CL-140846
Received: September 8, 2014 | Accepted: October 29, 2014 | Web Released: November 8, 2014
Ammonium Nitrate: A Biodegradable and Efficient Catalyst for the Direct Amidation
of Esters under Solvent-free Conditions
Perla Ramesh and Nitin W. Fadnavis*
Natural Products Chemistry Division, Indian Institute of Chemical Technology, Uppal Road, Hyderabad-500 007, India
(E-mail: fadnavis@iict.res.in)
A simple, metal-free, and environment-friendly procedure is
developed for the direct conversion of esters to amides using
ammonium nitrate as a catalyst under solvent-free conditions.
Aryls, heteroaryls, and aliphatic esters are easily converted to the
corresponding amides in excellent isolated yields (85-99%). An
enantiopure ester and amine were both shown to react without
racemization. The methodology has been successfully applied to
preparation of procainamide.
Ammonium salts have been employed as catalysts for the
aldol condensation,22 synthesis of imidazo[1,2-α]pyridines,23
Claisen-Schmidt reaction,24 synthesis of 2,4,5-trisubstituted
imidazoles,25 synthesis of fused 4H-chromene derivatives,26
amidation of phenol derivatives,27 etc., and we envisaged that
these could be used for the amidation reaction as well. Initially,
a model reaction of methyl phenylacetate (1) (1 equiv) and
pyrrolidine (2a) (3 equiv) to form 2-phenyl-1-(pyrrolidin-1-
yl)ethanone (3) was chosen to identify an appropriate ammoni-
um salt (50 mol % of ester) as a catalyst. A range of ammonium
salts were screened for the reaction under solvent-free conditions
at room temperature for 1 h and most of them provided moderate
to good yields of the amide (Table 1), with ammonium nitrate
as the best catalyst. In the absence of catalyst, amide formation
did occur, but in low yields (5-7%). A control reaction with
ammonium nitrate without amine also showed that ammonium
nitrate by itself did not give any amide product under the
experimental conditions. Similarly, amidation reaction using
phenylacetic acid instead of the ester derivative also failed to
produce any amide product.
To optimize the reaction, further experiments were carried
out at different ester to amine mole ratios and by varying the
concentration of ammonium nitrate. The reactions were carried
out at room temperature for 1 h, and the yields were determined
by HPLC analysis. We observed that the product yield (based
on ester) increases with amine concentration as expected for a
bimolecular reaction. The yield increases further on addition of
ammonium nitrate up to a certain level and then decreases with
increased ammonium nitrate concentration. At a high concen-
tration of ammonium nitrate, the reaction stops completely
(curve A, Figure 1).
The preparation of an amide bond is one of the fundamental
transformations in medicinal chemistry laboratories and organic
synthesis.1 Generally, starting from esters, a three-step sequence
of hydrolysis, activation, and treatment with an amine is
performed. The direct synthesis of amides from carboxylic acid
esters can be carried out using metal complexes such as
Sb(OEt)3,2 Zr(Ot-Bu)4-HOAt,3 AlMe3,4 NaOMe,5 KOt-Bu,6
DABAL-Me3,7 and MgX2.8 Other catalysts like InI3,9 zinc
dust,10 N-heterocyclic carbine,11 DBU,12 triazabicyclo[4.4.0]dec-
5-ene,13 and 1,2,4-triazole-DBU14 have also been reported. Very
recently, the organo-base-catalyzed amidation of esters with
amino alcohols has been reported.15 However, most of these
systems involve organic solvents and metal catalysts. Herein, we
report a simple, metal-free, and environment-friendly conversion
of esters to amides in the presence of ammonium nitrate under
the solvent-free condition. Aryls, heteroaryls, and aliphatic
esters are converted to the corresponding amides with amines as
well as with amino alcohols in good to excellent isolated yields
(Scheme 1).
The amides of cyclic amines like piperidine, pyrrolidine,
and morpholine exhibit a wide range of biological activities.
For example, piperidine amide derivatives act as enzyme
inhibitors,16 larvicidal agents,17 hepatoprotective agents,18 TRP
agonists,19 etc. Pyrrolidine amide derivatives also have a wide
range of biological activities such as antibacterial activity20 and
cytotoxic activity towards the human cervical carcinoma cell
line HeLa.21 The preparation of such amide derivatives by the
reaction between the amine and the ester can, in principle,
be carried out by a simple heating of the mixture together.
However, this reaction is slow and is accompanied by impurity
formation when the amine is exposed to high temperature for
extended periods. It is interesting to use a biodegradable and
nontoxic catalyst for the reaction.
These observations can be explained as follows. The
ammonium salt provides the proton to protonate the carbonyl
Table 1. Effect of different ammonium salts on amide formationa
Ammonium Salt
(50 mol%)
OCH3
N
HN
+
O
Solvent free, 1h
O
1
2a
3
Entry
Ammonium salt
Yield/%b
1
2
3
4
5
6
7
NH4Cl
62
82
75
73
69
56
5
NH4NO3
NH4SCN
HCOONH4
NH4OAc
(NH4)2CO3
No catalyst
O
O
R''
NH4NO3 (50 mol%)
HN
+
R''
Solvent free, RT or 50 °C
R
N
R
OR'
R'''
R'''
Aliphatic (or)
Aromatic ester
Amine (or)
Amino alcohol
up to 99 % Yield
aReaction conditions: 1 (1.0 mmol), 2a (3.0 mmol), and ammo-
nium salt (50 mol %) at room temperature under solvent-free
Scheme 1. Direct conversion of ester to amide using ammonium
nitrate as catalyst under solvent-free condition.
b
condition for 1 h. Product yield based on HPLC analysis.
© 2015 The Chemical Society of Japan