Nano rod-shaped and reusable basic Al2O3 catalyst for N-formylation of amines under solvent-free conditions: A novel, practical and convenient 'NOSE' approach

Article abstract of DOI:10.1039/c2gc16020j

An expeditious, simple, highly efficient, practical and green protocol for the N-formylation of alkyl/aryl amines and indole derivatives catalyzed by novel nano rod-shaped basic Al₂O₃ under solvent-free conditions has been developed. The catalyst is efficiently recycled up to the 5th run, an important point in the domain of green chemistry. The methodology provides cleaner conversion, shorter reaction times and high selectivity which makes the protocol attractive. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2gc16020j

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PAPER
Nano rod-shaped and reusable basic Al2O3 catalyst for N-formylation of
amines under solvent-free conditions: A novel, practical and convenient
‘NOSE’ approach†
Vijay Kumar Das,a Rashmi Rekha Devi,b Prasanta Kumar Raulb and Ashim Jyoti Thakur*a
Received 18th August 2011, Accepted 16th December 2011
DOI: 10.1039/c2gc16020j
An expeditious, simple, highly efficient, practical and green protocol for the N-formylation of alkyl/aryl
amines and indole derivatives catalyzed by novel nano rod-shaped basic Al2O3 under solvent-free
conditions has been developed. The catalyst is efficiently recycled up to the 5th run, an important point in
the domain of green chemistry. The methodology provides cleaner conversion, shorter reaction times and
high selectivity which makes the protocol attractive.
reaction conditions, formation of undesirable by-products, low
yields, while also leading to diformylation and/or lack of regio-
Introduction
In the wake of increasing awareness in environmentally benign
techniques during the past few years, organic synthesis under
solvent-free conditions has gained much popularity.1 In this
regard, the synthesis of N-bonded compounds has received con-
siderable attention from the sight of green chemistry.2 There is a
growing appreciation for N-formylation of primary or secondary
amines into formamides which is a common methodology in
synthetic organic chemistry. The reaction product, formamides
serve either as a polar solvent or as an important intermediate in
several organic transformations since their skeletons exist in
pharmaceutically valuable compounds such as fluoroquinolines,3
imidazoles,4 1,2-dihydro quinolines,5 nitrogen-bridged hetero-
cycles,6 oxazolidinones7 and cancer chemotherapeutic agents.8
They have also found significant applications as Lewis base cata-
lysts in various organic transformations,9–14 synthesis of forma-
midines,15 isocyanides16 and as N-formylating agents in histone
proteins as a secondary modification arising from oxidative
DNA damage.17
selectivity and tedious work up. Therefore, the synthesis of
formamides still remains an active research area in terms of oper-
ational simplicity and economic viability. In the recent years,
formic acid29–33 has been continually accepted as a potent for-
mylating agent owing to its lower toxicity, inexpensivity and
easy practical applicability.
With the nanotechnology now available to the scientists, of
late, Somorjai et al. emphasizes that catalysis by transition metal
nanoparticles is the central field of nanoscience and nanotechnol-
ogy,34 which are the frontiers between homogeneous and hetero-
geneous catalysis.35 The growing interest on the catalytic
properties of transition metal nanoparticles is due to their large
surface area, distinct electronic, optical, magnetic, thermal and
chemical properties.36 The ultimate goal to work with nanoparti-
cles is their high catalytic activity, recoverability, improved selec-
tivity, criteria of evolution and role in green chemistry.37 Hence,
organic synthesis catalyzed by metal/metal oxide nanoparticles38
has received tremendous importance in recent decades.
To cater the burgeoning needs and aspirations, we have been
focussing on the development of a protocol named ‘NOSE’39
(nanoparticles-catalyzed organic synthesis enhancement) chem-
istry in our laboratory. Nanoscale supports to create catalysts
with larger surface areas along with more edges and corners,
which can lead to higher performance of the catalyst. Other par-
ameters (e.g. oxygen mobility, etc.) might also play key role for
enhancing catalytic activity. There are few reports that describe
N-formylation of amines using nanoparticles. Preedasuriyachai
and co-workers40 have presented nanogold catalyzed N-formyla-
tion of amines under aerobic conditions with MeOH or formalin.
However, in terms of disadvantage, nanogold itself is very
expensive. To the best of our knowledge, N-formylation of
amine catalyzed by basic nano crystalline Al2O3 has not been
reported. Very recently, a research group has reported the nano-
crystalline Al2O3 catalyzed one-pot synthesis of poly-substituted
The literature is enumerated with several strategies18–28 pre-
scribed for N-formylation of amines. Regardless of the existing
methodologies, most of them suffer from different drawbacks
such as thermal instability, sensitivity to moisture, application of
toxic and expensive formylating agents and catalysts, poor atom
economy, high temperatures, prolonged reaction times, harsh
aDepartment of Chemical Sciences, Tezpur University, Napaam,
784028, India. E-mail: ashim@tezu.ernet.in; Fax: +91(3712)267005/6;
Tel: +91(3712)267008 ext. 5059
bDefence Research Laboratory, Post Bag No. 2, Tezpur, 784001, India.
Fax: +91(3712)258534; Tel: +91(3712)258508
†Electronic supplementary information (ESI) available: General exper-
imental methods, characterisation of the catalyst, general synthetic pro-
cedure, recycling potential of the nano alumina rods, physical and
spectroscopic data of compounds, 1H NMR and 13C NMR spectra of
compounds, reference. See DOI: 10.1039/c2gc16020j
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 847–854 | 847

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quinolines.41 There is an extensive study on the preparation and
properties of Al2O3 nanomaterial.42 The advantages43 of using
basic nano-Al2O3 is in terms of its crystalline size and shape,
abrasive and insulating properties, lower toxicity, large surface
area and their basic surface characteristics, high resistance
towards acids and bases, compatibility with very high tempera-
ture applications and has excellent wear resistance. Therefore, in
this paper, we wish to focus on an effective, convenient and
practical procedure employing nano rod-shaped basic Al2O3
(specific surface area approximately 185.63 m2 g−1 and a crystal-
line size of approximately 38 nm) to catalyze N-formylation of
1° and 2° amines efficiently as a part of our ‘NOSE’ chemistry
(Scheme 1) programme.
Fig. 1 SEM image of pure nano-Al2O3.
Results and discussion
The SEM image of a pure nano-Al2O3 sample has shown
agglomeration of particles (Fig. 1). The BET surface area of
nano-Al2O3 was found to be 185.6 m2 g−1 and the total pore
volume was 0.9777 mL g−1
.
EDX analyses of pure nano-Al2O3 (Fig. 2) showed that the
weight% of O and Al was 70.41 and 29.59 and atomic% was
80.05 and 19.95 respectively, as expected. Since the ratio of O to
Al in the sample is 2 : 3, thus, it is obvious that the percentage of
O is higher with respect to Al. Thus, the EDX suggests the pres-
ence of only O and Al in the nano-Al2O3 sample.
The XRD pattern of pure nano- Al2O3 (Fig. 3) shows that the
peak of the sample corresponds to those of γ-alumina.44
The crystalline sizes were determined by using Scherrer
equation and choosing the two highest peaks (400) and (100)
from the XRD pattern. The crystalline sizes were found to lie
between 39.7 and 37.4 nm. The average particle diameter calcu-
lated was 8.12 nm (SBET = 185.63 m2 g−1 and ρ = 3.98 g cm−3).
Fig. 4(a) and (b) show the TEM images of nano-Al2O3. The
nano rod-shape of the sample can be seen from these micro-
graphs. The average length of the nano-Al2O3 from TEM image
was found to be 25.5 nm and its average diameter was 7.18 nm.
It can also be seen that some agglomeration was present and this
was attributed to the large surface area of these nano rod-shaped
Al2O3.
Fig. 2 EDX of pure nano-Al2O3.
Typical SAED pattern of the Al2O3 nano rod was generated
and is shown in Fig. 5. It showed that the nano rods were well-
crystallined. The SAED patterns were calculated and identified
using JCPDS data card 10-425, indicating that these rings corre-
sponded to the diffraction planes of γ-Al2O3. No un-assigned
rings were left in the SAED patterns, eliminating the possibility
of formation of other types of metastable phases like δ-Al2O3,
θ-Al2O3, etc.
Fig. 3 XRD pattern of pure nano-Al2O3.
vapour. An absorption band at ca. 1620 cm−1 is characteristic of
alumina which is in accordance with the literature.45 The peak at
1040 cm−1 corresponds to the Al–O stretching vibration.46
After the characterisation of the nano-Al2O3, in order to opti-
mize the reaction conditions, a control experiment30 was carried
out by taking formic acid (98%, 0.11 mL, 3 mmol) and aniline
(0.09 mL, 1 mmol) as a model substrate by stirring at room
temperature without using any catalyst and solvent (Table 1,
entry 1). Under these conditions the reaction did not proceed and
starting materials remained intact. Then we poured acetonitrile
(5 mL) and continued stirring for 18 h and isolated the product
The FTIR spectrum of pure nano-Al2O3 is shown in Fig. 6.
The peak at 3500 cm−1 is attributed to the atmospheric water
Scheme 1 N-Formylation of amines.
848 | Green Chem., 2012, 14, 847–854
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under solvent-free conditions providing 28% yield (Table 1,
entry 4). We also conducted the reaction at 70 °C under solvent-
free conditions and isolated 42% yield (Table 1, entry 5). Un-
satisfied with these results, we felt the necessity of using a catalyst
to increase the yield. Therefore, we surveyed some Lewis acid
and base catalysts and out of them, we found a dramatic increase
in reaction rate and yield when we used nano basic Al2O3 (5 mol
%) at 40° C (Table 1, entry 15). We also attempted to compare
the catalytic action of bulk basic and acidic Al2O3 with nano
basic Al2O3 for the N-formylation of aniline, and we found
excellent yields associated with lesser reaction times and low cat-
alyst loadings in the case of nano-Al2O3 catalysis. We also tested
the influence of solvents on the reaction rate and yield by screen-
ing several solvents at 40 °C in the presence of Al2O3 nanoparti-
cles and found that formamide formation took place faster under
solvent-free conditions than in the presence of a solvent
(Table 1, entries 17–24). The turn over number (TON) was also
calculated for each catalyst under different conditions (Table 1)
and it is shown graphically in Fig. 7. From this graph, it can be
seen that the TON is the highest when nano-Al2O3 was used
under solvent-free conditions at 40 °C. Table 1 also displays the
turn over frequency (TOF) which was also at a maximum in the
case of nano rod-shaped Al2O3 being used as the catalyst under
solvent-free conditions at 40 °C. These comparative studies led
us to undertake the reaction under solvent-free conditions
because the reaction was sluggish and provided poor yields in
the presence of a solvent. The reactions were found to be mildly
exothermic which required initial cooling using an ice bath
while formic acid was added to the reaction mixture containing
alkyl/aryl amine and Al2O3 nano rods. Subsequently, the reaction
was allowed to come to ambient temperature.
Fig. 4 (a) TEM image of nano rod-shaped Al2O3 at 50 nm scale (b)
TEM image of nano rod-shaped Al2O3 at 20 nm scale.
Triggered by these interesting results, we proceeded to repeat
the model reaction with different quantities of formic acid and
catalyst loading. As indicated in Table 2, by increasing the quan-
tity of formic acid from 1.0 to 3.0 equiv. and increasing the cata-
lyst loading from 1 mol% to 5 mol%, the yield was clearly
improved along with the reduction of the reaction time. Further
increasing of the catalyst loading to 15 mol% and decreasing the
quantity of formic acid to 1.0 equiv. led to lower yields.
Fig. 5 Corresponding size distribution with inset showing SAED
patterns of nano-Al2O3.
Realising this enhancement of the N-formylation reaction by
nano-Al2O3, our ‘NOSE’ chemistry approach was extended to
other nanocatalysts considering the same model reaction. All
these nanocatalysts were purchased from Sigma Aldrich and
were used without further purification. The results are summar-
ised in Table 3. From Table 3, it is evident that when using a cat-
alyst loading of 5 mol%, only the basic Al2O3 nano rods showed
better catalytic performance at 40 °C (Table 3, entry 7). But, the
other mentioned nanocatalysts provided comparatively poorer
yields either at 40 °C or at 70 °C (Table 3, entries 1–6).
With these convenient experimental reaction conditions in
hand, we next assessed the generality for various aromatic and
aliphatic 1° and 2° amines under the standardized conditions and
the results are summarized in Table 4. Nano-Al2O3 is found to
be highly effective in formylating both electron-rich and elec-
tron-poor anilines in excellent yields (Table 4, entries 1–10).
Hosseini-Sarvari et al.28 recently reported that ZnO catalyzed the
Fig. 6 FTIR spectrum of nano-Al2O3.
in 5% yield (Table 1, entry 2). In order to improve the yield, we
searched for the best experimental conditions below 70 °C. By
keeping this in mind, we performed the reactions at 40° C in
acetonitrile and also by stirring under solvent-free conditions
(Table 1, entry 3). Interestingly, the reaction proceeded faster
N-formylation of p-nitro aniline providing 77% yield. However,
32
the procedure of Choi and co-workers
failed to give the
product when p-nitro aniline was treated with formic acid in
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Table 1 Optimization of the reaction conditionsa for the N-formylation of aniline
Entry
Catalyst
Solvent
Temp. (°C)
Time (h)
Yield (%)b
TON
TOF (h−1
)
1
2
3
4
None
None
None
None
None
H3BO3
Imidazole
Et3N
None
MeCN
MeCN
None
None
None
None
None
None
None
None
None
None
None
None
None
MeCN
THF
rt
rt
9
NRc
5%
12
28
42
0
0
0
0
0
15.6
0
0
20
0
0
0
0
0
0
1.95
0
0
2
18
15
10
7
8
9
9
10
9
7
7
40
40
70
40
40
40
40
40
40
40
40
40
40
70
40
40
40
40
40
40
40
40
5
6d
39
7d
NRc
NRc
50
8e
9d
PPh3
Pyridine
TiO2
10e
11d
12d
13e
14d
15fg
16fg
17fg
18fg
19fg
20fg
21fg
22fg
23fg
24fg
NRc
5
0
2
0.285
3.65
2.08
7
944.57
60
2.5
2.57
13.6
12
19.46
7.73
0
Bulk basic Al2O3
Bulk basic Al2O3
Bulk acidic Al2O3
Nano basic Al2O3
Nano basic Al2O3
Nano basic Al2O3
Nano basic Al2O3
Nano basic Al2O3
Nano basic Al2O3
Nano basic Al2O3
Nano basic Al2O3
Nano basic Al2O3
Nano basic Al2O3
64
78
35
<98
75
25
29
68
60
25.6
6.24
14
78.4
60
20
23.2
54.4
48
58.4
46.4
0
3
7
0.083
1
8
9
4
4
3
6
6
MeOH
EtOH
DMF
Toluene
DMSO
H2O
73
58
NRc
NRc
6
0
0
a Aniline (0.09 mL, 1 mmol), formic acid (0.11 mL, 3 mmol), solvent-free or solvent (5 mL), aerobic conditions. b Isolated yields. c No reaction was
observed. d 10 mol% catalyst was used. e 50 mol% catalyst was used. f 5 mol% catalyst was used. g Particle size (37.4–39.7 nm).
Table 2 Optimization of catalyst loading and amount of formic acida
Formic acid
(equiv.)
Catalyst
loading (mol%) Time (min)
Yield
(%)b
Entry
1
2
2
3
4
5
5
6
1.0
1.0
1.0
1.0
1.0
2.0
3.0
3.0
1
3
5
10
15
5
5
10
50
30
30
80
130
20
5
60
78
80
70
61
85
<98
80
10
a Reaction was performed at 40 °C under solvent-free and aerobic
conditions using nano basic Al2O3, b Isolated yield.
Fig. 7 TON of several catalysts from Table 1.
Table 3 Optimization with nanocatalysts
Temp.
(°C)
Time
(min)
Yield
(%)b
Entry
Nanocatalysta
1
2
3
4
5
α-Fe2O3 (19 nm)
γ-Fe2O3 (8 nm)
Fe2O3 (12 nm)
Fe3O4 (<50 nm)
FeO(OH)
40, 70
40, 70
40, 70
40, 70
40, 70
180
100
90
60
80
44, 60
50, 35
40, 60
70, 55
74, 36
Scheme 2 N-Formylation of aniline (model reaction).
toluene with a Dean–Stark trap. But, in our protocol using Al2O3
nano rods, the yield is comparatively enhanced (Table 4, entry
6). Phenyl hydrazine also reacted efficiently to afford the product
(Table 4, entry 11). The reaction of p-phenylene diamine pro-
ceeded with a slower rate, producing the expected N-formylation
product in 85% (Table 4, entry 12). But when o-phenylene
diamine was reacted, it underwent cyclization to give benzimida-
zole47 as the product (Table 4, entry 13). The formylation of
diphenyl amine proceeded with a faster rate yielding 97%
(Table 4, entry 14) of the product. The N-formylation of amino
acid derivatives was readily achieved using our protocol in very
(20–40 nm)
6
6
7
TiO2 (<80 nm)
MgO (<50 nm)
Nano basic Al2O3
(37.4–39.7 nm)
40, 70
40, 70
40, 70
300
60
5,60
trace
77, 68
>98,
75
a 5 mol% of catalyst was used. b Isolated yield.
high yields (Table 4, entries 15–16), which was not found in
the previous report.48 In the course of our studies, the transform-
ation of benzamide and acryl amide into the corresponding
850 | Green Chem., 2012, 14, 847–854
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Table 4 Nano rod-shaped Al2O3 catalyzed N-formylation of 1° and 2°
amines
Table 5 Nano-Al2O3 catalyzed N-formylation of indole and its
derivativesa
Entry
Amine 1
Time (min)
Yield (%)a,b
Entry
Substrate
Time (min)
Yield (%)b,c
1
2
3
4
5
6
7
8
C6H5NH2
5
<98
93
90
90
93
90
95
92
90
92
90
85
85
97
98
98
93
85
95
95
63
98
43
NRe
1
2
3
4
5
6
7
Indole
10
45
45
30
60
160
200
98
92
90
90
90
75
68
4-ClC6H4NH2
2-ClC6H4NH2
2-NO2C6H4NH2
3-NO2C6H4NH2
4-NO2C6H4NH2
4-MeOC6H4NH2
2-MeC6H4NH2
4-HOC6H4NH2
4-COOHC6H4NH2
C6H5NHNH2
4-NH2C6H4NH2
2-NH2C6H4NH2
(C6H5)2NH
NH2CH2COOH
CH3CH(Me)CH(NH2)COOH
C6H5CH2NH2
Imidazole
Piperazine
NH2(CH2)2NH2
Pyrrolidine
10
10
15
10
10
20
15
25
30
45
260
300
12
30
30
30
90
50
15
55
10
240
2-Methyl indole
3-Methyl indole
6-Bromo indole
Indol-3-acetonitrile
Indol-3-acetic acid
Indol-3-butyric acid
a Reaction conditions: 1 mmol indole, 3 mmol formic acid, 70 °C,
b Yields refer to the isolated pure products. c Products were characterised
by IR and NMR (1H and 13C) spectroscopy, MS and melting points.
9
10
11
12c
13c,d
14
15
16
17
18
19c
20c
21
22
23
24
25
26
27
28
29
with no side product(s) formation. Notably, a previous report of
N-formylation using KF–Al2O3,49 is associated with some disad-
vantages, such as, (a) the system worked only for 2° amines and
not for the 1° amines, (b) highly carcinogenic, chloroform was
used, (c) KF–Al2O3 system was not recyclable, which is a set
back from the aspect of economy and green chemistry. Similarly,
Al2O3 supported formic acid50 system also (a) took longer reac-
tion time, (b) provided poor yield, and (c) loading of alumina as
a support was quite higher.
In order to broaden the scope of using nano basic Al2O3 for
N-formylation reactions, we next attempted the reaction using
indole as a starting material. In this case, we could not obtain the
expected product in good yield at 40 °C. Of particular signifi-
cance, is that by raising temperature to 70 °C, the N-formylation
product was obtained in excellent yield (Table 5, entry 1). There-
fore, taking this to be the standard reaction conditions for
indoles, the generality of the reaction was investigated for
several indole derivatives and the results are presented in
Table 5.
CH3NH2
(CH3CHCH3)2NH
C6H5OH
C6H5CH2OH
C6H5CHNOH
C6H5CHNNH2
OHNH2·HCl
NRe
f
300
300
f
NRe
NRe
H2NNH2
a Yields refer to the isolated pure products, b Products were characterised
by IR and NMR (1H and 13C) spectroscopy, MS and also by comparing
their melting points/boiling points with the authentic ones, c 6 mmol
formic acid was used. d Benzimidazole was formed. e No reaction.
f Mixture of unknown compounds.
N-formylation products was also investigated. Both furnished
slightly lower yields (70% in 3 and 4 h respectively). It might be
due to the withdrawing of lone pair of electrons over N atom
towards the carbonyl group making the N atom electron deficient
for the nucleophilic attack. The reaction of benzyl amine and
imidazole under the present reaction conditions also furnished
N-formylation products in satisfactory yields (Table 4, entries 17
and 18). For aliphatic 1° and 2° amines, and diamines, the reac-
tion showed good results towards the formation of N-formylation
products under the present methodology (Table 4, entries
19–22). The N-formylation of sterically hindered diisopropyl
amine could generate only 43% yield of the product even after
conducting the reaction for 6 h (Table 4, entry 23). In an attempt
to transform phenol, benzyl alcohol, benzaldoxime, benzal-
dehyde hydrazone, hydroxyl amine and hydrazine hydrate into
corresponding N-formylation products, reactions were performed
under our conditions, however, the reactions failed even after
stirring for 24 h, where only starting material was recovered
(Table 4, entries 24–29). The transformation of anilines carrying
different electron-withdrawing and electron-donating moieties
into the corresponding N-formylation products proceeded
smoothly under the present reaction conditions, which demon-
strated the compatibility of those moieties towards the reaction
conditions. As a whole, the aryl and alkyl amines were converted
into the desired formamides with high purities and yields and
We were pleased to find that indoles substituted with electron-
donating groups at 2- and 3-positions underwent the N-formyla-
tion reaction effectively akin to indole, giving the desired pro-
ducts in good to high yields (Table 5, entries 2 and 3). 6-Bromo
indole, having an electron-withdrawing moiety also provided a
high yield under the present reaction conditions (Table 5, entry
4). Indole-3-acetonitrile also produced the N-formylation product
in high yield (Table 5, entry 5). Indole-3-acetic acid and indole-
3-butyric acid were also transformed into the corresponding
N-formylation products with somewhat lower yields (Table 5,
entries 6 and 7). It might be due to the steric crowding at the
3-position.
After gaining such versatile applications of nano basic Al2O3,
we were curious to see what would happen if we replaced formic
acid by acetic acid under the standard conditions (Scheme 3).
With this notion in mind, we checked the reaction with aniline
(10.7526 mmol, 1000 mg) and glacial acetic acid
(10.7526 mmol, 0.61 mL) in the presence of nano-Al2O3
(5.0 mol%, 54.8 mg) and we observed the formation of aceta-
mide with high yields, without any side product (Table 6, entry
1). The experimental conditions and details are described in
Table 6.
In our studies, we found that both the aryl and alkyl amines
underwent reaction with acetic acid in the presence of nano-
Al2O3, forming acetamide derivatives efficiently. It is found that
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Scheme 3 Synthesis of acetamide derivatives.
Table 6 Nano-Al2O3 catalyzed synthesis of acetamidea
Entry
R
Time (min)
Yield (%)bc
1
2
3
4
5
6
7
8
C6H5
10
18
20
15
15
35
20
15
45
30
10
25
260
360
99
90
90
90
85
70
95
92
80
88
93
98
4-ClC6H4
2-ClC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-MeOC6H4
2-MeC6H4
4-HOC6H4
4-COOHC6H4
C6H5CH2
CH3
9
10
11
12
13d
14d
Fig. 8 Comparison of XRD of (a) fresh nano-Al2O3 and (b) the recov-
ered one after 5th cycle.
4-NH2C6H4
2-NH2C6H4
Trace
85e
a Reaction condition: 1 mmol aryl/alkyl amines, 1 mmol acetic acid,
5 mol% nano basic Al2O3, 70 °C. b Yields refer to the isolated pure
products. c Products were characterised by IR, NMR (1H and 13C), MS
and melting points. d 2 mmol acetic acid was used. e Benzimidazole was
formed.
Fig. 9 SEM image of recovered nano-Al2O3 after the 5th cycle.
chain monocarboxylic acids (such as lauric and behenic acid)
remained unreactive with aniline even after stirring at 80–100 °C
for more than 24 h.
To present a mechanistic rationale of this protocol, a plausible
mechanism for the N-formylation of amines catalyzed by nano
basic Al2O3 is depicted in Scheme 4. It has been proposed that
the action of nano Al2O3 as a Lewis base increases the electron
density on the carbon centre of the formic acid, possibly via the
formation of an intermediate (I). This increase in electron
density normally translates to enhanced nucleophilicity of the
acceptor subunit. However, due to the counterintuitive conse-
quence of the binding of a Lewis base, the electrophilic character
of the acceptor in the reactive intermediate (I) is enhanced.
Finally, elimination of water from (II) leads to the formation of
the N-formylation product.
It is important to emphasise that catalyst recyclability is an
essential aspect of the green chemistry. Therefore, the recycling
potential of the nano-Al2O3 was also inspected during our
studies of the model reaction (Scheme 2). It is our pleasure to
mention that nano-Al2O3 is found to be equally effective from
fresh up to the 5th cycle without significant loss of activity.
Scheme 4 Plausible mechanism for the N-formylation of amines.
aryl amines substituted with electron-withdrawing moieties pro-
duced significantly lower yields of products than those substi-
tuted with electron-donating moieties (Table 6, entries 1–12).
Under the present reaction conditions, p-phenylene diamine
showed a trace yield (Table 6, entry 13) of product. However,
with o-phenylene diamine, instead of furnishing an amide, cycli-
zation occurred and 2-methyl benzimidazole was obtained in
good yield (Table 6, entry 14). Furthermore, the attempt to use
cyano acetic acid and trifluoro acetic acid for the synthesis of
expected products failed under the present conditions. Our
studies revealed that the treatment of aniline with propionic acid
and butanoic acid in the presence of nano basic Al2O3 produced
the corresponding amides in moderate yields (45% and 50%
respectively) upon heating at 70 °C for 15 h. However, dicar-
boxylic acids (such as adipic and malonic acid) and the long
852 | Green Chem., 2012, 14, 847–854
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Table 7 Recycling potential of nano-Al2O3
No. of cyclesa
Fresh
Run 1
Run 2
Run 3
Run 4
Run 5
Run 6
Run 7
Run 8
Run 9
Yield (%)b
Time (min)
TON
98
5
78.4
98
5
78.4
98
5
78.4
98
5
78.4
98
5
78.4
98
5
78.4
90
25
72
85
40
68
75
60
60
60
180
48
a Reaction conditions: 3.225 mmol aniline, 9.6774 mmol formic acid, 0.16129 mmol (5 mol%) nano basic Al2O3, 40 °C. b Yields refer to the isolated
pure products.
It could also be efficiently reused in the 6th cycle, however, in
subsequent cycles the yield of the product started to decrease.
The XRD pattern of the fresh nano-Al2O3 was compared with
the recovered one after the 5th cycle (Fig. 8).
It was observed from the Fig. 8 that the intensity of the two
highest peaks in fresh nano-Al2O3 decreased in the recycled one
after 5th run and it might be due to the dislocation of the crystal
planes which might be the legitimate cause for the considerable
lowering of yield of the N-formylation product in 6th run and
so on.
SEM micrograph of recovered nano-Al2O3 after the 5th run is
shown in Fig. 9. High agglomeration of the nano-Al2O3 was
observed, which might also play a role in reducing the yield and
Fig. 10 Catalyst recyclability chart.
reaction rate. It is clear from Table 7 that the TON of the catalyst
is retained from the fresh to the 5th cycle and then it starts
declining.
Authors are thankful to University Grant Commission, New
Delhi-Special Assistance Programme (UGC-SAP) [no. F.3-30/
2009(SAP-II) dated 31.03.2009] and Department of Science and
Technology- Fund for Improvement of S&T Infrastructure in
Higher Educational Institutions (DST-FIST) programme [no. SR/
FST/CS-II-001/2009 dated 17.11.2009] for providing infrastruc-
ture facilities required for this research work and VKD thanks
UGC for Rajiv Gandhi National Fellowship to him. The authors
would also like to acknowledge Mr. Ratan Baruah for carrying
out SEM studies and fruitful discussions.
After the reaction, ethyl acetate was poured into the reaction
mixture and then it was centrifuged (3000 rpm) to pellet out the
nano-Al2O3. The separated particles were washed with hot
ethanol (3 × 10 mL) to remove all the organic impurities.
Finally, it was decanted and dried in an oven at 80 °C for 6 h.
The particles so obtained were then reused for evaluating their
performances in the next cycle.
The recyclability chart of the catalytic potential of the nano-
Al2O3 is shown in Fig. 10. It is thus clear from Fig. 8 that the
catalytic activity was maintained up to the 5th run and after that
it started decreasing considerably.
Notes and references
1 (a) M. A. P. Martins, C. P. Frizzo, N. D. Moreira, L. Buriol and
P. Machado, Chem. Rev., 2009, 109, 4140; (b) P. J. Walsh, H. Li and C.
A. de Parrodi, Chem. Rev., 2007, 107, 2503; (c) K. Tanaka and F. Toda,
Chem. Rev., 2000, 100, 1025; (d) G. Nagendrappa, Resonance, 2002, 7,
59.
2 (a) K. Shimizu, K. Ohshima and A. Satsuma, Chem.–Eur. J., 2009, 15,
9977; (b) C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007,
317, 790; (c) L. U. Nordstrom, H. Vogt and R. Madsen, J. Am. Chem.
Soc., 2008, 130, 17672.
3 A. Jackson and O. Meth-Cohn, Chem. Commun., 1995, 1319.
4 B.-C. Chen, M. S. Bendarz, R. Zhao, J. E. Sundeen, P. Chen, Z. Shen,
A. P. Skoumbourdis and J. C. Barrish, Tetrahedron Lett., 2000, 41, 5453.
5 K. Kobayashi, S. Nagato, M. Kawakita, O. Morikawa and H. Konishi,
Chem. Lett., 1995, 57.
6 A. Kakehi, S. Ito, S. Hayashi and T. Fujii, Bull. Chem. Soc. Jpn., 1995,
68, 3573.
7 B. B. Lohray, S. Baskaran, B. S. Rao, B. Y. Reddy and I. N. Rao, Tetrahe-
dron Lett., 1999, 40, 4855.
8 G. R. Petit, M. V. Kalnins, T. M. H. Liu, E. G. Thomas and K. Parent,
J. Org. Chem., 1961, 26, 2563.
9 S. Kobayashi and K. Nishio, J. Org. Chem., 1994, 59, 6620.
10 S. Kobayashi, M. Yasuda and I. Hachiya, Chem. Lett., 1996, 407.
11 K. Iseki, S. Mizuno, Y. Kuroki and Y. Kobayashi, Tetrahedron, 1999, 55,
977.
Conclusions
In conclusion, in a novel and convenient protocol we have
shown that the N-formylation of amines occurs under solvent-
free conditions using nano rod-shaped basic Al2O3 as an
efficient catalyst. The advantages offered by this method include
(a) simple experimental procedure and reaction setup only at
40 °C/70 °C, (b) does not require any specialized equipment, (c)
high yields of desired products, (d) proceeds under ambient con-
ditions with diverse substrate compatibility, (e) good chemo-
selectivity, (f) suitable recyclability, (g) moisture stability of the
catalyst, (h) cost effectiveness, and (i) environmentally benign
along the line of green chemistry. The application of nano-Al2O3
in organic synthesis is not fully explored. Hence, as communi-
cated here, we are optimistic that metal nanoparticles including
Al2O3 nano rods would find increasing applications for new
chemical transformations, including those which enable the syn-
thesis of complex natural products and derivatives. Efforts are
currently underway in our research group to apply this ‘NOSE’
chemistry to the construction of other potentially valuable
organic molecules like pyrimidine derivatives.
12 (a) N. A. Kraus, Synthesis, 1973, 361; (b) H. Kizuka and D. R. Elmaleh,
Nucl. Med. Biol., 1993, 20, 239.
13 I. M. Downie, M. J. Earle, H. Heaney and K. F. Shuhaibar, Tetrahedron,
1993, 49, 4015.
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 847–854 | 853

View Online
14 J. Hartinez and J. Laur, Synthesis, 1982, 979.
34 J. Grunes and G. A. Somorjai, Chem. Commun., 2003, 2257.
15 D. Joulain, Flavour Fragrance J., 1987, 2, 149.
16 Y. Han and L. Cai, Tetrahedron Lett., 1997, 38, 5423.
17 (a) J. Waki and J. Meienhofer, J. Org. Chem., 1977, 42, 2019; (b) I. Ugi,
Angew. Chem., Int. Ed. Engl., 1982, 21, 810; (c) U. Schollkopf, Angew.
Chem., Int. Ed. Engl., 1977, 16, 339.
18 T. Jiang, X. Zhou, K. Taghizadeh, M. Dong and C. P. Dedon, Proc. Natl.
Acad. Sci. U. S. A., 2007, 104, 60.
19 B. Das, M. Krishnaiah, P. Balasubramanyam, B. Veeranjaneyulu and
D. N. Kumar, Tetrahedron Lett., 2008, 49, 2225.
20 D. R. Hill, C. N. Hsiao, R. Kurukulasuriya and S. J. Wittenberger, Org.
Lett., 2002, 4, 111.
21 P. G. Reddy and S. Baskaran, Tetrahedron Lett., 2002, 43, 1919.
22 P. G. Reddy, G. D. K. Kumar and S. Baskaran, Tetrahedron Lett., 2000,
41, 9149.
23 J. Deutsch, R. Eckelt, A. Köckritz and A. Martin, Tetrahedron, 2009, 65,
10365.
24 T. V. Pratap and S. Baskaran, Tetrahedron Lett., 2001, 42, 1983.
25 S. Kotha, M. Behera and P. Khedkar, Tetrahedron Lett., 2004, 45, 7589.
26 M. Rahman, D. Kundu, A. Hajra and A. Majee, Tetrahedron Lett., 2010,
51, 2896.
35 D. Astruc, F. Lu and J. R. Aranzaes, Angew. Chem., Int. Ed., 2005, 44,
7852.
36 (a) M. T. Reetz and G. Lohmer, Chem. Commun., 1996, 1921;
(b) M. T. Reetz and E. Westermann, Angew. Chem., Int. Ed., 2000, 39,
165; (c) C. Ramarao, S. V. Ley, S. C. Smith, I. M. Shirley and
N. DeAlmeida, Chem. Commun., 2002, 1132.
37 (a) J. A. Gladysz, Pure Appl. Chem., 2001, 73, 1319; (b) J. A. Gladysz,
Chem. Rev., 2002, 102, 3215.
38 S. Wang, Z. Wang and Z. Zha, Dalton Trans., 2009, 9363.
39 In analogy with MORE (microwave-induced organic reaction enhance-
ment) chemistry, we have coined the term ‘NOSE’ chemistry.
40 P. Preedasuriyachai, H. Kitahara, W. Chavasiri and H. Sakurai, Chem.
Lett., 2010, 39, 1174.
41 S. Sadjadi, S. Shiri and R. Hekmatshoar, Monatsh. Chem., 2009, 140,
1343.
42 (a) C. Huang, J. Wang and C. Huang, Mater. Lett., 2005, 59, 3746;
(b) Y. Zhang, J. Liu, H. R. Q. Zhang and X. Zhang, Chem. Phys. Lett.,
2002, 360, 579.
43 M. Shojaie-Bahaabad and E. Taheri-Nassaj, Mater. Lett., 2008, 62, 3364.
44 (a) A. Bhatnagar, E. Kumar and M. Sillanpaa, Chem. Eng. J., 2010, 163,
317; (b) A. I. Y. Tok, F. Y. C. Boey and X. L. Zhao, J. Mater. Process.
Technol., 2006, 178, 270; (c) D. A. Fletcher, R. F. McMeeking and
D. Parkin, J. Chem. Inf. Model., 1996, 36, 746.
27 O. Saidi, M. J. Bamford, A. J. Blacker, J. Lynch, S. P. Marsden,
P. Plucinski, R. J. Watson and J. M. J. Williams, Tetrahedron Lett., 2010,
51, 5804.
28 M. Hosseini-Sarvari and H. Sharghi, J. Org. Chem., 2006, 71, 6652.
29 J. G. Kim and D. K. Jang, Synlett., 2010, 14, 2093.
30 J. G. Kim and D. K. Jang, Synlett., 2010, 8, 1231.
31 A. Chandra Shekhar, A. R. Kumar, G. Sathaiah, V. L. Paul, M. Sridhar
and P. S. Rao, Tetrahedron Lett., 2009, 50, 7099.
45 T. Tsuchida, Solid State Ionics, 1993, 63, 464.
46 M. Zhareslu, M. Crisan, M. Preda, V. Fruth and S. Preda,
J. Optoelectron. Adv. Mater., 2003, 5, 1411.
47 B. Krishnakumar and M. Swaminathan, J. Mol. Catal. A: Chem., 2011,
334, 98.
32 S. H. Jung, J. H. Ahn, K. S. Park and J. K. Choi, Bull. Korean Chem.
Soc., 2002, 23, 149.
33 M. R. M. Bhojegowd, A. Nizam and M. A. Pasha, Chin. J. Catal., 2010,
31, 518.
48 M. Lei, M. Lei and H. Lihong, Tetrahedron Lett., 2010, 51, 4186.
49 M. Miharaa, Y. Ishino, S. Minakatab and M. Komatsu, Synthesis, 2003,
15, 2317.
50 B. Desai, T. N. Danksa and G. Wagner, Tetrahedron Lett., 2005, 46, 955.
854 | Green Chem., 2012, 14, 847–854
This journal is © The Royal Society of Chemistry 2012