Melamine trisulfonic acid-catalyzed N-formylation of amines under solvent-free conditions

Article abstract of DOI:10.1007/s11164-012-0803-7

A highly convenient method for N-formylation of amines via treatment by formic acid in the presence of melamine trisulfonic acid as a catalyst has been developed. This method showed improvements over previous reports in terms of yield, reaction time and chemoselectivity.

Full text of DOI:10.1007/s11164-012-0803-7

Res Chem Intermed (2013) 39:2843–2848
DOI 10.1007/s11164-012-0803-7
Melamine trisulfonic acid-catalyzed N-formylation
of amines under solvent-free conditions
•
Xiao Juan Yang Yong Sen Zhang
Received: 3 July 2012 / Accepted: 31 August 2012 / Published online: 15 September 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A highly convenient method for N-formylation of amines via treatment
by formic acid in the presence of melamine trisulfonic acid as a catalyst has been
developed. This method showed improvements over previous reports in terms of
yield, reaction time and chemoselectivity.
Keywords N-formylation Á Melamine trisulfonic acid Á Formamides Á Solvent-free
Introduction
The formyl group is an important amino protecting group in peptide synthesis [1].
Formamides are important intermediates in organic synthesis that have been used in
the synthesis of biological active compounds, for example, fluoroquinolones [2],
substituted imidazoles [3], 1,2-dihydroquinolines [4], and nitrogen-bridged hetero-
cycles[5]. They are also widely used as precursors for the preparation of isocyanates
[6], formamidines [7], and nitriles [8]. The most common methods for the synthesis
of formamides are the reaction of amines with formic acid, in the presence of a
2-
catalyst, such as TiO2-P25 [9], TiO2–SO4
[10], nano-MgO [11], Amberlite
IR-120 [12], I2 [13], VB1 [14], In [15], sulfonic acid supported on hydroxyapatite-
encapsulated-c-Fe2O3 nanocrystallites [16], ZnCl2 [17], NiO2 [18], polyethylene
glycol [19], and ZnO2 [20]. These methods are suitable for certain synthetic
conditions; however, many of these procedures are associated with one or more
disadvantages such as expensive reagents, longer reaction times, tedious work-up
X. J. Yang (&)
College of Chemistry and Chemical Engineering, Xinxiang University, Xinxiang 453003,
Henan, China
e-mail: yangxiaojuan2005@126.com
Y. S. Zhang
The Third Affiliated Hospital, Xinxiang Medical University, Xinxiang 45300, Henan, China
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X. J. Yang, Y. S. Zhang
procedure, low selectivity, and large amounts of catalysts which would eventually
result in the generation of large amounts of toxic waste.
Recently, melamine trisulfonic acid (MTSA) has emerged as a promising solid
acid catalyst for acid-catalyzed reactions, such as synthesis of b-acetamido ketones
[21], oxathioacetalyzation of aldehydes [22], nitrosation of secondary amines, and
oxidation of urazoles [23]. This catalyst is safe, easy to handle, and environmentally
benign, and presents fewer disposal problems. MTSA as a solid acid catalyst is
prepared from the reaction of melamine with neat chlorosulfonic acid at room
temperature (Scheme 1).
In this paper, we present a novel, mild, and efficient method for the
N-formylation of amines using amines and formic acid in the presence of MTSA
as a catalyst (Scheme 2).
Results and discussion
Initially, when the reaction of aniline (1 mmol) and formic acid (2 mmol) with a
catalytic amount of MTSA (0.03 mmol) was heated at 60 °C under solvent-free
conditions as a simple model substrate, the reaction proceeded rapidly to give the
corresponding N-phenylformamide in high yield after a relatively short reaction
time.
To clarify the generality of this reaction, several amine derivatives were treated
with formic acid under solvent-free conditions to afford the corresponding
formamides 3. The results are shown in Table 1. All known compounds were
characterized by comparison of their physical and spectroscopic data with authentic
samples. We found that anilines containing electron-donating substituents such as
–CH3, –OCH3, and –OH (entries 2–6) and electron-withdrawing groups such as
–NO2 and halides (entries 7–11) did not affect the reaction time and yields.
Aliphatic and secondary cyclic amines are also giving moderate yields of the
product (entries 13–18).
The general reaction mechanism involves nucleophilic attack of amines on the
protonation of the carbonyl group of formic acid, which leads to the formation of
intermediates 4, which is transformed into the desired formylated product, water,
and proton, which further catalyzes the reaction (Scheme 3).
To illustrate the efficiency of the proposed method, Table 2 compares some of
our results with some of those reported in the literature for relevant reagents, which
demonstrates its significant superiority. Compared with some of the reported
methods in Table 2, the present method has a short reaction time, good yield, and
NH2
N
NHSO3H
N
neat
r.t.
N
N
ClSO3H (3eq.)
+ 3HCl
+
H2N
N
NH2
HO3SHN
N
NHSO3H
Scheme 1 Synthesis of MTSA
123

Melamine trisulfonic acid-catalyzed N-formylation of amines
2845
R1
R2
Scheme 2 N-formylation of
amines using amines and formic
acid in the presence of MTSA
R1
MTSA
NCHO
+ HCOOH
NH
neat, 60°C
R2
1
2
3
solvent-free conditions. In addition, MTSA is a stable, cost effective, recyclable,
and noncorrosive catalyst with high efficiency.
Conclusion
We have developed a simple, mild, and environmentally benign method for
N-formylation of amines with formic acid catalyzed by MTSA at 60 °C. This
method offers the advantage of shorter reaction times, high chemoselectivity, and
easy workup. We believe that this methodology could be an important addition to
the existing methodologies.
Experimental
NMR spectra were determined on Bruker AV-400 instrument at room temperature
using tetramethylsilane as internal standard. Coupling constants (J) were measured
in Hz; infrared (IR) spectra were determined on FTS-40 infrared spectrometer. Mass
spectra were taken on a Macro mass spectrometer (Waters) by electrospray method.
Commercially available reagents were used throughout without further purification
unless otherwise stated.
Preparation of MTSA catalyst
A 250-mL suction flask charged with 5 mL chlorosulfonic acid (75.2 mmol) was
equipped with a gas inlet tube for conducting HCl gas over an adsorbing solution.
Melamine (3.16 g, 25.07 mmol) was added in small portions over a period of
30 min at room temperature. HCl gas evolved from the reaction vessel immediately
(Scheme 1). After completion of the addition of melamine, the mixture was
shaken for 30 min; meanwhile, the residual HCl was removed by suction. MTSA
(7.7 g, 85 %) was obtained as a white solid.
General procedure for the preparation of 3
A mixture of amines (1 mmol), formic acid (2 mmol), and MTSA (0.03 mmol) was
prepared and stirred at 60 °C for appropriate time (Table 1). After completion of the
reaction (TLC), the mixture was diluted with CH2Cl2 (20 mL), washed with H2O
(10 mL), and then dried over anhydrous MgSO4. After filtration and evaporation of
the solvent, the residue was purified by column chromatography on silica gel to give
the formylated product. All the compounds are known and their physical properties
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X. J. Yang, Y. S. Zhang
Table 1 Synthesis of formamides catalyzed by MTSA
Entry
1
Amines
Products
Time (min)
60
Yield (%)b
98
NHCHO
NH2
3a
3b
NHCHO
NHCHO
NH2
2
3
45
45
96
94
NH2
3c
NH2
NHCHO
NHCHO
4
60
97
H3CO
HO
H3CO
HO
3d
3e
NH2
5
6
40
40
96
93
OH
Cl
OH
NHCHO
NHCHO
NH2
NH2
3f
Cl
7
75
92
3g
NHCHO
NHCHO
NHCHO
NH2
8
60
75
90
90
93
94
90
89
Cl
Cl
3h
3i
NH2
9
Br
Br
O2N
O2N
NH2
NH2
10
11
3j
NHCHO
O2N
O2N
3k
3l
N
NHCHO
N
NH2
12
13
14
90
90
75
91
91
93
NHCHO
NH2
NH2
3m
3n
NHCHO
NHCHO
NH2
15
16
90
90
90
89
3o
NCHO
NH
3p
NCHO
NCHO
NH
NH
17
18
75
75
90
89
3q
3r
O
O
Reaction conditions: amines (1 mmol), formic acid (2 mmol), MTSA (0.03 mmol), neat, 60 °C
a
Isolated yield
123

Melamine trisulfonic acid-catalyzed N-formylation of amines
2847
OH2
OH
R1
R2
H+
OH
-H2O
-H+
O
H
N
NCHO
H
H
OH
R1
R2
H
OH
N
R1 R2
4
3
Scheme 3 The general reaction mechanism
Table 2 Comparison of different catalysts for formation of N-phenylformamide
Entry
Catalyst (mol%)
Equivalent ratio
amine:formic acid
Temperature
(°C)
Time
(min)
Yield
(%)a
References
1
2
3
4
5
a
I2 (5)
1:2
70
120
120
1
94
97
98
96
98
[13]
In (10)
1:3
70
[15]
Nano-MgO (25)
ZnCl2 (100)
MTSA (3)
1:1.5
1:3
MW
70
[11]
60
[17]
1:2
60
60
This study
Isolated yield
1
are the same as the reported values. H NMR, IR, and mass spectral data of all the
products match the reported data.
Acknowledgment We are pleased to acknowledge the financial support from Xinxiang University.
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