Toluene was found
to be the solvent of choice giving a 96% yield in 12 h, whereas
acetonitrile and DMF were inferior (Table 1, entries 5, 9 and
10). Solvent free conditions were also viable, and a reaction
could be conducted smoothly at 100 uC and yielded 87% of
the product (Table 1, entry 11).
With the optimized conditions in hand, a number of
structurally diverse amides and amines were screened to
demonstrate the general applicability and efficacy of this
protocol and the results are summarized in Table 2.
Benzamides containing electron-donating or electron-with-
drawing functionalities underwent facile reactions with
various amines, including aniline, benzylamine, 2-pheny-
Encouraged by these promising results, we turned our
attention to N-formylation of amines though transamidation
using formamide. The N-formylation of amines is one of the most
important reactions in organic and industrial chemical synthesis.
Formamides are also useful as an intermediate in the construction
of active pharmaceutical ingredients. The transamidation reaction
of formamide with aniline was conducted under the standardised
conditions. The reaction was fast and went to completion in 90
min giving a 98% yield. The reaction was also attempted under
solvent free conditions and to our surprise the reaction was
Scheme 1 Transamidation reaction of benzamide and benzylamine to form
N-benzylbenzamide.
RSC Adv.
This journal is ß The Royal Society of Chemistry 2013