Direct amide bond formation from carboxylic acids and amines using activated alumina balls as a new, convenient, clean, reusable and low cost heterogeneous catalyst

Article abstract of DOI:10.1039/c2gc35880h

For the first time, we have used activated alumina balls (3-5 mm diameter) for amide synthesis from carboxylic acids (unactivated) and amines (unactivated) under neat reaction conditions that produce no toxic by-products and has the advantages of being low-cost, easily available, heterogeneous, reusable and environmentally benign with no troublesome/hazardous disposal of the catalyst.

Full text of DOI:10.1039/c2gc35880h

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PAPER
Direct amide bond formation from carboxylic acids and amines using
activated alumina balls as a new, convenient, clean, reusable and low cost
heterogeneous catalyst†
Sabari Ghosh,a Asim Bhaumik,b John Mondal,b Amit Mallik,c Sumita Sengupta (Bandyopadhyay)d and
Chhanda Mukhopadhyay*a
Received 9th June 2012, Accepted 13th September 2012
DOI: 10.1039/c2gc35880h
For the first time, we have used activated alumina balls (3–5 mm diameter) for amide synthesis from
carboxylic acids (unactivated) and amines (unactivated) under neat reaction conditions that produce no
toxic by-products and has the advantages of being low-cost, easily available, heterogeneous, reusable and
environmentally benign with no troublesome/hazardous disposal of the catalyst.
of the most popular and reliable functional groups in all branches
of organic chemistry. Improved methods for the synthesis of an
Introduction
The amide bond plays a major role in the elaboration and com-
position of biological systems. It is one of the most important
linkages in organic chemistry and constitutes the key functional
group in peptides, polymers, many natural products and pharma-
ceuticals.1 An in-depth analysis of the comprehensive medicinal
chemistry database revealed that the carboxamide group appears
in more than 25% of known drugs.2 A recent report by the
American Chemical Society Green Chemistry Institute Pharma-
ceutical Roundtable (ACS GCIPR) has found that amide for-
mation, avoiding poor atom economy reagents, is the priority
area of research for the pharmaceutical industry.3a Catalytic
amide formation was recently highlighted as a reaction of impor-
tance from a ‘green chemistry’ perspective.3b As many as 65%
of drug molecules prepared by leading pharmaceutical compa-
nies contain an amide unit, indicating its importance and preva-
lence in synthetic organic chemistry. The occurrence of an amide
functionality, particularly in peptides and proteins, sometimes
gives the incorrect impression that there are no remaining syn-
thetic challenges. This is surprising, as it is often the case that
even simple amides resist formation, forcing practitioners to
resort to ever more exotic and expensive reagents for their syn-
thesis. Furthermore, the favourable properties of amides, such as
high polarity, stability and conformational diversity, make it one
amide functionality, particularly waste-free and suitable for frag-
ment coupling, are in great demand.
In general, traditional approaches for amide synthesis rely
heavily on the use of activated carboxylic acids and amines,
which often require stoichiometric amounts of coupling reagents
and produce toxic chemical waste.4,2a Catalytic oxidative
methods have become a powerful tool for the construction of
amide complexes, in which oxygen atoms of amides generally
originate from oxone/H2O2 5 or oxygen-containing carbonyl pre-
cursors including aldehydes6 and alcohols.7 Such well developed
oxidative reactions usually require stoichiometric oxidants such
as TBHP6a,b and oxone,5,6c expensive or relatively complex tran-
sition metal catalysts such as Ru,7a–c Rh,6d,7d and Mn5 com-
plexes. Catalytic hydration of organonitriles was also researched
extensively by Bera et al. and Tu et al.8 An organometallic cata-
lyst was developed that utilizes a ligand scaffold to engage in
secondary interactions with water and thus facilitates the
hydration of nitriles.8a Transition metal-free catalytic hydration
of organonitriles to amides was also developed by Tu et al.8b
Direct uncatalyzed formation of amides has been observed as
a background reaction in studies of catalytic amide formation.
Cossy and Palegrosdemange (1989) reported the synthesis of a
small range of amides at 140 °C under neat conditions in the
presence of 4 Å molecular sieves9 and a later report by Gooßen
et al. showed a larger range of amides could be formed under
solvent-free thermal conditions (160 °C), again in the presence
of molecular sieves.10 Whiting et al. (2006) observed 60% con-
version into N-benzyl-4-phenylbutyramide after heating 4-phe-
nylbutyric acid and benzylamine in toluene at reflux for 22 hours
in the presence of 3 Å molecular sieves11 and also published a
detailed study into the reaction mechanism by which direct
amide bond formation may occur in non-polar, aprotic sol-
vents.12 Clark et al. (2009) reported a heterogeneous silica cata-
lyst for direct amidation in refluxing toluene.13
aDepartment of Chemistry, University of Calcutta, 92 APC Road,
Kolkata-700009, India. E-mail: cmukhop@yahoo.co.in;
Tel: +91 9433019610
bDepartment of Materials Science, Indian Association for the
Cultivation of Science, Jadavpur, Kolkata, 700 032, India
cDepartment of Chemical Technology, University of Calcutta, 92 APC
Road, Kolkata-700009, India
dDepartment of Biophysics, Molecular Biology and Bioinformatics,
University of Calcutta, 92 APC Road, Kolkata-700009, India
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc35880h
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Table 1 Synthesis of heptanoic acid (4-chloro-phenyl)-amide
Results and discussion
The present methodology, which utilizes cheap and easily avail-
able alumina balls (activated) as a heterogeneous catalyst, opens
up a new and attractive window for the one-step synthesis of an
amide functionality in a less hazardous metal-free methodology.
From the environmental and economic point of view, a reaction
with inexpensive heterogeneous catalyst is always desired. The
direct condensation to form amides is highly desirable as both
poor atom economy and step economy can be avoided, the only
side product being water. Moreover, the use of alumina balls in
assisting amide synthesis lead to a very clean reaction and the
end of life prospects for the catalyst are attractive, as minimal
preparation is required when disposal is eventually needed. This
direct condensation also leads to easy procurement of the com-
ponents. Herein, we demonstrate the first example of a hetero-
geneously catalyzed reaction of carboxylic acids with amines to
form amides and H2O using the easily available simple activated
alumina ball catalyst.
Activated alumina balls (ESI Part 1, Fig. S1–S3†) is an alumi-
num oxide which is highly porous and exhibits a tremendous
surface area. Activated alumina (balls) is resistant to thermal
shock and abrasion and does not shrink, swell, soften or disinte-
grate during the reaction. The EDS X-ray spectrum of an
alumina ball shows 46.90% by weight of oxygen and 53.10% by
weight of aluminium (ESI Part 1, Table S1, Fig. S4†). With the
aim of developing a new high activity green catalyst for a direct
amidation reaction, we effectively carried out the synthesis with
an alumina (balls) catalyst.
Calcination
temperature (°C)
Catalyst
loading (wt%)
Conversionb
(%)
Catalyst
Neutral alumina
—
0
0
0
0
0
0
0
0
0
65
65
50
73
73
73
65
95
95
70
98
98
0
10
20
0
10
20
50
0
10
50
5
10
20
50
5
10
20
5
10
20
—
Neutral alumina
700
Alumina ballsc
Alumina ballsc
—
120
Alumina ballsc
Alumina ballsc
None
400
700
—
a 0–50 wt% of catalyst in relation to total mass of reagents (exact
catalyst loading mentioned in column 3 of the table), neat reaction
conditions at 140 °C for 3 hours, 10 mmol of Heptanoic acid and
10 mmol of 4-chloroaniline. b Isolated yield. c Activated alumina balls
from Sorbead India.
The reaction of 4-chloroaniline with heptanoic acid, as a
model reaction, was examined under various catalytic conditions
(Table 1). There was no reaction in the absence of a catalyst.
Neutral alumina failed to give the desired product. Activated
alumina balls very successfully catalysed the amide synthesis.
Activation temperatures were investigated (Table 1) and calcina-
tion at 700 °C gave the highest yields (98%). A comparable
activity was observed also at 400 °C calcination (95%). There is
a sharp jump in the yield (Fig. 1) upon increasing the calcination
temperature from 120 °C (73%) to 400 °C (95%). The calcina-
tion temperature was not increased over 700 °C since a nearly
quantitative yield was obtained (98%). A very high catalyst
loading was not required (only 10 wt% of the total mass of the
reactants gave the highest yields, see Table 1) which is another
advantage of this methodology. Removing water from the system
was also not required. Reaction under an inert atmosphere did
not enhance the yields. This is a solvent-free synthesis and there-
fore volatile solvents or procuring “dry” solvents were not
required, thus simplifying the process. By-products were not
observed and only unreacted acid and amine remained in trace
amounts. The carbon balance of the reaction was 100%
(% carbon in the reactants incorporated into the final product).
A maximum activity of calcinations at 700 °C can be attribu-
ted to the fact that the morphology of the alumina balls change
upon calcination, with a sharp decrease in the BET surface area
(Fig. 2). Although, this change in the structure of the alumina
balls is not very prominent (Fig. S1 and S2,† ESI Part 1), the
high resolution SEM images (Fig. 3) show that the shape
changes from “spherical” to “rhombohedral” and the size of the
aggregated particles increases upon calcination to 120 °C
Fig. 1 Variation of isolated yield of heptanoic acid (4-chloro-phenyl)-
amide (3ik, Table 2) with change in calcination temperature of the cata-
lyst alumina balls.
(average 710 nm aggregates), 400 °C (average 768 nm aggre-
gates) and finally to 700 °C (average 794 nm aggregates). The
change is very distinct at 700 °C. This change in shape leading
to an increased particle aggregate size, in turn leading to a
decreased BET surface area (Fig. 2), which leads to a nearly
quantitative reaction yield, i.e., 98% (Table 1), of compound
heptanoic acid (4-chloro-phenyl)-amide (3ik, Table 2).
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Fig. 2 Variation of the BET surface area of the alumina ball catalyst
with the activation temperature.
Using the above optimized conditions, the scope of the acti-
vated alumina balls as catalyst was explored for the direct amida-
tion of a variety of carboxylic acids and amines. The results are
summarized in Table 3. The acids p, g, q and n were prepared
by refluxing succinic anhydride (5) with pyrrolidine (4a), piper-
idine (4b), morpholine (4c) and N-methyl piperazine (4d)
(Scheme 1). These sensitive functionalised acids were then
reacted with the corresponding amines in the presence of acti-
vated alumina balls to form the amide (diamide in these cases)
in compounds 3gh, 3gj, 3gm, 3nl, 3no, 3gl, 3go, 3pl, 3po, 3ql
and 3qo in considerable yields.
The catalyst displayed high activity for amidation of all com-
binations of aromatic and aliphatic carboxylic acids and amines.
The reaction shows good results without any significant
influence of the structure of the reactants on the product yields.
A minimum of around 70% yield is reached in the cases studied.
We propose the highly porous and aggregated particle nature of
these activated alumina ball catalysts (see SEM images, Fig. 3
and the porosimetry data, graphs Table 3, Fig. 4–9) is respon-
sible for such high yielding reactions. The SEM images (Fig. 3)
indicate that the size of the aggregated particle increases with the
increase in the activation temperature. This is reflected in the
decrease of the BET surface area in that order (Table 3). A
maximum activity of the sample on activation at 700 °C could
be attributed to the fact that the morphology of the alumina ball
changes upon calcination. The particle aggregates change shape
from spherical to rhombohedral upon calcination to 700 °C.
Further, the porosity measurement showed that the surface area
of the material (by nitrogen adsorption at 77 K) decreases upon
increasing of the activation temperature from 120 °C, 400 °C
and 700 °C, and did not correlate directly with the catalyst
activity. However, the pore volume (0.3635 ccg−1) and pore
width (10.8 nm) is maximum at the 700 °C activation temp-
erature and these factors play the most important role. This high
pore width and pore volume favors easy diffusion of the substrate
and product molecules during the reaction. When the calcined
alumina spheres adsorb the water and, as one of the products is
removed from the reaction media, the reaction equilibrium is
constantly shifted towards the formation of amide and thus
higher yields are obtained. The surface area (88 m2 g−1) and
Fig. 3 From top: the close-up SEM images of an activated alumina
ball before calcination (99–175 nm particle aggregates), after calcination
at 120 °C, 400 °C and 700 °C. The particle aggregates change shape
from spherical to rhombohedral upon calcination to 700 °C. The particle
aggregate size (enlarged SEM images with the particular aggregate size
given in ESI,† Part 1) also increases progressively upon calcination at
120 °C (614–818 nm aggregates), 400 °C (636–889 nm aggregates) and
700 °C (587–938 nm aggregates).
pore volume (0.1675 ccg−1) of neutral alumina is very low when
compared to that of the alumina balls even at room-temperature
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Table 2 Results for the reaction of direct amide bond synthesisa,b
a Reaction conditions: 1 (10 mmol), 2 (10 mmol), Alumina balls (10 wt% in relation to total mass of reagents), neat reaction, 140 °C, 3 hours.
b Isolated yields based on 1. c Reaction was recorded on a 10 mmol scale and also a 100 mmol scale with similar isolated yields.
(255 m2 g−1 surface area and 0.3140 ccg−1 pore volume) indicat-
ing that it is the ball nature with particular aggregated particle
morphology of the alumina that is responsible for the higher
catalytic activity. Powder XRD analysis of neutral alumina and
the alumina balls activated at different temperatures was also
carried out. Powder XRD is due to the particular alumina phase
of a sample, which is the same for all samples. So there was
only very little difference in the XRD patterns with catalytic
activity (Fig. 4). As the activity is dependent on the ball form of
the alumina calcined at different temperatures, the powder XRD
patterns hardly made any difference. The textural properties of
the catalysts as obtained initially from the SEM images and
again as measured by N2 physisorption at 77 K were informative
as stated above. These alumina balls are neutral reactants and
hence there is no question of protonation of the amines to give
an inactive salt. A scale-up reaction was also studied (Table 2,
product 3ic) on a 100 mmol scale with 95% isolated yield. The
reaction of p-anisidine with heptanoic acid on a 100 mmol scale
proceeds just as well as the reaction on a 10 mmol scale. The
synthesized aliphatic functionalized acids p, g, q and n could
survive the present reaction conditions indicating the mildness of
the reaction.
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Table 3 The summarised porosimetry data as obtained from the N2
physisorption method23
BET surface Pore
Pore
volume
area
width
Neutral alumina
RT alumina ball
88 m2 g−1
8.18 nm 0.1675 ccg−1
5.68 nm 0.3140 ccg−1
5.6 nm
6.03 nm 0.3614 ccg−1
0.3635 ccg−1
255 m2 g−−11
120 °C activated alumina ball 245 m2 g−1
400 °C activated alumina ball 231 m2 g
0.3136 ccg−1
700 °C activated alumina ball 122 m2 g−1 10.8 nm
Fig. 5 N2 adsorption–desorption isotherm of the alumina balls at RT.
Pore size distributions estimated through the NLDFT method is shown
in the inset. BET surface area of this RT sample is 255 m2 g−1. Pore
width 5.64 nm; pore volume 0.3140 ccg−1
.
Scheme 1 Synthesis of the carboxylic acids p, g, q and n and their
corresponding reaction to form the desired amide bond.
Fig. 6 N2 adsorption–desorption isotherm of the alumina balls
calcined at 120 °C. Pore size distributions estimated through the NLDFT
method is shown in the inset. BET surface area of the alumina balls
calcined at 120 °C is 245 m2 g−1. Pore width 5.6 nm; pore volume
Fig. 4 Wide angle powder XRD patterns of the alumina balls calcined
at 120 °C (a); the alumina balls at RT (b); neutral alumina (c); the
alumina balls calcined at 700 °C (d) and the alumina balls calcined at
400 °C (e).
0.3136 ccg−1
.
Deactivation of the catalyst on storage was also investigated
by following the change in activity on long term exposure to the
atmosphere (Table 5). The synthesis of heptanoic acid (4-methoxy-
phenyl)-amide was taken as the model reaction. Even after being
exposed for a week the catalyst remains active and gave a yield
of 85% without pre-activation to 700 °C. Long term exposure
for a month led to 80% yield without pre-treatment.
Table 6 shows a comparison of our alumina ball system with
the previously reported K60 silica system for amide syntheses as
reported by Clark et al.13 Both are heterogeneous catalysts. Both
catalysts deliver the best results when activated at 700 °C.
The separation and recovery of the catalyst is an important
step in the synthesis of fine chemicals, performed generally
either by centrifuge or filtration with reduced efficiency. In this
catalytic system, because of the macroscopic “ball” nature of the
alumina catalyst, it can be recovered simply by filtration. Consid-
ering heptanoic acid (4-methoxyphenyl)-amide as the model, the
crude reaction mixture is dissolved in dichloromethane and
filtered. The alumina balls are further washed and dried under
vacuum. These same alumina balls are used for catalysis in a
new reaction in order to test its level of reusability (Table 4).
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Fig. 9 N2 adsorption–desorption isotherm of neutral alumina. Pore
size distributions estimated through the NLDFT method is shown in the
inset. BET surface area of neutral alumina is 88 m2 g−1. Pore width
Fig. 7 N2 adsorption–desorption isotherm of the alumina balls
calcined at 400 °C. Pore size distributions estimated through the NLDFT
method is shown in the inset. BET surface area of the alumina balls
calcined at 400 °C is 231 m2 g−1. Pore width 6.03 nm; pore volume
8.18 nm; pore volume 0.1675 ccg−1
.
0.3614 ccg−1
.
Table 4 Effect of reuse on yield of heptanoic acid (4-methoxy-
phenyl)-amidea,b
1st use
2nd use
3rd use
Reactivation temperature
Yieldc (%)
CH2Cl2 wash (dried under vacuum)
120 °C
700 °C
85
88
90
82
85
90
81
83
88
a Reaction conditions as in Table 3. b There was no loss of catalyst on
transfer due to the macroscopic “ball” nature of the catalyst.
c Recrystallized isolated yield.
Table 5 Change in isolated yield of heptanoic acid (4-methoxyphenyl)-
amide with timea,b
Time of exposure in air
12 hours 24 hours 1 week 1 month
Unactivated catalyst
Activated catalyst (700 °C) 93
90
88
93
85
89
80
85
Fig. 8 N2 adsorption–desorption isotherm of the alumina balls
calcined at 700 °C. Pore size distributions estimated through the NLDFT
method is shown in the inset. BET surface area of the alumina balls
calcined at 700 °C is 122 m2 g−1. Pore width 10.8 nm; pore volume
a Reaction conditions as in Table 3. b Recrystallized isolated yield given
under each column.
0.3635 ccg−1
.
However, our alumina ball catalyst also gives comparable yields
when activated at 400 °C. Thus, our catalyst can function at a
considerably lower calcination temperature. K60 silica requires
refluxing toluene for promoting the amide bond formation.
Alumina balls as catalyst can promote the same reaction using a
solvent free methodology (see Table 6). On average, a 20 wt%
catalyst loading is required for optimal yields in the case of K60
silica.13 The catalyst loading for the alumina balls is only 10 wt%.
Many factors must be considered when designing cleaner syn-
thetic routes. Table 6 also gives a comparison based on
established green chemistry metrics.24 This shows that alumina
balls activated at 700 °C are substantially cleaner and more
efficient than the alternative heterogeneous K60 methodology,
especially in terms of the ratio of waste to product (E-factor in
our alumina balls catalysed reaction is 0.15 for compound 3sm,
see Table 6) and mass intensity (MI 1.60 for compound 3sm in
our methodology, Table 6). In an ideal situation, the mass inten-
sity would approach 1. Therefore, the green metrics of this
present methodology is much more towards the ideal results.
The challenge for green chemistry and green engineering is to
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Table 6 A comparison of efficiency between catalysts in the synthesis of N-phenyl-benzamide (3sm)a
Catalyst
Catalyst loading (wt%)
Solvent
Yieldb (%)
E-factor
Mass intensity
Atom economy (%)
K60 silica12
50
10
Toluene
—
47
75
2.73
0.15
19.13
1.60
92
92
Alumina ballc
a 10 mmol each of the starting materials benzoic acid and aniline, neat reaction, 140 °C, 3 hours for the reaction with alumina ball catalyst. b Isolated
yield. c Calcined at 700 °C.
decrease significantly the material intensities observed, for
example, the mass intensity by at least an order of magnitude, if
not more. It is better to prevent waste than to treat or cleanup
waste after it is formed.
cyclopropanecarboxylic acid (naphthalen-1-ylmethyl)-amide was
2.03 g (90%).
Amide analytical data
Cyclopropanecarboxylic acid (naphthalen-1-ylmethyl)-amide
(3ab). White solid; m.p. 167 °C (EtOAc); H NMR (300 MHz,
Conclusions
1
DMSO-d6): δ 8.54 (br s, 1H, NH), 8.02 (d, J = 7.2 Hz, 1H, Ar),
7.91 (d, J = 8.1 Hz, 1H, Ar), 7.82 (d, J = 7.2 Hz, 1H, Ar),
7.52–7.42 (m, 4H), 4.71 (d, J = 5.4 Hz, 2H, benzylic),
1.59–1.58 (m, 1H), 0.69–0.61 (m, 4H); 13C NMR (75 MHz,
DMSO-d6): δ 172.5, 134.9, 133.4, 131.0, 128.5, 127.6, 126.3,
125.8, 125.7, 125.5, 123.6, 13.6, 6.3; IR(KBr) 3296 (NH), 1627
(CvO), 1537 (NH def) cm−1; Anal. calcd for C15H15NO:
C, 79.97; H, 6.71; N, 6.22 and found C, 79.99; H, 6.70; N, 6.25.
In conclusion, the present methodology opens up an interesting
and attractive sustainable avenue for the synthesis of amide func-
tionalities. We use a solvent-free protocol for amide bond for-
mation using non-toxic, inexpensive and biocompatible alumina
balls. The advantage of this environmentally benign and safe
protocol includes a simple reaction setup which does not require
any specialised equipment, mild reaction conditions, high
product yields, short reaction times, the possibility for reusing
the catalyst and solvent-free conditions. As we learn better ways
to synthesize complex, highly functionalized amide-based struc-
tures without the need for aggressive reactants and cumbersome
protecting groups, synthetic amides will provide a new gener-
ation of functional materials with controllable higher-order
properties.
Cyclopropanecarboxylic acid (4-methoxy-phenyl)-amide (3ac).
1
Blue solid; m.p. 127 °C (EtOAc); H NMR (300 MHz, CDCl3):
δ 7.92 (br s, 1H, NH), 7.38 (d, J = 8.7 Hz, 2H, Ar), 6.79 (d, J =
8.4 Hz, 2H, Ar), 3.75 (s, 3H, OCH3), 1.50–1.48 (m, 1H), 1.01
(m, 2H), (m, 2H); 13C NMR (75 MHz, CDCl3): δ 172.1, 156.1,
131.4, 121.8, 114.0, 55.4, 15.3, 7.6; IR(KBr) 3299 (NH), 1652
(CvO), 1524 (NH def) cm−1; Anal. calcd for C11H13NO2:
C, 69.09; H, 6.85; N, 7.32 and found C, 69.10; H, 6.86; N, 7.34.
Experimental section
N-(4-Methoxyphenyl)-4-nitrobenzamide (3dc). Yellow solid;
m.p. 199 °C (MeOH); H NMR (300 MHz, DMSO-d6) δ 8.32
General information
1
Amides were synthesized under neat reaction conditions at
140 °C and an air atmosphere. The typical quantities used were
10 mmols of acid, 10 mmols of amine, and varying quantities of
activated alumina ball catalyst. NMR spectra were obtained on a
300 MHz Bruker spectrometer using CDCl3 or DMSO-d6
solvent. Powder X-ray diffraction patterns of the samples were
analyzed by using a Philips X’Pert PRO Diffractometer. Nitro-
gen adsorption–desorption isotherms of the samples were
recorded on a Quantachrome Autosorb 1C, at 77 K. Prior to the
gas adsorption measurements, the samples were degassed at
473 K for 6 hours under high vacuum.
(d, J = 8.7 Hz, 2H, Ar), 8.04 (d, J = 8.7 Hz, 2H, Ar), 7.88 (s,
1H, NH), 7.55 (d, J = 8.9 Hz, 2H, Ar), 6.93 (d, J = 8.9 Hz, 2H,
Ar), 3.75 (s, OCH3, 3H,); 13C NMR (75 MHz, DMSO-d6) δ
163.3, 155.9, 149.0, 140.7, 131.7, 129.0, 123.4, 122.1, 113.8,
55.1; IR(KBr) 2932 (NH), 1621 (CvO) cm−1; Anal. calcd for
C14H12N2O4: C, 61.76; H, 4.44; N, 10.29 and found C, 61.73;
H, 4.47; N, 10.30.
N-(3,4-Dimethylphenyl)-butyramide
(3ef). Brown
solid;
1
m.p. 60 °C (EtOAc); H NMR (300 MHz, CDCl3): δ 7.95 (br s,
1H, NH), 7.32 (s, 1H, Ar), 7.25 (d, J = 9 Hz, 1H, Ar), 7.02 (d,
J = 7.8 Hz, 1H, Ar), 2.32 (t, J = 7.2 Hz, 2H), 2.19 (s, 3H, Ar
CH3), 1.77–1.74 (m, 2H) and 0.97 (t, J = 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 171.8, 136.9, 135.6, 132.4, 129.7, 121.6,
117.7, 39.2, 19.7, 19.1, 19.0 and 13.6; IR(KBr) 3300 (NH),
1660 (CvO) cm−1; Anal. calcd for C12H17NO: C, 75.35; H,
8.96; N, 7.32 and found C, 75.33; H, 8.93; N, 7.35.
General procedure for amide synthesis
Cyclopropanecarboxylic acid (naphthalen-1-ylmethyl)-amide
(3ab). Cyclopropanecarboxylic acid (0.80 ml, 10 mmol),
C-naphthalen-1-yl-methylamine (1.47 ml, 10 mmol) and acti-
vated alumina balls calcined at 700 °C (243.3 mg) were heated
to 140 °C in a round bottomed flask. After 3 hours the hot reac-
tion mixture was diluted with ethyl acetate and filtered through a
sintered glass funnel, the catalyst was washed with 20 ml of hot
ethyl acetate and dried under vacuum. The yield obtained for
N-(4-Nitrophenyl)-4-oxo-4-piperidin-1-yl-butyramide (3gh).
White solid; m.p. 180 °C (CHCl3); 1H NMR (300 MHz,
CDCl3): δ 10.05 (br s, 1H, NH), 8.10 (d, J = 9 Hz, 2H, Ar), 7.69
(d, J = 9 Hz, 2H, Ar), 3.59–3.49 (m, 4H), 2.83 (s, 4H),
1.66–1.61 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 171.1, 170.4,
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138.6, 128.7, 124.8, 119.1, 46.5, 43.1, 32.7, 28.9, 26.3, 25.5,
24.2; IR(KBr) 2931 (NH), 1623 (CvO) cm−1; Anal. calcd for
C15H19N3O4: C, 59.01; H, 6.27; N, 13.76 and found C, 59.04;
H, 6.27; N, 13.75.
171.1, 170.4, 138.6, 128.7, 123.6, 123.3, 119.7, 46.5, 43.1, 32.7,
28.9, 26.3, 25.5, 24.4; IR(KBr) 3270 (NH), 1622 (CvO) cm−1
;
Anal. calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76 and
found C, 69.21; H, 7.74; N, 10.77.
N-Anthracen-2-yl-4-(4-methyl-piperazin-1-yl)-4-oxo-butyramide
(3nl). Greenish-brown solid; m.p. 141 °C (DMSO); 1H NMR
(300 MHz, DMSO-d6): δ 10.21 (s, 1H, NH), 8.45 (d, J =
9.3 Hz, 2H, Ar), 8.36 (s, 1H, Ar), 7.99 (d, J = 9.0 Hz, 3H, Ar),
7.53 (dd, J = 9.0, 1.8 Hz, 1H, Ar), 7.46–7.38 (m, 2H, Ar),
3.44–3.40 (m, 4H), 2.62 (br s, 4H), 2.28 (br s, 2H), 2.21–2.18
(m, 2H), 2.14 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 171.2,
169.8, 136.5, 131.8, 130.4, 128.7, 128.5, 128.1, 127.7, 125.9,
125.6, 124.9, 121.1, 113.5, 54.8, 54.4, 45.7, 44.7, 41.1, 31.6,
27.7; IR(KBr) 3263 (NH), 1650 (CvO) cm−1; Anal. calcd for
C23H25N3O2: C, 73.57; H, 6.71; N, 11.19 and found C, 73.55;
H, 6.70; N, 11.21.
Heptanoic acid p-tolylamide (3ij). Light brown solid;
m.p. 80 °C (EtOAc); H NMR (300 MHz, CDCl3): δ 7.76 (br s,
1
1H, NH), 7.39 (d, J = 7.5 Hz, 2H, Ar), 7.08 (d, J = 7.5 Hz, 2H,
Ar), 2.35–2.29 (m, 5H, Ar CH3 and COCH2), 1.69 (m, 2H),
1.29 (br s, 6H), 0.85 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 171.7, 135.4, 133.6, 129.3, 120.1, 37.6, 31.5, 28.9,
25.6, 22.4, 20.7, 13.9; IR(KBr) 3314 (NH), 1659 (CvO) cm−1
;
Anal. calcd for C14H21NO: C, 76.67; H, 9.65; N, 6.39 and found
C, 76.67; H, 9.65; N, 6.40.
Heptanoic acid (4-methoxyphenyl)-amide (3ic). Light brown
1
solid; m.p. 70 °C (EtOAc); H NMR (300 MHz, CDCl3): δ 8.04
(br s, 1H, NH), 7.40 (d, J = 8.7 Hz, 2H, Ar), 6.79 (d, J = 8.7 Hz,
2H, Ar), 3.75 (s, 3H), 2.31 (t, J = 7.5 Hz, 2H), 1.69–1.62
(m, 2H), 1.27 (br s, 6H), 0.85 (t, J = 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 172.0, 156.4, 130.9, 122.1, 114.0, 55.4,
37.3, 31.5, 28.9, 25.8, 22.4, 13.9; IR(KBr) 3316 (NH), 1654
(CvO) cm−1; Anal. calcd for C14H21NO2: C, 71.46; H, 8.99;
N, 5.95 and found C, 71.47; H, 9.00; N, 5.95.
N-Anthracen-1-yl-4-(4-methyl-piperazin-1-yl)-4-oxo-butyramide
(3no). Reddish-brown sticky solid; 1H NMR (300 MHz,
DMSO-d6): δ 10.06 (s, 1H, NH), 8.79 (s, 1H, Ar), 8.54 (s, 1H,
Ar), 8.05 (br s, 2H, Ar), 7.88–7.87 (m, 1H, Ar), 7.68 (br s, 1H,
Ar), 7.49 (br s, 3H, Ar), 3.45 (br s, 4H), 2.75–2.70 (m, 4H),
2.26–2.21 (m, 4H), 2.13 (s, 3H); 13C NMR (75 MHz,
DMSO-d6): δ 171.5, 170.0, 133.9, 131.9, 131.1, 131.0, 128.4,
127.9, 126.4, 125.9, 125.8, 125.2, 121.7, 120.0, 117.8, 54.8,
54.4, 45.7, 44.7, 41.2, 31.3, 27.9; IR(KBr) 3259 (NH), 1641
(CvO) cm−1; Anal. calcd for C23H25N3O2: C, 73.57; H, 6.71;
N, 11.19 and found C, 73.58; H, 6.69; N, 11.19.
Heptanoic acid (4-chlorophenyl)-amide (3ik). Light brown
solid; m.p. 174 °C (EtOAc); 1H NMR (300 MHz, CDCl3): δ
7.45 (br s, 1H, NH), 7.39 (d, J = 8.7 Hz, 2H, Ar), 7.18 (d, J =
8.4 Hz, 2H, Ar), 2.26 (t, J = 7.5 Hz, 2H), 1.67–1.53 (m, 2H),
1.22 (br s, 6H), 0.81 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 171.7, 136.5, 129.2, 128.9, 121.1, 37.7, 31.5, 28.9,
25.5, 22.5, 14.0; IR(KBr) 3310 (NH), 1659 (CvO) cm−1; Anal.
calcd for C13H18ClNO: C, 65.13; H, 7.57; N, 5.84 and found
C, 65.15; H, 7.57; N, 5.83.
N-Anthracen-2-yl-4-oxo-4-piperidin-1-yl-butyramide
(3gl).
Greenish-brown solid; m.p. 165 °C (DMSO); 1H NMR
(300 MHz, DMSO-d6): δ 10.02 (s, 1H, NH), 8.29 (d, J =
9.3 Hz, 2H, Ar), 8.21 (s, 1H, Ar), 7.83 (d, J = 9.0 Hz, 3H, Ar),
7.37 (d, J = 9.0 Hz, 1H, Ar), 7.31–7.25 (m, 2H, Ar), 3.25–3.21
(m, 4H), 2.31 (br s, 4H), 1.40–1.36 (m, 4H), 1.22 (br s, 2H);
13C NMR (75 MHz, DMSO-d6): δ 171.3, 169.4, 136.5, 131.8,
130.4, 128.8, 128.5, 128.2, 127.8, 125.9, 125.7, 124.9, 121.1,
113.5, 45.8, 42.1, 31.7, 27.6, 26.1, 25.4, 24.2; IR(KBr) 3267
(NH), 1646 (CvO) cm−1; Anal. calcd for C23H24N2O2:
C, 76.64; H, 6.71; N, 7.77 and found C, 76.65; H, 6.74; N, 7.75.
N-Anthracen-2-yl-butyramide (3el). Yellow solid; m.p. above
260 °C (MeOH); 1H NMR (300 MHz, DMSO-d6): δ 10.09
(s, 1H, NH), 8.48–8.35 (m, 3H, Ar), 8.00–7.93 (m, 3H, Ar),
7.52 (d, J = 9.6 Hz, 1H, Ar), 7.43 (m, 2H, Ar), 2.34 (t, J =
7.8 Hz, 2H), 1.67–1.60 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H);
13C NMR (75 MHz, DMSO-d6): δ 171.3, 136.5, 131.8, 130.4,
128.8, 128.5, 128.2, 127.8, 125.9, 125.7, 124.9, 121.1, 113.5,
39.2, 19.7, 19.2, and 13.7; IR(KBr) 3410 (NH), 1627 (CvO)
cm−1; Anal. calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32 and
found C, 82.12; H, 6.52; N, 5.30.
N-Anthracen-1-yl-4-oxo-4-piperidin-1-yl-butyramide
(3go).
Yellow solid; m.p. 161 °C (DMSO); 1H NMR (300 MHz,
DMSO-d6): δ 10.02 (s, 1H, NH), 8.79 (s, 1H, Ar), 8.55 (s, 1H,
Ar), 8.06–8.03 (m, 2H, Ar), 7.87 (d, J = 8.7 Hz, 1H, Ar), 7.68
(d, J = 6.6 Hz, 1H, Ar), 7.51–7.44 (m, 3H, Ar), 3.43–3.42 (m,
4H), 2.76–2.68 (m, 4H), 1.54–1.40 (m, 6H); 13C NMR
(75 MHz, DMSO-d6): δ 171.7, 169.7, 133.9, 132.0, 131.2,
131.0, 128.4, 127.9, 126.6, 126.4, 125.9, 125.3, 121.8, 120.1,
45.9, 42.2, 31.4, 28.0, 26.1, 25.5, 24.2; IR(KBr) 3275 (NH),
4-Oxo-4-piperidin-1-yl-N-p-tolyl-butyramide
(3gj). White
solid; m.p. 134 °C (CHCl3); 1H NMR (300 MHz, CDCl3): δ
9.02 (s, 1H, NH), 7.36 (d, J = 8.4 Hz, 2H, Ar), 6.98 (d, J =
8.4 Hz, 2H, Ar), 3.48 (br s, 2H), 3.35 (br s, 2H), 2.68 (s, 4H),
2.21 (s, 3H, Ar CH3), 1.56–1.47 (m, 6H); 13C NMR (75 MHz,
CDCl3): δ 170.9, 170.5, 136.0, 133.2, 130.1, 129.2, 123.2,
119.8, 46.6, 43.1, 32.7, 28.9, 26.3, 25.5, 24.4, 20.8; IR(KBr)
3270 (NH), 1623 (CvO) cm−1; Anal. calcd for C16H22N2O2: C,
70.04; H, 8.08; N, 10.21 and found C, 70.05; H, 8.09; N, 10.21.
1640 (CvO), 1533 (NH def) cm−1
; Anal. calcd for
C23H24N2O2: C, 76.64; H, 6.71; N, 7.77 and found C, 76.61; H,
6.74; N, 7.77.
N-Anthracen-2-yl-4-oxo-4-pyrrolidin-1-yl-butyramide (3pl).
Brown solid; m.p. 200 °C (MeOH); 1H NMR (300 MHz,
CDCl3): δ 9.86 (s, 1H, NH), 8.49 (s, 1H, Ar), 8.26 (s, 2H, Ar),
7.90–7.85 (m, 3H, Ar), 7.52–7.40 (m, 3H, Ar), 3.47 (t, J =
6.0 Hz, 4H), 2.82–2.71 (m, 4H), 2.03–1.85 (m, 4H); 13C NMR
(75 MHz, CDCl3): δ 170.9, 169.8, 135.3, 131.5, 131.3, 130.1,
4-Oxo-N-phenyl-4-piperidin-1-yl-butyramide
(3gm). White
solid; m.p. 123 °C (CHCl3); 1H NMR (300 MHz, CDCl3): δ
9.08 (s, 1H, NH), 7.48 (d, J = 8.1 Hz, 2H, Ar), 7.21–7.15 (m,
2H, Ar), 6.98–6.93 (m, 1H, Ar), 3.48 (br s, 2H), 3.35 (br s, 2H),
2.68 (s, 4H), 1.56–1.44 (m, 6H); 13C NMR (75 MHz, CDCl3): δ
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N-Isopropylbenzamide (3st). White solid, m.p. 102 °C
(EtOAc); H NMR (300 MHz, CDCl3): δ 7.75 (d, J = 7.2 Hz,
128.3, 128.0, 127.5, 127.1, 125.2, 124.8, 124.6, 124.1, 120.6,
114.1, 45.9, 45.2, 31.5, 29.3, 25.3, 23.7; IR(KBr) 3293 (NH),
1621 (CvO) cm−1; Anal. calcd for C22H22N2O2: C, 76.28;
H, 6.40; N, 8.09 and found C, 76.28; H, 6.42; N, 8.09.
1
2H, Ar), 7.47–7.35 (m, 3H, Ar), 6.22 (br s, 1H, NH), 4.30–4.24
(m, 1H), 1.24 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3):
δ 166.8, 134.8, 131.1, 128.4, 126.8, 41.8, 22.7; IR(KBr)
3299 (NH), 1631 (CvO), 1534 (NH def) cm−1; Anal. calcd for
C10H13NO: C, 73.59; H, 8.03; N, 8.58 and found C, 73.56;
H, 8.01; N, 8.60.
N-Anthracen-1-yl-4-oxo-4-pyrrolidin-1-yl-butyramide (3po).
Brown solid; m.p. 190 °C (MeOH); 1H NMR (300 MHz,
CDCl3): δ 9.66 (s, 1H, NH), 8.74 (s, 1H, Ar), 8.42 (s, 1H, Ar),
8.15–7.98 (m, 3H, Ar), 7.80 (d, J = 8.4 Hz, 1H, Ar), 7.49–7.42
(m, 3H, Ar), 3.62 (t, J = 6.9 Hz, 2H), 3.46 (t, J = 6.6 Hz, 2H),
2.98–2.95 (m, 2H), 2.88–2.82 (m, 2H), 2.01–1.79 (m, 4H);
13C NMR (75 MHz, DMSO-d6): δ 171.7, 169.9, 133.9, 132.0,
131.2, 131.0, 128.4, 127.9, 126.4, 125.9, 125.3, 121.7, 120.0,
46.0, 45.5, 31.1, 29.4, 25.7, 24.1; IR(KBr) 3265 (NH), 1627
(CvO), 1542 (NH def) cm−1; Anal. calcd for C22H22N2O2:
C, 76.28; H, 6.40; N, 8.09 and found C, 76.30; H, 6.42; N, 8.09.
1
N-Isopropylheptanamide (3it). Brown sticky liquid, H NMR
(300 MHz, CDCl3): δ 5.88 (br s, 1H, NH), 4.04–3.93 (m, 1H),
2.06 (t, J = 7.5 Hz, 2H), 1.55–1.48 (m, 2H), 1.20 (s, 6H), 1.06
(d, J = 6.3 Hz, 6H), 0.81 (t, J = 6.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 172.3, 41.0, 36.7, 31.4, 28.7, 25.7, 22.5,
22.3, 13.8; IR(KBr) 3287 (NH), 1643 (CvO), 1550 (NH def)
cm−1; Anal. calcd for C10H21NO: C, 70.12; H, 12.36; N, 8.18
and found C, 70.13; H, 12.36; N, 8.20.
N-Anthracen-2-yl-4-morpholin-4-yl-4-oxo-butyramide (3ql).
Brown solid, m.p. 190 °C (DMSO); 1H NMR (300 MHz,
DMSO-d6): δ 10.19 (s, 1H, NH), 8.48–8.37 (m, 3H, Ar),
8.00–7.97 (m, 3H, Ar), 7.53 (d, J = 8.1 Hz, 1H, Ar), 7.42 (br s,
2H, Ar), 3.55–3.41 (m, 8H), 2.64 (s, 4H); 13C NMR (75 MHz,
DMSO-d6): δ 171.1, 170.1, 142.2, 136.4, 131.8, 130.4, 128.8,
128.5, 128.1, 127.7, 125.8, 125.6, 124.9, 121.1, 113.5, 66.2,
Acknowledgements
One of the authors (SG) thanks the UGC, New Delhi, for her
fellowship (SRF). We also acknowledge the grant received from
the UGC funded Major project, F. no. 37-398/2009 (SR) dated
11-01-2010.
45.3, 41.6, 31.5, 27.5; IR(KBr) 3252 (NH), 1653 (CvO) cm−1
;
Anal. calcd for C22H22N2O3: C, 72.91; H, 6.12; N, 7.73 and
found C, 72.90; H, 6.12; N, 7.70.
Notes and references
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Linkage: Structural Significance in Chemistry, Biochemistry, and
Materials Science, John Wiley & Sons, New York, 1999; (c) J. Rebek,
Acc. Chem. Res., 1999, 32, 278; (d) R. P. Cheng, S. H. Gellman and
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(b) A. K. Ghose, V. N. Viswanadhan and J. J. Wendoloski, J. Comb.
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N-Anthracen-1-yl-4-morpholin-4-yl-4-oxo-butyramide (3qo).
Brown solid, m.p. 185 °C (MeOH); 1H NMR (300 MHz,
CDCl3): δ 9.17 (s, 1H, NH), 8.61 (s, 1H, Ar), 8.42 (s, 1H, Ar),
8.07–8.01 (m, 3H, Ar), 7.89 (d, J = 8.4 Hz, 1H, Ar), 7.49–7.41
(m, 3H, Ar), 3.96–3.87 (m, 6H), 3.70–3.65 (m, 2H), 2.98–2.96
(m, 2H), 2.85–2.84 (m, 2H); 13C NMR (75 MHz, CDCl3):
δ 171.5, 170.9, 132.7, 132.1, 131.5, 131.4, 128.4, 127.8, 126.8,
125.9, 125.6, 125.3, 125.0, 120.0, 118.8, 66.6, 66.3, 45.6, 42.1,
32.5, 29.0; IR(KBr) 3276 (NH), 1654 (CvO) cm−1; Anal. calcd
for C22H22N2O3: C, 72.91; H, 6.12; N, 7.73 and found C, 72.90;
H, 6.12; N, 7.75.
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5 W. K. Chan, C. M. Ho, M. K. Wong and C. M. Che, J. Am. Chem. Soc.,
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2008, 130, 17672; (c) A. J. A. Watson, A. C. Maxwell and
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559.
1-Pyrrolidin-1-yl-heptan-1-one (3ir). Brown liquid, b.p. 297
5 °C (760 mm Hg pressure); H NMR (300 MHz, CDCl3): δ
1
3.42–3.34 (m, 4H, NCH2), 2.20 (t, J = 7.5 Hz, 2H), 1.93–1.74
(m, 4H, NCH2CH2), 1.60–1.53 (m, 2H), 1.32–1.24 (m, 6H),
0.83 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 176.4,
46.6, 45.6, 34.8, 31.6, 29.1, 26.1, 24.9, 24.4, 22.5, 14.0; IR
(KBr) 3442 (NH), 1613 (CvO) cm−1; Anal. calcd for
C11H21NO: C, 72.08; H, 11.55; N, 7.64 and found C, 72.08; H,
11.52; N, 7.63.
8 (a) P. Daw, A. Sinha, S. M. W. Rahaman, S. Dinda and J. K. Bera,
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and Q. Wang, Green Chem., 2012, 14, 921.
N-Phenyl-benzamide (3sm). White solid, m.p. 165 °C
(CH2Cl2); H NMR (300 MHz, CDCl3): δ 8.02 (s, 1H, NH),
1
9 J. Cossy and C. Palegrosdemange, Tetrahedron Lett., 1989, 30, 2771.
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7.86 (d, J = 7.5 Hz, 2H, Ar), 7.65 (d, J = 7.8 Hz, 2H, Ar), 7.53
(t, J = 7.2 Hz, 1H, Ar), 7.45 (t, J = 7.8 Hz, 2H, Ar), 7.36 (t, J =
7.8 Hz, 2H, Ar), 7.15 (t, J = 7.5 Hz, 1H, Ar); 13C NMR
(75 MHz, CDCl3): δ 165.9, 137.9, 134.9, 131.8, 129.0, 128.6,
127.0, 124.5, 120.3; IR(KBr) 3342 (NH), 1653 (CvO) cm−1
;
Anal. calcd for C13H11NO: C, 79.16; H, 5.62; N, 7.10 and found
C, 79.18; H, 5.62; N, 7.12.
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H. B. Zhang, J. Comb. Chem., 2010, 12(3), 307.
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