Sulfated tungstate catalyzed highly accelerated N-formylation

Article abstract of DOI:10.1016/j.tetlet.2012.04.058

Sulfated tungstate catalyzed, green, rapid, and practical method for N-formylation of amines using formic acid under solvent-free conditions is described. This method showed improvements over the reported in terms of yield, reaction time, and chemoselectivity.

Full text of DOI:10.1016/j.tetlet.2012.04.058

Tetrahedron Letters 53 (2012) 3259–3263
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sulfated tungstate catalyzed highly accelerated N-formylation
⇑
Sagar P. Pathare, Ravindra V. Sawant, Krishnacharya G. Akamanchi
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 January 2012
Revised 9 April 2012
Accepted 12 April 2012
Available online 20 April 2012
Sulfated tungstate catalyzed, green, rapid and practical method for N-formylation of amines using formic
acid under solvent-free conditions is described. This method showed improvements over the reported in
terms of yield, reaction time and chemoselectivity.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Heterogeneous catalysis
Sulfated tungstate
Amines
Formic acid
N-formylation
Pursuit of green, catalytic, convenient and practical methods for
organic synthesis and commercial process is of current interest.
Recently we have introduced sulfated tungstate, as solid acid cata-
acid–CDMT,21 formic acid esters22 and mixed anhydrides such as
2
3–25
acetic–formic, p-TSA–formic acids.
in combination, with ammonium formate, sodium formate, and
Formic acid has been used
2
6
27
1
28
lyst and demonstrated its effectiveness in catalysis of amidation,
with polyethylene glycol as solvent. Various catalysts used are
Ritter, Biginelli, Willgerodt-Kindler4 and Strecker5 reactions. Its
easy preparation, mild acidity, stability, reusability and eco-friend-
liness has inspired us to explore its potential to catalyze many
other useful reactions.
2
3
ZnCl
,
29
KF-alumina, sulfated titania, Amberlite IR 120, in-
30
31
32
2
3
3
34
35
dium metal, iodine, and recent additions include ZnO and sul-
36
2
fonic acid supported hydroxyapatite encapsulated c-Fe O3. Since
sulfated tungstate is mild acid, easy to prepare and recyclable, as
already revealed in its other applications, we investigated its po-
tential for catalyzing the N-formylation reaction and the results
are presented in this Letter.
Preliminary investigations were carried out using p-chloroani-
line as model substrate (Scheme 1) to find suitability of sulfated
tungstate as a catalyst and optimize reaction conditions. The re-
sults are given in Table 1.
When a mixture of p-chloroaniline and formic acid (1:1.2 equiv)
and 10 wt % of sulfated tungstate was stirred at rt, the product was
formed after 3 h with 80% yield (Table 1, entry 1). Then the reaction
was attempted at higher tempertures; at 40 °C gave 65% yield of N-
(p-chlorophenyl) formamide in 12 h but the reaction was incom-
plete (Table 1, entry 2). At 55 °C and 70 °C, the reaction got highly
accelarated and complete cosumption of p-chloroaniline was ob-
served in 150 min and 10 min, respectively, giving almost quanti-
tative yield (Table 1, entries 3 and 4). Satisfied with these results,
detail investigations were undertaken to establish catalytic role
Formylation of amines, generally affected by reaction between
amines and formic acid, is one of the most important reactions in
organic and industrial chemicals synthesis. Formamides find wide
applications. They have been used as industrial chemicals, for
example diethylformamide, as important precursors in the synthe-
sis of fungicides and herbicides, intermediates in the synthesis of
pharmaceutically important fluoroquinolones such as norfloxacin,
ciprofloxacin, 1,2-dihydroquinolines,7 oxazolidinones,8 nitrogen-
6
9
bridged heterocycles, and cancer chemotherapeutic agents.
Acetiamine, octotiamine, fursultiamine, and formoterol are some
examples of formamide containing drugs which are in clinical
use. Formamides are Lewis bases and are known to catalyze
reactions, such as, allylation and hydrosilylation of carbonyl com-
1
0,11
pounds.
Furthermore, formamides are very useful reagents in
the classical Vilsmeier formylation reactions and in the synthesis
1
2
13–15
of formamidines and isocyanides.
Formyl group is a useful
amino-protecting group in peptide synthesis.1
6,17
Several methods have been reported for N-formylation of
amines, and these include, use of formylating reagents/systems
such as chloral, formic acid–DCC, formic acid–EDCI, formic
H
NH2
Sulfated tungstate
N
H
1
8
19
20
HCOOH
O
Cl
Cl
⇑
Corresponding author. Tel.: +91 22 33612214; fax: +91 22 24145614.
E-mail address: kgap@rediffmail.com (K.G. Akamanchi).
Scheme 1. N-formylation of p-chloroaniline.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.058

3
260
S. P. Pathare et al. / Tetrahedron Letters 53 (2012) 3259–3263
Table 1
did not show any such limitation and reaction with o-nitroaniline
Results of optimization studiesa
was smooth giving 89% yield, though the reaction was slightly
slower and took 30 min to complete (Table 3, entry 10). It is signif-
icant that even heterocyclic amine, 2-aminothizole, reacted equally
well (Table 3, entry 12). Aliphatic primary amines also underwent
N-formylation with equal ease (Table 3, entries 13–18) and even
b
Entry
Sulfated tungstate (wt%)
Temp (°C)
Time (h) /min
Yield (%)
1
2
3
4
5
6
7
8
10
10
10
10
—
1
5
20
rt
(6)
80
65
98
98
58
97
98
98
40
55
70
70
70
70
70
(12)
150
10
(12)
360
120
10
benzylamine, that was previously reported to provide low yield
28
(
42%) , furnished almost quantitative yield (99%) (Table 3, entry
1
3). In case of N-phenylanilines reaction was conducted with
3 equiv of formic acid, to overcome the difficulty of solidification
during the reaction, which gave very good yields (Table 3, entry
a
Reaction condition: p-chloroaniline (1 g, 7.84 mmol) and formic acid (0.43 g,
2
1). Similarly aliphatic, both acyclic and cyclic, secondary amines
had under gone reaction efficiently giving very good yields (Table
, entries 19, 20, 23, and 24). N-formylation of -amino acids ( -va-
line and -phenylalanine) was examined in the presence of sulfated
tungstate, but reaction did not occur. But the corresponding car-
boxyl group-protected -amino acids reacted smoothly to give
9
.41 mmol).
Isolated yield.
b
3
a
L
L
of sulfated tungstate and to optimize the catalyst amount. A con-
trol experiment was conducted in the absence of sulfated tungstate
at 70 °C and; the reaction was very slow and remained incomplete
even after 12 h giving only 58% yield (Table 1, entry 5), thus clearly
establishing catalytic role of sulfated tungstate. Experiments were
performed at 70 °C in presence of different amouts of the catalyst.
Using lesser amounts than 10 wt %, viz. 1 wt % and 5 wt %, showed
drop in reaction rate but gave 97% and 98% yields in 360 min and
a
the expected products in high yields (Table 3, entries 25 and 26).
In contrast, it is noteworthy that aniline having the carboxyl
substituent, as in p-aminobenzoic acid, underwent this reaction
smoothly (Table 3, entry 6). In case of substrates carrying phenolic
and hydroxyl groups, where there is scope for competitive
O-formylation, still only N-formylated products were isolated
(Table 3, entries 4, 5, and 18) indicating high chemoselectivity.
The work-up procedure is simple; catalyst is filtered off by
diluting the reaction mixture with ethyl acetate, followed by con-
centration of organic layer after giving water washes. The products
obtained in many cases were of high purity and did not require
any further purification. Thus, the protocol developed represents,
an efficient, improved, and convenient methodology for
N-formylation.
1
20 min, repectively (Table 1, entries 6 and 7), and using higher
amount of 20 wt % showed no detrimental effect (Table 1, entry
8
). Therefore an amount of 10 wt % sulfated tungstate and tempert-
3
7
aure of 70 °C was concluded as optimum for further studies.
Reaction was also studied in different solvents, including aceto-
nitrile, tetrahydrofuran, dichloromethane and toluene under reflux
conditions, the reaction rates in general were slow, in all solvents,
and the best results were obtained in toluene giving 95% yield in
6
h.
To assess the prominency of sulfated tungstate among other
Reusability study of the catalyst was performed, by following
standard protocol previously reported by us, and found that the
2
catalysts for the formation of N-(p-chlorophenyl) formamide, com-
parative experimental data were taken from literature and com-
catalyst was stable and reusable four times without any significant
loss of activity with marginal drop in yield from 98% to 93% with
respect to fresh and fourth recycle, respectively (Table 4).
In order to prove that the reaction is heterogeneous, a standard
leaching experiment was conducted by hot filtration method.2
Since the reaction was very rapid at 70 °C, for the study lower tem-
perature of 55 °C was chosen. Two parallel reactions, labeling one
as control, were run for 1 h in the presence of the catalyst. The con-
trol reaction was worked up (yield 62%) and from the second reac-
tion, catalyst was removed by filtration at the reaction temperature
and the filtered reaction mixture was heated without the catalyst
for 2 h and worked up (yield 65%). It was observed that there
was no significant improvement in the yield of N-(p-chlorophenyl)
formamide over the control reaction, indicating no homogeneous
catalyst was involved.
piled in Table 2. Among the other catalysts viz. I
2
, Amberlite IR
1
20, ZnO, silica, silicotungstic acid and sulfated titania, sulfated
tungstate were found to be the most efficient in terms of mole ra-
tio, time and yield (Table 2, entries 1–7).
Encouraged by the remarkable results, and in order to show
generality and scope of this new protocol, we used various struc-
turally diverse primary and secondary amines, including variously
substituted aromatic, heteroaromatic, aliphatic, and
a-amino
acids. In all cases N-formylation reaction was very rapid giving
yields ranging from 84% to almost quantitative depending on
substrates and the results are summarized in Table 3. Aromatic
primary amines, irrespective of bearing electron-donating or elec-
tron-withdrawing functionalities, were found to undergo N-formy-
lation in a facile manner giving very good to excellent yields (Table
Some attempts have been made towards understanding the
mechanism and the studies carried out were as follows. To under-
stand the interaction between reagents and the catalyst, the
3
, entries 1–11). Previously, the N-formylation of ortho- and para-
23
nitroanilines has been reported to be difficult but our protocol
Table 2
a
Comparison of different catalysts for formation of N-(p-chlorophenyl)formamide
Wt %b
Equivalent ratio amine/formic acid
Time (min)/temperature
Yield (%)
c
Ref.
Entry
Catalyst
1
2
3
4
5
6
7
Iodine
Amberlite IR 120
ZnO
7
78
17
20
20
78
10
1:2
1:3
1:3
1:1.2
1:1.2
1:3
240/70 °C
70/Microwave
45/70 °C
180/70 °C
10/70 °C
96
95
94
95
98
98
98
34
32
35
—
—
31
This work
Silica
Silicotungstic acid
Sulfated titania
Sulfated tungstate
160/rt
10/70 °C
1:1.2
a
b
c
Reaction condition: p-chloroaniline (1 g, 7.84 mmol) and formic acid (0.43 g, 9.41 mmol).
For ready comparison converted into wt %.
Isolated yield.

S. P. Pathare et al. / Tetrahedron Letters 53 (2012) 3259–3263
3261
Table 3
Substrate scopea
Entry
1
Amine
Product
Time (min)
10
Yieldb
NH2
H
N
H
O
99
98
O
NH2
H
N
H
2
3
10
10
NH2
H
N
H
98
H CO
O
3
H CO
3
NH2
OH
H
N
H
4
5
6
7
8
9
10
10
10
10
10
10
96
97
90
92
98
98
O
O
O
OH
NH2
H
N
H
HO
O
HO
NH2
H
N
H
HOOC
O
HOOC
NH2
Cl
H
N
H
Cl
NH2
NH2
H
N
H
Cl
Br
O
Cl
Br
H
N
H
O
NH2
NO2
H
N
H
1
0
1
30
10
89
91
NO2
NH2
H
N
H
1
O N
O
2
O N
2
N
S
N
NH2
NH
1
1
2
3
S
10
10
87
99
H
O
NH2
H
H
N
O
NH2
H
H
N
O
1
1
4
5
10
10
98
O
NH2
H
99d
N
H
(
continued on next page)

3
262
S. P. Pathare et al. / Tetrahedron Letters 53 (2012) 3259–3263
Table 3 (continued)
Entry
Amine
Product
Time (min)
10
Yieldb
90
NH2
H
H
N
O
1
6
NH2
H
H
N
1
1
7
8
30
30
89
86
O
NH2
H
H
HO
N
HO
O
H
1
9
NH
N
30
84
O
O
N
H
88c
87
2
0
1
N
30
45
H
H
N
H
O
N
2
NH
N
H
2
2
3
30
30
83
82
O
2
N
N
H
O
O
H
O
O
N
2
2
4
5
30
10
80
N
H
H
COOCH3
NH2
COOCH3
95d
HN
O
H
COOCH3
NH2
COOCH3
2
6
10
89d
HN
O
H
a
b
c
Reaction conditions: amine (1 equiv), formic acid (1.2 equiv) and catalyst (10 wt %) at 70 °C, solvent free.
Isolated yield.
Reaction was performed by passing dimethylamine gas.
d
No racemization was observed, judged by closeness of measured and reported values of specific rotations.38,39
catalyst was suspended in formic acid and stirred for 10 min and
filtered, the catalyst was washed with chloroform and air dried
for 2 h and FT-IR was recorded. The IR spectra showed peaks corre-
sponding to formic acid (1724 cm ) indicating its adsorptions on
the catalyst.
In another experiment the catalyst was suspended in aniline
and stirred for 10 min and filtered, the catalyst was washed with
chloroform and air dried for 2 h and FT-IR was recorded. There
were no peaks corresponding to aniline and only catalyst peaks
were observed, indicating that, aniline was not adsorbed on the
catalyst.
and reaction mixture was filtered, and the catalyst was washed
with chloroform and air dried for 2 h and FT-IR was recorded.
The IR spectrum showed peaks corresponding to amide carbonyl,
NH, phenyl ring of aniline, indicative of formation of amide.
From these above three experiments, the plausible mechanism
of the N-formylation can be proposed as involving activation of for-
mic acid by the catalyst followed by nucleophilic attack of aniline
and subsequent formation of amide.
It is established that sulfated tungstate is a mild, efficient,
chemoselective and recyclable catalyst for N-formylation of a vari-
ety of amines including, primary and secondary aromatic, hetero-
aromatic, aliphatic amines and amino acid esters. It scores high
over the previously known catalysts on many parameters including
À1
A third experiment was performed as follows. Formic acid, ani-
line, and the catalyst were stirred at room temperature for 10 min

S. P. Pathare et al. / Tetrahedron Letters 53 (2012) 3259–3263
3263
Table 4
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1
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1
1
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98
97
97
95
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Third recycle
Fourth recycle
a
Reaction condition: p-chloroaniline (1 g, 7.84 mmol) and formic acid (0.43 g,
.41 mmol) at 70 °C for 10 min.
Loss of catalyst (<5%) during handling.
9
b
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work-up procedures thus scoring high on eco-friendliness.
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Acknowledgment
The authors thank the University Grants Commission of India
for financial support.
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3
7. Preparation of sulfated tungstate: Anhydrous sodium tungstate (32.9 g, 0.1 mol)
was added portionwise, maintaining the temperature between 0 and 5 °C, to a
stirred solution of chlorosulfonic acid (23.2 g, 0.2 mol) in chloroform (150 ml)
contained in a 250 ml round bottom flask fitted with CaCl2 drying tube, placed
in an ice bath. After completion of addition, the mixture was stirred further for
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
1
h. A yellowish-white solid obtained was filtered, washed repeatedly with
deionized water until the filtrate was neutral and free from chloride ions
detected by AgNO test) and dried in an oven for 2 h at 100 °C to get 34 g of
sulfated tungstate.
General procedure for N-formylation reaction: A stirred mixture of amine
1 mmol), formic acid (0.4 g, 1.2 mmol), and sulfated tungstate (10 wt %) was
0
4.058.
(
3
References and notes
(
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2
H O
(
2 Â 10 ml), dried over anhydrous Na
2 4
SO and the solvent was evaporated
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3
3
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