Tetrahedron Letters
A green protocol for the N-formylation of amines using molybdate
sulfuric acid as a reusable solid catalyst
⇑
Bahador Karami , Mahnaz Farahi, Fariba Pam
Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 June 2014
Revised 6 September 2014
Accepted 24 September 2014
Available online 2 October 2014
A novel and efficient method for the N-formylation of amines via the reaction of orthoformates and
amines is developed. The reactions are mediated by a catalytic amount of molybdate sulfuric acid as a
heterogeneous solid acid.
Ó 2014 Published by Elsevier Ltd.
Keywords:
N-formylation
Orthoformate
Amine
Molybdate sulfuric acid
A useful reaction in organic chemistry is the N-formylation of
amines to give formamide derivatives. Formamides have been
tive to sulfuric acid and has been used in some organic
reactions.
1
13,14
used as intermediates for the synthesis of many pharmaceutical
In continuation of our interest in using heterogeneous solid cat-
2
15–17
compounds such as fluoroquinolones, substituted aryl imida-
alysts,
herein an efficient method is reported for the N-formy-
zoles, 1,2-dihydroquinolines,4 and nitrogen-bridged heterocy-
3
lation of amines by the reaction of orthoformates 1 and amines 2
using molybdate sulfuric acid (MSA) as a reusable solid Brönsted
acid (Scheme 1).
5
cles. Moreover, the formyl group can be used as an amino-
protecting group for the synthesis of peptides and N-formylamino
acid esters, which can be applied as starting materials in peptide
synthesis.
Initially, the solvent-free reaction between triethyl orthofor-
mate (1.1 mmol) and aniline (1 mmol) was performed at room
temperature in the absence of a catalyst as a model reaction. No
N-formylation of the amine occurred, even after 24 h. Next, the
model reaction was investigated in the presence of different cata-
lysts under various conditions (Table 1).
6
Many strategies have been developed for the preparation of N-
formyl amines. They can be obtained from reactions of the corre-
7
sponding amines with formic acid and acetic anhydride, in situ
8
9
formed formic anhydride, chloral followed by elimination,
1
0
11
ammonium formate, and other reagents. However, many of
these methods suffer from drawbacks such as the use of expensive
and toxic formylating agents, formation of by-products, difficult
accessibility of the formylating agents, etc. Hence, new, safe, and
efficient synthetic methods are of practical value for the prepara-
tion of N-formyl amines.
According to Table 1, the best result was obtained by perform-
ing the model reaction using 2 mol % of molybdate sulfuric acid
(MSA) in refluxing ethanol (Table 1, entry 10). The superiority of
this solid acid as an analog of sulfuric acid compared with liquid
sulfuric acid is attributed to the surface hydrophilic porosity,
higher capacity, and large surface area of MSA.
With the advance of green chemistry, heterogeneous solid acids
have been used in various organic transformations as eco- and
environmentally friendly catalysts. These solid acids have many
benefits such as recyclability and non-toxicity, cleaner and easier
work-up procedures, and reduced reaction times.12 Molybdate sul-
furic acid (MSA) is an inexpensive and easily handled solid alterna-
Next, the generality of the procedure was evaluated using the
reactions of various primary and secondary amines under the opti-
mized reaction conditions. In most cases, the reactions proceeded
MSA (2 mol%)
EtOH, reflux
HC(OR)3 HNRR"
'
'
"
HCONRR
3
1
2
⇑
Scheme 1. N-Formylation of amines in the presence of molybdate sulfuric acid
(MSA).
040-4039/Ó 2014 Published by Elsevier Ltd.
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