Nano-Magnetic Sulfonic Acid Catalyzed Facile Synthesis of Diverse Amide Derivatives

Article abstract of DOI:10.1055/s-0036-1588319

The excellent surface catalytic potential of Fe₃O₄-OSO₃H is utilized in the synthesis of symmetrically and unsymmetrically substituted urea derivatives via transamidation reactions. The scope of the surface catalysis is further extended in transamidation reactions of cyclic and acyclic amide derivatives, and in the amidation of fatty acids. In both transamidation and amidation reactions, the catalyst is reusable up to five times without significant loss in its activity.

Full text of DOI:10.1055/s-0036-1588319

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
J. Kothandapani et al.
Paper
Synthesis
Nano-Magnetic Sulfonic Acid Catalyzed Facile Synthesis of Diverse
Amide Derivatives
O
O
Jagatheeswaran Kothandapani
Asaithampi Ganesan
R1
R1
R1
N
N
H
N
H
R3
H
R3-COOH
O
Subramaniapillai Selva Ganesan*
NH2
H2N
R1-NH2
Department of Chemistry, School of Chemical and Biotechnology,
SASTRA University, Thanjavur 613401, India
selva@biotech.sastra.edu
O
R1 = alkyl/aryl
R2 = H/CH3/NC4H8O
R3 = C13H27, C17H35
O
O
R1
R2
R1
NH2
NH2
N
H
N
H
R2
newly formed bonds
shown in thick black colour
Reaction conditions
Fe3O4–OSO3H, Neat, 120 °C, 2 h
Transamidation
21 examples (up to 96% yield)
Fatty acid amidation
9 examples (up to 94% yield)
Received: 16.06.2016
Accepted after revision: 30.08.2016
Published online: 28.09.2016
O
Cl
O
N
4
7
N
DOI: 10.1055/s-0036-1588319; Art ID: ss-2016-z0393-op
16
H
Anti-proliferative (Ref. 5)
Antimicrobial (Ref. 4)
Abstract The excellent surface catalytic potential of Fe3O4–OSO3H is
utilized in the synthesis of symmetrically and unsymmetrically substi-
tuted urea derivatives via transamidation reactions. The scope of the
surface catalysis is further extended in transamidation reactions of cy-
clic and acyclic amide derivatives, and in the amidation of fatty acids. In
both transamidation and amidation reactions, the catalyst is reusable
up to five times without significant loss in its activity.
H
H
OH
O
Cl
N
N
N
5
7
N
O
Antitubercular (Ref. 6)
F
Cytokinin active (Ref. 7)
OMe
O
N
Key words magnetic sulfonic acid, green synthesis, transamidation,
fatty acid amidation, chemoselectivity
N
N
Me
HN
HN
Anti-HIV (Ref. 10)
O
H
N
H
N
Ph
N
N
N
Amide bonds are very important units that are present
in many natural products as well as in biologically relevant
molecules.1 Amide derivatives are found abundantly in
commercial polymers and also in peptide dendrimers.2 Fat-
ty acid amides exhibit excellent anti-inflammatory,3 anti-
microbial,4 antiproliferative,5 and antitubercular6 activities
(Figure 1).
H
H
O
O
Me
Me
Anti-ulcerogenic (Ref. 11)
α-Chymotrypsin inhibitor (Ref. 12a)
H
H
N
N
Ar
Ar
O
Hemolytic activity (Ref. 12b)
Figure 1 Representative examples of bioactive amides
Substituted ureas have found applications as cytokinin
active molecules,7 and as anticancer,8 antimelanoma,9 anti-
HIV,10 and anti-ulcerogenic agents11 (Figure 1). They also
exhibit α-chymotrypsin inhibitory and hemolytic activi-
ties.12 Apart from bioactive molecule synthesis, amides are
also used in the recognition of zwitterions and for selective
binding of anions.13 Furthermore, excellent asymmetric in-
ductions were reported for the reactions performed with
chiral urea derivatives.14
Though transamidation is an elegant way to access di-
verse amide derivatives, the weak electrophilic nature of
the amide carbonyl carbon and the use of mild Brønsted
acidic catalysts for activation of the carbonyl group leads to
prolonged reaction times to attain appreciable conver-
sions.15–17 Moreover, many of the previously reported cata-
lysts18 for transamidation and amidation reactions have no-
table disadvantages such as the requirement of strict anaer-
obic conditions, the use of hazardous organic solvents,
difficulties associated with isolation of the catalyst from the
reaction medium, etc. These problems can be circumvented
by performing the reaction on the surface of strongly acidic
sulfonic acid catalysts under solvent-free conditions. Sul-
fonic acid anchored on a heterogeneous platform exhibited
good catalytic potential due to the presence of multiple cat-
alytically active Brønsted acidic sites.19
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
J. Kothandapani et al.
Paper
Synthesis
Among the available heterogeneous supports for func-
tionalization, the use of magnetically separable Fe3O4
nanoparticles as the platform has unmatched advantages
such as ease of catalyst preparation and functionalization,
facile and convenient magnetic recovery of the catalyst
from the reaction mixture, etc. A recent review by Astruc
and Wang provided a good insight into the applications of
magnetically separable nanocatalysts in diverse organic
transformations.20 We have recently reported facile and
green Fe3O4–OSO3H-catalyzed C–C and C–N bond-forming
reactions.21 Herein, we report the synthesis of symmetri-
cally/unsymmetrically substituted ureas and fatty acid am-
ide derivatives catalyzed by Fe3O4–OSO3H under green, sol-
vent-free reaction conditions.
non-polar solvents (toluene). Reactions in polar protic sol-
vents gave moderately better yields than those in non-polar
and polar aprotic solvents (Table 1, entries 4 and 5 vs 6–8).
The results presented in Table 1 confirmed that the reaction
on the surface of the catalyst proceeded with an unprece-
dented rate (Table 1, entry 3 vs 4–8). Under neat conditions,
the high interaction of the substrate and the catalyst might
have enhanced the electrophilicity of the amide carbonyl
through hydrogen bonding interactions.
To understand the role of the sulfonic acid and Fe3O4 on
the transamidation, the reaction was also carried out sepa-
rately with Fe3O4, chlorosulfonic acid (ClSO3H), silica sul-
fonic acid (SiO2–OSO3H), p-toluenesulfonic acid (PTSA), and
Fe2O3 (Figure 2).
Fe3O4–OSO3H-Catalyzed Transamidation Reaction
Fe3O4
We started our investigations on the transamidation re-
action of urea (1a) with aniline as a model system. The ra-
tionale behind choosing urea as the substrate was the
available scope for exploring chemoselective transamida-
tion reactions with unsymmetrically substituted urea de-
rivatives. Our choice of Fe3O4–OSO3H as the catalyst was
due to the combined effect of strong Brønsted acidity with
the ease of magnetic separation of the catalyst. The Fe3O4–
OSO3H catalyst was prepared based on a previously report-
ed literature procedure.22 Investigation of the Fe3O4–
OSO3H-catalyzed transamidation of urea gave the symmet-
rically substituted urea derivative 2a in good yield under
neat conditions within two hours (Table 1, entry 3).
32%
Fe2O3
ClSO3H
24%
58%
O
N
N
H
H
2a
92%
71%
PTSA
Fe3O4–OSO3H
54%
Table 1 Fe3O4–OSO3H-Catalyzed Transamidation of Ureaa
SiO2–OSO3H
NH2
Figure 2 Efficiency of different Lewis/Brønsted acids on the transami-
dation reaction
O
O
Fe3O4–OSO3H
+
H2N
NH2
N
N
2 h
1a
H
H
These results suggest that neither Fe3O4 nor sulfonic
acid were adequate for the transamidation of urea. The su-
perior performance of the Fe3O4–OSO3H catalyst over PTSA
could be due to the presence of multiple catalytically active
Brønsted acidic sites on the surface of the catalyst. To un-
derstand the relatively high catalytic potential of Fe3O4–
OSO3H over SiO2–OSO3H, the sulfonic acid loading on the
surface was calculated.21 It was found that Fe3O4–OSO3H
had a sulfonic acid group loading of 0.70 mmol g–1 whilst
SiO2–OSO3H had a loading of 0.53 mmol g–1. We presume
that the nano Fe3O4 provided a higher surface area than
bulk SiO2 for sulfonic acid functionalization. Interestingly,
the synthesis of 2a performed with Fe3O4–OSO3Na failed to
yield the product. This signifies the importance of unmodi-
fied sulfonic acid moieties on the surface of Fe3O4 for the
transamidation reaction.
2a 92%
Entry
Solvent
Temp (°C)
Yield (%)
b
1
2
3
4
5
6
7
8
–
r.t.
–
b
–
60
<5
92c
54
62
27
<5
38
b
–
120
reflux
reflux
reflux
120
120
H2O
EtOH
toluene
DMF
DMSO
a Unless otherwise mentioned, all the reactions were carried out with urea
(1a) (1 mmol), aniline (2 mmol) and catalyst (25 mg) for 2 h.
b Reaction was performed under neat conditions.
c Catalyst recyclability studies: run (yield) = 1 (92%); 2 (92%); 3 (90%); 4
(87%); 5 (85%).
To understand the scope of the transamidation reaction
with electron-rich and electron-deficient anilines, a repre-
sentative transamidation reaction of urea was screened
with 4-methylaniline and 4-chloroaniline. The Fe3O4–
OSO3H-catalyzed transamidation reaction was found to be
To substantiate the significance of surface catalysis, the
transamidation reaction of urea was performed in a series
of polar protic (H2O, EtOH), polar aprotic (DMSO, DMF) and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
J. Kothandapani et al.
Paper
Synthesis
R
general for both anilines (see Figure 3). Though both prod-
ucts were obtained in good yields, the reaction rate with
electron-rich 4-methylaniline was higher than with 4-chlo-
roaniline. This difference in reactivity could be due to delo-
calization of the lone electron pair on nitrogen into the aro-
matic ring due to the inductively electron-withdrawing na-
ture of the chloro group. To further confirm the nature of
the substituent on the reaction rate, the transamidation re-
action was performed with strongly electron-withdrawing
4-nitro- and 2-nitroaniline derivatives. As expected, the
formation of the corresponding products was not observed.
Although the rate of transamidation was different for 4-
methylaniline and 4-chloroaniline, attempts to synthesize
unsymmetrically substituted ureas via one-pot transamida-
tion reactions were not successful.
O
O
H2N
R
N
N
N
NH2
H
O
conditions A
Z
2g–i
up to 88%
R = H, Me, Cl
Z = O (1b); CH2 (1c)
conditions A
Fe3O4–OSO3H
neat, 120 oC
3 h
conditions A
conditions A
R = H
NH2
H2N
O
O
N
NH2
N
H
N
H
H
2f
2j
92% (with 1b)
65% (with 1c)
88%
Scheme 2 Synthesis of unsymmetrically substituted urea derivatives
Synthesis of Unsymmetrically Substituted Urea Deriv-
atives
Fe3O4–OSO3H offers an easy and convenient access to highly
valuable unsymmetrically substituted urea derivatives.
Since the nature of amine group and its reactivity
played a crucial role in determining the type of product
formed in the reaction with unsymmetrically substituted
ureas (Scheme 2), it was of interest to further investigate
the role of steric crowding around amine groups on their
reactivity toward unsubstituted urea. We performed the
transamidation reaction with sterically less hindered ben-
zylamine and the relatively more hindered R-(+)-α-methyl-
benzylamine. Similar to the transamidation reaction with
aromatic amines (Table 1), benzylamine also gave symmet-
rically substituted transamidation product 2d in good yield.
Intriguingly, the relatively more hindered R-(+)-α-methyl-
benzylamine stopped at the unsymmetrically substituted
monotransamidation stage and the product 2f was ob-
tained in 92% yield (Scheme 3). We presume that the rela-
tively bulky methyl group in 2f restricts the second nucleo-
philic attack of the chiral amine at the carbonyl group. It
was previously reported in the literature that the Fe(III)-
catalyzed transamidation reaction of urea with sterically
less hindered arylamines gave symmetrical disubstituted
ureas, whilst reactions with the relatively more hindered
piperidine yielded monosubstituted urea products.23a De-
During the course of our investigations on transamida-
tion reactions of formamide and N,N-dimethylformamide
derivatives, we have identified that Fe3O4–OSO3H failed to
initiate the transamidation reaction of a tertiary amide
(Scheme 1).
O
Fe3O4–OSO3H
O
H
NH2
neat, 120 °C, 2 h
H
N
H
NH2
O
3
Fe3O4–OSO3H
Me
no reaction
H
N
neat, 120 °C, 2 h
Me
Scheme 1 Fe3O4–OSO3H-catalyzed transamidation reaction
Changing the reaction temperature, the amount of cata-
lyst, or increasing the reaction time did not change the
course of the reaction. This distinct difference in reactivity
of primary and tertiary amides led us to explore the possi-
bility of the synthesis of unsymmetrically substituted urea
derivatives. It was surmised that transamidation of a urea
derivative with a primary amide at one end and a tertiary
amide on the other might lead to the formation of unsym-
metrically substituted urea derivatives. To our delight,
transamidation reactions performed with morpholine-4-
carboxamide (1b) yielded chemoselective monotransami-
dation at the primary amide side and the products 2g–i
were obtained in good yields (Scheme 2). Interestingly, the
transamidation reaction of 1b or 1c with R-(+)-α-methyl-
benzylamine yielded chemoselective monotransamidation
at the tertiary amide end and the product 2f was obtained
in 92% and 65% yield, respectively. At this juncture, the rea-
son behind selective transamidation of R-(+)-α-methylben-
zylamine at the tertiary amide end was not clear. To further
elucidate the chemoselective transamidation reaction, the
unsymmetrically substituted urea 2g was subjected to the
transamidation reaction with R-(+)-α-methylbenzylamine.
The expected product 2j was obtained in 88% yield. Thus,
H
O
H
H
H
H
H
NH2
O
N
N
H
H
H2N
NH2
2d 96%
1a
CH3
H
O
steric
hindrance
CH3
H
NH2
N
NH2
92%
H
2f
valuable intermediate
for ERK inhibitor synthesis
(Ref. 23b)
Scheme 3 Fe3O4–OSO3H-catalyzed synthesis of unsymmetrically sub-
stituted ureas
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
J. Kothandapani et al.
Paper
Synthesis
tailed mechanistic investigations on the transamidation of
unsymmetrically substituted ureas are underway in our
laboratory.
products in good yields under neat conditions. The results
are presented in Figure 3.
Synthesis of Fatty Acid Amide Derivatives
To further extend the scope of this protocol, we have ex-
tended the transamidation to reactions of phthalimide with
primary amine derivatives. Phthalimide derivatives are
used as precursors for pesticides and fine chemicals,15 and
are also used for the selective protection of primary amines
in the presence of secondary amines.23a The formation of
phthalimide is essential in the synthesis of several natural
products and bioactive molecules. To our delight, Fe3O4–
OSO3H catalyzed the reactions performed with phthalimide
and primary amine derivatives to yield the corresponding
phthalimide-protected amines in excellent yields (Scheme
4).
Akin to the transamidation reaction, direct amidation of
an unactivated fatty acid with an amine is yet another chal-
lenging reaction. Nature has its own unique ways to pre-
pare highly valuable fatty acid amides from their precur-
sors under ambient conditions. It is therefore of interest to
investigate the catalytic potential of Fe3O4–OSO3H in fatty
acid amidation reactions. Conventional amidation reactions
with fatty acid chlorides are considered as less atom eco-
nomical reactions. Preliminary screening of the efficiency
of different catalysts in the fatty acid amidation reaction re-
vealed that Fe3O4–OSO3H displayed exceptional efficiency
compared to other Lewis or Brønsted acids (Table 2, entries
6 vs 1–5).
Decreasing the mole ratio of p-anisidine from three to
two equivalents reduced the product yield (Table 2, foot-
note f). Similarly, reducing the reaction temperature form
120 °C to 100 °C drastically affected the yield of the product
(Table 2, entry 7). To study the generality of the process, the
reaction was performed with different fatty acid (C18, C14)
derivatives and aromatic/aliphatic amines under the opti-
mized conditions. All the products were obtained in excel-
lent yields (Figure 4). The fatty acid amidation reaction per-
formed with aliphatic secondary amines (morpholine and
piperidine) and with an aromatic secondary amine (diphe-
nylamine) did not yield the desired product.
O
O
O
O
R
H
NH2
H3C
NH2
R
H
N
H
R–NH2
H3C
NH
O
Reaction conditions
Fe3O4–OSO3H
NH
neat, 120 °C, 2 h
O
O
O
R
N
Scheme 4 Fe3O4–OSO3H-catalyzed transamidation of diverse amide
derivatives
In conclusion, we have developed a facile and environ-
mentally benign method for both transamidation and fatty
acid amidation reactions catalyzed by Fe3O4–OSO3H. The
same catalyst also facilitated the chemoselective transami-
dation reaction to form unsymmetrically substituted urea
After optimizing the reaction conditions for a cyclic am-
ide derivative, the Fe3O4–OSO3H-catalyzed transamidation
methodology was extended to acyclic monoamide deriva-
tives such as acetamide, formamide, etc. (Scheme 4). To our
delight, both amide derivatives gave the corresponding
O
Cl
Cl
O
O
O
N
N
H
H
N
N
N
N
N
N
H
H
H
H
H
H
2a (92%)
2b (91%)
2c (94%)
2d (96%)
Cl
O
O
O
N
O
O
O
O
N
N
N
N
N
N
H
NH2
H
H
H
N
N
O
O
O
O
H
H
2g (85%)
2h (88%)
2f (92%)
2i (85%)
2e (86%)
H
H
H
N
O
H
H
N
H
O
N
H
H
N
N
H
N
N
O
O
H
H
O
Cl
Br
2j (88%)
3a (89%)
3b (91%)
3c (93%)
3d (86%)
4a (85%)
O
O
H
O
N
H
N
H
N
N
OH
N
N
O
O
O
Cl
O
O
O
4b (86%)
4c (89%)
4d (84%)
5a (90%)
5b (88%)
5c (90%) O
Figure 3 Substrate scope for the Fe3O4–OSO3H-catalyzed transamidation reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
J. Kothandapani et al.
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Synthesis
Table 2 Screening of the Reaction Condition for the Synthesis of 6aa
for the synthesized molecules were recorded on a Bruker AVANCE II
spectrometer using TMS as an internal standard and CDCl3 or DMSO-
d6 as the solvent. For 6g, 1H NMR (500 MHz) was recorded on a Bruker
AVANCE III spectrometer using TMS as an internal standard and CDCl3
as the solvent.
NH2
H
OH
catalyst
N
16
+
16
reaction
conditions
O
O
OMe
6a 94%
OMe
Symmetrically/Unsymmetrically Substituted Ureas 2a–j; General
Procedure
Entry
Catalyst
Time (h)
Yield of 6a (%)b
Urea/morpholine-4-carboxamide/N-phenylmorpholine-4-carboxam-
ide (1.0 mmol), aromatic/aliphatic amine (2.0/1.0 mmol) and Fe3O4–
OSO3H (25 mg) were added to a round-bottom flask and heated to
120 °C for 2 h. The progress of the reaction was monitored by TLC. Af-
ter completion of the reaction, the mixture was cooled to r.t. and
EtOAc (1 × 20 mL) was added. The catalyst was isolated from the reac-
tion mixture using an external magnet. The EtOAc layer was washed
with 5% HCl (1 × 10 mL) and H2O (1 × 10 mL), and dried over anhy-
drous Na2SO4, filtered and the solvent was evaporated under reduced
pressure. The crude residue was purified by silica gel column chroma-
tography (EtOAc–hexane, 1:1).
1
2
3
4
5
6
7
Fe3O4
Fe2O3
2
2
28
<5
SiO2–OSO3H
ClSO3H
2
49
2
42
PTSAc
2
68
Fe3O4–OSO3Hd
Fe3O4–OSO3H
2
94e (84)f
23g
12
a All the reactions were carried with stearic acid (1 mmol), p-anisidine (3
mmol), catalyst (25 mg), and the reaction mixture was heated at 120 °C for
2 h.
1,3-Diphenylurea (2a)
Colorless solid; yield: 195 mg (92%); mp 234–235 °C (Lit.24 234–
237 °C).
1H NMR (300 MHz, DMSO-d6): δ = 6.96 (t, J = 7.5 Hz, 2 H), 7.28 (t, J =
8.4 Hz, 4 H), 7.45 (d, J = 8.7 Hz, 4 H), 8.66 (s, 2 H).
b Yield of isolated product.
c p-Toluenesulfonic acid.
d The reaction carried out with Fe3O4–OSO3Na did not yield the desired
product.
e Catalyst recyclability studies: run (yield) = 1 (94%); 2 (94%); 3 (93%); 4
(91%); 5 (91%).
f The reaction was carried out with p-anisidine (2 mmol).
g The reaction was carried out at 100 °C.
1,3-Bis(4-chlorophenyl)urea (2b)
Colorless solid; yield: 255 mg (91%); mp 300–301 °C (Lit.25 302 °C).
1H NMR (300 MHz, DMSO-d6): δ = 7.33 (dd, J = 6.9, 2.1 Hz, 4 H), 7.48
(dt, J = 9.0, 2.1 Hz, 4 H), 8.87 (s, 2 H).
H
H
H
N
N
N
16
16
16
O
O
O
O
Cl
1,3-Bis(4-methylphenyl)urea (2c)
6a (94%)
6b (91%)
6c (88%)
Colorless solid; yield: 225 mg (94%); mp 262–264 °C (Lit.25 269 °C).
1H NMR (300 MHz, DMSO-d6): δ = 2.23 (s, 6 H), 7.07 (d, J = 8.4 Hz, 4
H), 7.32 (d, J = 8.4 Hz, 4 H), 8.45 (s, 2 H).
H
N
H
N
H
N
16
16
16
O
O
O
Br
6d (92%)
6e (87%)
6f (90%)
NO2
1,3-Dibenzylurea (2d)
Pale yellow solid; yield: 230 mg (96%); mp 170–172 °C (Lit.25 165–
166 °C).
1H NMR (300 MHz, CDCl3): δ = 4.36 (d, J = 5.7 Hz, 4 H), 4.77 (br s, 2 H),
H
H
H
N
N
N
12
12
16
O
O
O
Cl
7.22–7.34 (m, 10 H).
6g (76%)
6h (89%)
6i (92%)
Figure 4 Substrate scope for the fatty acid amidation reaction
1,3-Bis(4-methoxyphenyl)urea (2e)
Brown solid; yield: 234 mg (86%); mp 238–240 °C (Lit.25 240 °C).
1H NMR (300 MHz, DMSO-d6): δ = 3.70 (s, 6 H), 6.86 (d, J = 7.2 Hz, 4
H), 7.33 (d, J = 9.0 Hz, 4 H), 8.37 (s, 2 H).
derivatives. All the products were obtained in good to excel-
lent yields.
[(1R)-1-phenylethyl]urea (2f)
Colorless solid; yield: 150 mg (92%); mp 124 °C (Lit.26 118–120 °C).
1H NMR (300 MHz, DMSO-d6): δ = 1.29 (d, J = 6.9 Hz, 3 H), 4.70 (q, J =
7.5 Hz, 1 H), 5.42 (s, 2 H), 6.41 (d, J = 8.1 Hz, 1 H), 7.17–7.33 (m, 5 H).
Urea and phthalimide were purchased from Loba Chemie Pvt Ltd. Ar-
omatic anilines and morpholine were purchased from Sigma Aldrich,
Avra Chemicals and SD Fine Chemicals Limited. Anhydrous iron chlo-
ride, iron sulfate pentahydrate, ammonium hydroxide and the fatty
acids were purchased from Avra Chemicals. The products were puri-
fied by column chromatography over Merck silica gel (60–120 mesh)
and for the preparation of SiO2-OSO3H Merck silica gel (230–400
mesh) was used. Melting points were determined using an Optics
Technology digital melting point apparatus with silicon oil bath and
are uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra
N-Phenylmorpholine-4-carboxamide (2g)
Brown solid; yield: 175 mg (85%); mp 152–156 °C (Lit.27 158–160 °C).
1H NMR (300 MHz, CDCl3): δ = 3.48 (t, J = 4.5 Hz, 4 H), 3.74 (t, J = 4.8
Hz, 4 H), 6.38 (s, 1 H), 7.03–7.13 (m, 1 H), 7.26–7.36 (m, 4 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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J. Kothandapani et al.
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Synthesis
N-(4-Methylphenyl)morpholine-4-carboxamide (2h)
N-(4-Chlorophenyl)acetamide (4b)
Brown solid; yield: 193 mg (88%); mp 153 °C (Lit.28 155 °C).
Pale yellow solid; yield: 145 mg (86%); mp 133 °C (Lit.31 133–135 °C).
1H NMR (300 MHz, CDCl3): δ = 2.30 (s, 3 H), 3.46 (t, J = 4.5 Hz, 4 H),
3.73 (t, J = 5.1 Hz, 4 H), 6.35 (s, 1 H), 7.10 (d, J = 8.4 Hz, 2 H), 7.22 (d, J =
8.4 Hz, 2 H).
1H NMR (300 MHz, CDCl3): δ = 2.18 (s, 3 H), 7.26 (br s, 1 H), 7.28 (d, J =
8.4 Hz, 2 H), 7.45 (d, J = 8.7 Hz, 2 H).
N-(4-Methylphenyl)acetamide (4c)
Colorless solid; yield: 132 mg (89%); mp 147–149 °C (Lit.31 149–
152 °C).
N-(4-Chlorophenyl)morpholine-4-carboxamide (2i)
Brown solid; yield: 204 mg (85%); mp 172–175 °C (Lit.29 199–202 °C).
1H NMR (300 MHz, CDCl3): δ = 3.51 (t, J = 4.5 Hz, 4 H), 3.72 (t, J = 5.1
Hz, 4 H), 7.18–7.27 (m, 2 H), 7.36–7.42 (m, 2 H), 8.20 (s, 1 H).
1H NMR (300 MHz, CDCl3): δ = 2.16 (s, 3 H), 2.31 (s, 3 H), 7.12 (d, J =
8.1 Hz, 2 H), 7.20 (br s, 1 H), 7.45 (d, J = 9.0 Hz, 2 H).
3-(Phenyl)-1-[(1R)-1-phenylethyl]urea (2j)23b
N-(4-Methoxyphenyl)acetamide (4d)
Colorless solid; yield: 210 mg (88%); mp 222–224 °C.
Colorless solid; yield: 138 mg (84%); mp 128 °C (Lit.31 126–128 °C).
1H NMR (300 MHz, DMSO-d6): δ = 1.38 (d, J = 7.2 Hz, 3 H), 4.80 (q, J =
7.2 Hz, 1 H), 6.60 (d, J = 7.8 Hz, 1 H), 6.87 (td, J = 7.2, 0.9 Hz, 1 H), 6.96
(td, J = 7.5, 1.2 Hz, 1 H), 6.90–7.14 (m, 3 H), 7.20–7.27 (m, 2 H), 7.30–
7.43 (m, 1 H), 7.46 (d, J = 1.2 Hz, 1 H), 8.37 (s, 1 H), 8.65 (s, 1 H).
1H NMR (300 MHz, CDCl3): δ = 2.16 (s, 3 H), 3.79 (s, 3 H), 6.85 (dd, J =
6.9, 2.1 Hz, 2 H), 7.11 (br s, 1 H), 7.38 (dd, J = 6.8, 3.3 Hz, 2 H).
2-Benzyl-2,3-dihydro-1H-isoindole-1,3-dione (5a)
Off-white solid; yield: 213 mg (90%); mp 117–121 °C (Lit.32 115.9–
116.0 °C).
Aliphatic and Cyclic Amides 3a–d, 4a–d, 5a–c; General Procedure
Formamide/acetamide/phthalimide (1.0 mmol), aromatic/aliphatic
amine (1.0 mmol) and Fe3O4–OSO3H (25 mg) were added to a round-
bottom flask and heated at 120 °C for 2 h. After completion of the re-
action, the products were isolated as described above. For compounds
3a–d, additional signals were observed in the 1H NMR spectra due to
the presence of rotamers.30
1H NMR (300 MHz, CDCl3): δ = 4.85 (s, 2 H), 7.23–7.29 (m, 3 H), 7.42–
7.45 (m, 2 H), 7.67–7.73 (m, 2 H), 7.79–7.89 (m, 2 H).
2-(2-Hydroxyethyl)-2,3-dihydro-1H-isoindole-1,3-dione (5b)
Off-white solid; yield: 168 mg (88%); mp 130–132 °C (Lit.32 126.1–
126.7 °C).
1H NMR (300 MHz, CDCl3): δ = 2.43 (br s, 1 H), 3.86–3.93 (m, 4 H),
7.73 (q, J = 6.9 Hz, 2 H), 7.86 (q, J = 5.4 Hz, 2 H).
N-Phenylformamide (3a)
Yellow solid; yield: 107 mg (89%); mp 42–44 °C (Lit.30 46–47 °C).
1H NMR (300 MHz, CDCl3): δ = 7.10 (dd, J = 8.7, 3.3 Hz, 2 H), 7.16–7.20
(m, 2 H), 7.35 (q, J = 7.5 Hz, 4 H), 7.55 (dd, J = 7.5, 1.2 Hz, 2 H), 8.37 (br
s, 1 H), 8.38 (d, J = 1.5 Hz, 1 H), 8.69 (d, J = 11.4 Hz, 1 H).
2-[(1R)-1-Phenylethyl]-2,3-dihydro-1H-isoindole-1,3-dione (5c)33
Off-white solid; yield: 225 mg (90%); mp 172 °C.
1H NMR (300 MHz, CDCl3): δ = 1.93 (d, J = 7.5 Hz, 3 H), 5.57 (q, J = 7.2
Hz, 1 H), 7.23–7.28 (m, 1 H), 7.34 (t, J = 4.8 Hz, 2 H), 7.51 (d, J = 8.1 Hz,
2 H), 7.65–7.70 (m, 2 H), 7.78–7.82 (m, 2 H).
N-(4-Chlorophenyl)formamide (3b)
Brown solid; yield: 141 mg (91%); mp 96–98 °C (Lit.30 98–99 °C).
1H NMR (300 MHz, CDCl3): δ = 7.03 (dt, J = 6.6, 1.8 Hz, 2 H), 7.27–7.36
(m, 6 H), 7.50 (dt, J = 8.7, 3.0 Hz, 3 H), 8.04 (s, 1 H), 8.38 (d, J = 1.5 Hz,
1 H), 8.65 (d, J = 11.4 Hz, 1 H).
Fatty Acids Amides 6a–i; General Procedure
The fatty acid (stearic acid, myristic acid) (1.0 mmol), aromatic amine
(3.0 mmol) and Fe3O4–OSO3H (25 mg) were added to a round-bottom
flask and heated to 120 °C for 2 h. The progress of the reaction was
monitored by TLC. After completion of the reaction, the mixture was
cooled to r.t. and EtOAc (1 × 20 mL) was added. The catalyst was iso-
lated from the reaction mixture using an external magnet. The EtOAc
layer was washed with 5% HCl (1 × 10 mL) and H2O (1 × 10 mL), and
dried over anhydrous Na2SO4, filtered and the solvent was evaporated
under reduced pressure. The crude mixture was purified by silica gel
column chromatography (EtOAc–hexane, 1:4).
N-(4-Methylphenyl)formamide (3c)
Brown solid; yield: 125 mg (93%); mp 45–47 °C (Lit.30 48–49 °C).
1H NMR (300 MHz, DMSO-d6): δ = 2.25 (s, 3 H), 7.05–7.13 (m, 3 H),
7.47 (d, J = 8.4 Hz, 1 H), 8.23 (d, J = 1.8 Hz, 1 H), 8.69 (d, J = 11.1 Hz, 1
H), 10.09 (br s, 1 H).
N-(4-Bromophenyl)formamide (3d)
Dark yellow solid; yield: 172 mg (86%); mp 110–112 °C (Lit.30 111–
113 °C).
1H NMR (300 MHz, CDCl3): δ = 6.97 (d, J = 8.7 Hz, 2 H), 7.22 (br s, 1 H),
7.45–7.47 (m, 6 H), 7.49 (d, J = 8.7 Hz, 2 H), 7.83 (br s, 1 H), 8.39 (s, 1
H), 8.65 (d, J = 11.1 Hz, 1 H).
N-(4-Methoxyphenyl)octadecanamide (6a)
Colorless solid; yield: 364 mg (94%); mp 50–54 °C (Lit.4 54–56 °C).
1H NMR (300 MHz, CDCl3): δ = 0.80 (t, J = 6.6 Hz, 3 H), 1.15–1.17 (m,
28 H), 1.62–1.64 [m, 2 H (moisture peak also merged)], 2.25 (t, J = 7.5
Hz, 2 H), 3.72 (s, 3 H), 6.79 (d, J = 9.0 Hz, 2 H), 6.99 (br s, 1 H), 7.34 (d,
J = 8.7 Hz, 2 H).
N-Phenylacetamide (4a)
Colorless solid; yield: 114 mg (85%); mp 110–112 °C (Lit.31 112–
13C NMR (75 MHz, CDCl3): δ = 14.1, 22.7, 25.7, 29.3, 29.4, 29.5, 29.6,
29.7, 31.9, 37.6, 55.4, 114.1, 121.7, 131.1, 156.3, 171.3.
114 °C).
1H NMR (300 MHz, CDCl3): δ = 2.18 (s, 3 H), 7.11 (t, J = 7.2 Hz, 1 H),
7.20 (br s, 1 H), 7.32 (t, J = 8.1 Hz, 2 H), 7.49 (d, J = 7.8 Hz, 2 H).
N-Phenyloctadecanamide (6b)
Colorless solid; yield: 327 mg (91%); mp 84–86 °C (Lit.34 85–87 °C).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
J. Kothandapani et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 6.6 Hz, 3 H), 1.25–1.32 (m,
26 H), 1.61–1.74 (m, 4 H), 2.35 (t, J = 7.8 Hz, 2 H), 7.10 (t, J = 7.5 Hz, 1
H), 7.15 (br s, 1 H), 7.32 (t, J = 7.5 Hz, 2 H), 7.51 (d, J = 7.8 Hz, 2 H).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588319.
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N-(4-Chlorophenyl)octadecanamide (6c)
Colorless solid; yield: 346 mg (88%); mp 55–58 °C (Lit.4 55–57 °C).
References
1H NMR (300 MHz, CDCl3): δ = 0.81 (t, J = 6.9 Hz, 3 H), 1.18–1.25 (m,
25 H), 1.54–1.67 (m, 5 H), 2.27 (t, J = 7.8 Hz, 2 H), 7.10 (br s, 1 H), 7.20
(d, J = 7.2 Hz, 2 H), 7.40 (d, J = 8.7 Hz, 2 H).
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N-(4-Methylphenyl)octadecanamide (6d)
Colorless solid; yield: 344 mg (92%); mp 70–71 °C (Lit.34 70–71 °C).
1H NMR (300 MHz, CDCl3): δ = 0.81 (t, J = 6.3 Hz, 3 H), 1.18–1.25 (m,
27 H), 1.59–1.66 (m, 3 H), 2.23 (s, 3 H), 2.26–2.28 (m, 2 H), 7.02–7.05
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N-(3-Nitrophenyl)octadecanamide (6e)
Colorless solid; yield: 352 mg (87%); mp 43–45 °C (Lit.4 49–51 °C).
1H NMR (300 MHz, CDCl3): δ = 0.81 (t, J = 6.3 Hz, 3 H), 1.18–1.27 (m,
28 H), 1.67–1.69 (m, 2 H), 2.33 (t, J = 7.2 Hz, 2 H), 7.30 (br s, 1 H), 7.42
(t, J = 8.1 Hz, 1 H), 7.88 (dt, J = 6.0, 2.1 Hz, 2 H), 8.29 (t, J = 2.1 Hz, 1 H).
N-(4-Bromophenyl)octadecanamide (6f)
Colorless solid; yield: 394 mg (90%); mp 35–38 °C (Lit.4 37–39 °C).
1H NMR (300 MHz, CDCl3): δ = 0.81 (t, J = 6.3 Hz, 3 H), 1.18–1.25 (m,
25 H), 1.55–1.66 (m, 5 H), 2.27 (t, J = 7.8 Hz, 2 H), 7.09 (br s, 1 H), 7.18
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N-Benzyloctadecanamide (6g)
White solid; yield: 282 mg (76%); mp 85–87 °C (Lit.35 84–86 °C).
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26 H), 1.62–1.68 (m, 4 H), 2.21 (t, J = 4.5 Hz, 2 H), 4.44 (d, J = 3.6 Hz, 2
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N-Phenyltetradecanamide (6h)
Colorless solid; yield: 269 mg (89%); mp 48–50 °C (Lit.4 49–51 °C).
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N-(4-Chlorophenyl)tetradecanamide (6i)
Colorless solid; yield: 310 mg (92%); mp 80–84 °C (Lit.4 85–87 °C).
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Acknowledgment
Financial support from the Science and Engineering Research Board,
DST-SERB (No. EMR/2016/000317) and the Council of Scientific and
Industrial Research, CSIR [80(0085)/16/EMR-II] is gratefully acknowl-
edged. The authors thank SASTRA University for providing lab space
and NMR facilities. S.S.G. thanks Dr. P. Vairaprakash for useful discus-
sions and J.K. thanks SASTRA University for financial assistance.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H