Fe(ClO 4) 3 ·h 2 O-Catalyzed Ritter Reaction: A Convenient Synthesis of Amides from Esters and Nitriles

Article abstract of DOI:10.1055/s-0037-1610658

An efficient and inexpensive synthesis of N-substituted amides from the Ritter reaction of nitriles with esters catalyzed by Fe(ClO ₄) ₃ ·H ₂ O is described. Fe(ClO ₄) ₃ ·H ₂ O is an economically efficient catalyst for the Ritter reaction under solvent-free conditions. Reactions of a range of esters (benzyl, sec-alkyl, and tert-butyl esters) with nitriles (primary, secondary, tertiary, and aryl nitriles) were performed to provide the corresponding amides in high to excellent yields.

Full text of DOI:10.1055/s-0037-1610658

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–H
letter
A
en
C. Feng et al.
Letter
Synlett
Fe(ClO4)3·H2O-Catalyzed Ritter Reaction: A Convenient Synthesis
of Amides from Esters and Nitriles
R1: benzyl, sec-alkyl
Chengliang Fenga
Bin Yana
Guibo Yina
Junqing Chenb
Min Ji*b
O
O
tert-butyl
R1
42 examples
72–94% yield
R1
R2
N
H
O
O
Fe(ClO4)3⋅H2O (5 mol%)
R2 CN
+
80 °C
R2: aryl, benzyl,
O
O
O
O
14 examples
88–97% yield
sec-alkyl
R2
N
H
O
Ac2O, Fe(ClO4)3⋅H2O
a Institute of Pharmaceutical Engineering, Jiangsu
College of Engineering and Technology, Nantong,
Jiangsu 226000, P. R. of China
CN
OH
N
H
1 example
84% yield
+
80 °C
one-pot reaction
fcl085620@163.com
b School of Biological Sciences & Medical Engineering,
Southeast University, Nanjing, Jiangsu 211189,
P. R. of China
O
O
O
O
O
drug synthesis
(87%)
N
H
N
N
O
O
itopride
Received: 06.06.2018
Accepted after revision: 24.08.2018
Published online: 26.09.2018
Fortunately, various new catalysts have been developed to
replace the acids.8 These new effective catalysts include
Lewis acids and organic catalysts such as boron trifluoride,9
o-benzenedisulfonimide,10 iodine (I2),11 FeCl3,12 CoCl2,13
Fe3+-montmodlonite,14 DNBSA,15 SBNPSA,16 Al(HSO4)3,17
In(OTf)3,18 sulfated tungstate,19 SBSANS,20 CoFe2O4@SiO2–
DASA,21 PFPAT,22 Cu(OTf)2,23 and others.
DOI: 10.1055/s-0037-1610658; Art ID: st-2018-b0459-l
Abstract An efficient and inexpensive synthesis of N-substituted am-
ides from the Ritter reaction of nitriles with esters catalyzed by
Fe(ClO4)3·H2O is described. Fe(ClO4)3·H2O is an economically efficient
catalyst for the Ritter reaction under solvent-free conditions. Reactions
of a range of esters (benzyl, sec-alkyl, and tert-butyl esters) with nitriles
(primary, secondary, tertiary, and aryl nitriles) were performed to pro-
vide the corresponding amides in high to excellent yields.
The classical Ritter reaction is the reaction of nitriles
with alcohols or alkenes to produce amides.8 On the other
hand, the Ritter reaction could also been carried out by us-
ing esters (Scheme 1, paths a–d).22,24–29 However, these re-
actions still have some drawbacks including the use of ac-
ids, expensive catalysts, high reaction temperature, long re-
action time, and high catalyst loading. Furthermore, it was
noted that most of the reports focused on tert-butyl acetate
as a substrate. And only three papers involved the employ-
ment of benzyl acetate (Scheme 1, path b),28 1-phenylethyl
acetate (Scheme 1, path c),29 and cyclohexyl acetate
(Scheme 1, path d)26 in the Ritter reaction. Thus, there is a
need to explore a new system that employs metal catalysts
with a new starting material. Herein, an efficient and mild
methodology was developed for the synthesis of amides
through the reaction of nitriles and esters catalyzed by
Fe(ClO4)3·H2O, and the corresponding amides were achieved
in good to excellent yields.
To explore this approach, the reaction of benzyl acetate
with benzonitrile by using an Fe catalyst was chosen as a
model reaction for the optimization study. The results are
summarized in Table 1. Initially, we tested various Fe cata-
lysts such as FeCl3, Fe(NO3)3·8H2O, Fe(ClO4)3·H2O, Fe(OTf)2,
FeBr2, FeCl2·4H2O, Fe2(SO4)3·3H2O, and Fe(OTf)3 for this reac-
tion, in which Fe(ClO4)3·H2O was found to be the best cata-
lyst for providing an excellent yield of the desired product
N-benzylbenzamide (a) (entry 3). However, the catalysts
such as FeCl3, Fe(OTf)2, FeBr2, FeCl2·4H2O, and Fe(OTf)3 fur-
nished the N-benzylbenzamide (a) in moderate to good
Key words Ritter reaction, Fe(ClO4)3·H2O, esters, nitriles, solvent-free
reactions
The amide compounds are important building blocks in
organic synthesis. They not only constitute versatile inter-
mediates for the synthesis of various peptides and lactam
structures, but also serve as key precursors in the synthesis
of a variety of natural products and pharmaceuticals.1,2 The
traditional methodology for amide formation is the acyla-
tion of amines with carboxylic acid, acid chlorides, anhy-
drides, active esters, and so on.3 Moreover, some alternative
methods including the Staudinger reaction,4 the Schmidt
reaction,5 the Beckmann rearrangement,6 the oxidative
amidation of aldehydes and alcohols7 have also been developed
to provide amides. However, many of these methods have
the innate drawbacks of producing a stoichiometric amount
of byproducts and of employing highly hazardous reagents.
In recent years, the direct transformation of nitriles to
amides by the Ritter reaction has emerged as an atom eco-
nomical alternative. The reaction is a simple one-pot strate-
gy for amide formation by condensation of alcohols, or suit-
ably substituted alkenes with nitriles in the presence of a
stoichiometric amount of a strong acid.8 Although effective,
the employment of the large amount of toxic and corrosive
acids in the reaction limits its application on large scale.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

B
C. Feng et al.
Letter
Synlett
Table 1 Optimization of Reaction Conditionsa
Previous works
O
O
catalyst
a)
O
+
R
CN
O
ref 22, 24–29
O
R
N
CN
H
catalyst
O
O
N
H
+
O
T, t
O
silica
a
sulfuric acid
N
ref 28
b)
+
R
H
60 °C
CN
O
Entry
Catalyst (mol%)
T (°C)
t (h)
Yield (%)b
R
1
2
FeCl3 (5)
80
80
5
5
67
n.r.
87
38
41
48
73
n.r.
n.r.
57
71
76
83
82
86
88
88
86
53
59
71
78
83
88
88
O
I2
Fe(NO3)3·9H2O (5)
Fe(ClO4)3·H2O (5)
Fe(OTf)2 (5)
R
CN
+
O
ref 29
ref 26
R
N
c)
d)
3
80
80
5
80 °C, 18 h
H
R: aryl, alkyl
4
5
5
FeBr2 (5)
80
5
O
ZnCl2/SiO2
100 °C
O
6
FeCl2·4H2O (5)
Fe(OTf)3 (5)
80
5
+
R
CN
R
N
O
H
7
80
5
R: aryl, CH3
8
Fe2(SO4)3·3H2O (5)
–
80
5
This work
O
O
9
80
5
R
R
R1
N
O
R1 CN
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Fe(ClO4)3·H2O (5)
Fe(ClO4)3·H2O (5)
Fe(ClO4)3·H2O (5)
Fe(ClO4)3·H2O (5)
Fe(ClO4)3·H2O (5)
Fe(ClO4)3·H2O (5)
Fe(ClO4)3·H2O (5)
Fe(ClO4)3·H2O (5)
Fe(ClO4)3·H2O (5)
Fe(ClO4)3·H2O (1)
Fe(ClO4)3·H2O (1)
Fe(ClO4)3·H2O (2)
Fe(ClO4)3·H2O (2)
Fe(ClO4)3·H2O (4)
Fe(ClO4)3·H2O (4)
Fe(ClO4)3·H2O (10)
r.t.
40
24
24
24
12
5
+
R: benzyl, sec-alkyl,
tert-butyl
Fe(ClO4)3⋅H2O (5 mol%)
e)
R1: aryl, benzyl,
80 °C, 2–8 h
O
sec-alkyl
O
O
50
R1
N
H
O
O
60
O
70
OH
Ac2O, Fe(ClO4)3⋅H2O
N
H
100
100
100
120
80
3
+
CN
80 °C
5
12
2
Scheme 1 Ritter reaction with esters
5
yields (entries 1 and 4–6), whereas, Fe(NO3)3·8H2O and
Fe(SO4)3·3H2O were ineffective (entries 2 and 8). Moreover,
the product formation was not observed in the absence of
catalyst (entry 9).
80
12
5
80
80
12
5
This result prompted us to investigate the amount of the
catalyst and the effect of the reaction temperature for the
effective progress of the reaction. Similarly, benzyl acetate
and benzonitrile were selected as the model substrates to
optimize the amount of Fe(ClO4)3·H2O. It was observed that
when the mixture was stirred in the presence of 1.0, 2.0,
4.0, 5.0, and 10.0 mol% Fe(ClO4)3·H2O the product N-benzyl-
benzamide (a) was separated with yields of 53, 71, 83, 87,
and 88% after five hours, respectively (Table 1, entries 3, 19,
21, 23, and 25). Although the employment of 4.0 mol% catalyst
could also afford the product (a) in good yield (88%) by pro-
longing the reaction time (12 hours), 5.0 mol % of catalyst was
seen to be sufficient to obtain the best yield (Table 1, entry 3).
Further investigation of the effect of the reaction temperature
(Table 1, entries 10–18) indicated that 80 °C was suitable for
this reaction.
80
80
12
5
80
a Reaction conditions: benzyl acetate (6 mmol), benzonitrile (5 mmol).
b Isolated yields; n.r. = no reaction.
mary alkyl, sec-alkyl, and tert-butyl esters) were investigat-
ed for the reaction with benzonitrile. The results are sum-
marized in Table 2. We found that acetic esters (benzyl and
sec-alkyl esters) could proceed well and afford the corre-
sponding amides in good to excellent yields. It was noted
that acetic benzyl esters bearing either electron-donating
or electron-withdrawing substituents afforded the prod-
ucts in good to excellent yields, indicating that the reaction
was not sensitive to electronic effects (Table 2, entries 1–6).
In addition, this reaction procedure worked well with tert-
butyl acetate, and the target product (j) was obtained in
94% yield (Table 2, entry 10). The sec-alkyl esters including
cyclohexyl acetate cyclopentyl acetate, and isopropyl ace-
tate could all be employed and the corresponding amides
Prompted by the efficiency of the above methodology,
we examined the scope and generality of the Ritter reaction
with Fe(ClO4)3·H2O (5.0mol %) at 80 °C under solvent-free
conditions. First, a wide range of acetic esters (benzyl, pri-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

C
C. Feng et al.
Letter
Synlett
Table 2 (continued)
were delivered in 83–87% yield (Table 2, entries 7–9). Un-
fortunately, when the system was applied to ethyl acetate
no reaction was observed (Table 2, entry 13).
Entry
R
Product, t (h), yield (%)b
O
Table 2 Reaction of Benzonitrile and Esters (benzyl, sec-alkyl, tert-bu-
N
H
9
isopropyl
tyl, and Primary Alkyl Esters)a
i, (5), (83)
O
O
CN
Fe(ClO4)3 H2O
80 °C
R
O
R
+
N
O
H
N
H
10
11
tert-butyl
a–m
j, (5), (94)
Entry
1
R
Product, t (h), yield (%)b
O
O
N
H
C6H5CHCH3
N
H
C6H5CH2
k, (5), (88)
a, (5), (87)
O
Cl
O
12
13
C6H5CHC6H5
N
H
N
H
2
3
2-ClC6H4CH2
l, (5), (85)
b, (5), (88)
O
O
N
H
N
H
ethyl
4-NO2C6H4CH2
NO2
m, (24), (n.r.)
c, (6), (76)
a Reaction conditions: The reaction of benzonitrile (5 mmol) and esters (6
mmol) was carried out in the presence of Fe(ClO4)3·H2O (5 mol%) at 80 °C
for 5–6 h.
O
b Isolated yields; n.r. = no reaction.
N
H
4
5
6
7
8
4-CH3C6H4CH2
2-CH3C6H4CH2
4-ClC6H4CH2
cyclopentyl
d, (5), (90)
Next, a series of nitriles including primary, secondary,
and tertiary nitriles were investigated again under the same
reaction conditions, as shown in Table 3. The results indi-
cate that the electron-donating substituents at the para,
meta, and ortho site of the aryl nitriles might have no im-
pact on the reaction and afforded the corresponding amide
products in similar yields. It was observed that benzyl ace-
tate reacted with 3-methylbenzonitrile, 2-methylbenzoni-
trile, and 4-methylbenzonitrile and provided desired prod-
ucts N-benzyl-3-methylbenzamide (n), N-benzyl-2-meth-
ylbenza-mide (o), and N-benzyl-4-methylbenzamide (p) in
86, 87, and 87% yield, respectively (Table 3, entries 1–3).
Similar results were observed for electron-withdrawing
substituents of the aryl nitriles (Table 3, entries 4–7). Elec-
tron-donating or electron-withdrawing substituents on the
aryl nitriles produced good to excellent yields of amides
(Table 3, entries 1–8), indicating that the reaction was also
not sensitive to electronic effects. When the reaction proce-
dure was performed with benzyl nitriles, the corresponding
amides were also obtained in good to excellent yields after
eight hours. Furthermore, the reaction proceeded well with
secondary and tertiary nitriles, and afforded the target mol-
O
N
H
e, (5), (88)
O
N
H
Cl
f, (5), (91)
O
N
H
g, (5), (86)
O
N
H
cyclohexyl
h, (5), (87)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

D
C. Feng et al.
Letter
Synlett
Table 3 (continued)
ecules in good yields. For example, a reaction of 1-phenyl-
cyclobutanecarbonitrile and cyclopropyl cyanide with ben-
zyl acetate afforded the products (w and x) in 89 and 84%
yield, respectively (Table 3, entries 10 and 11). Furthermore,
tert-butyl acetate also reacted well with a series of substi-
tuted aromatic nitriles and benzyl nitriles and afforded the
corresponding N-tert-butyl amides in good to excellent
yields (Table 3, entries 17–26). In addition, we found that
acetic sec-alkyl and primary alkyl esters did not react with
benzyl nitriles (Table 3, entries 14 and 27–28). Moreover,
acetic esters did not react with acetonitrile (Table 3, entry 29).
Entry
R
R1
Product, t (h), yield (%)b
O
N
H
8
C6H5CH2
4-MeOC6H4
O
u, (5), (89)
Cl
O
N
H
9
C6H5CH2
2,6-Cl2C6H3
cyclopropyl
Cl
v, (5), (83)
Table 3 Reaction of Various Nitriles and Acetic Estersa
O
O
O
Fe(ClO4)3 H2O
80 °C
N
10
C6H5CH2
H
+
R1–CN
R
R
R1
N
O
H
w, (6), (89)
n–z and 1a–1p
O
Entry
1
R
R1
Product, t (h), yield (%)b
N
11
12
C6H5CH2
C6H5C(CH2)3
O
H
N
H
C6H5CH2
C6H5CH2
C6H5CH2
3-CH3C6H4
2-CH3C6H4
4-CH3C6H4
x, (8), (84)
y, (8), (82)
z, (8), (85)
n, (5), (86)
O
O
O
N
O
C6H5CH2
C6H5CH2
H
N
H
2
3
o, (5), (87)
O
N
H
13
14
15
C6H5CH2
4-CH3C6H4CH2
N
H
p, (5), (87)
O
cyclohexyl
C6H5CH2
N
H
N
H
1a, (24), (n.r.)
4
5
6
7
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
4-F3CC6H4
F3C
O
q, (5), (94)
N
H
cyclopentyl 4-CH3OC6H4
O
O
F
N
H
1b, (5), (85)
3-FC6H4
O
r, (5), (89)
N
H
16
17
cyclohexyl
4-F3CC6H4
O
F3C
N
H
4-NO2C6H4
1c, (5), (90)
O2N
O
s, (8), (72)
N
H
O
tert-butyl
4-NO2C6H4
Br
O2N
N
3-BrC6H4
H
1d, (5), (81)
t, (5), (88)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

E
C. Feng et al.
Letter
Synlett
Table 3 (continued)
Entry
29
R
R1
Product, t (h), yield (%)b
Entry
R
R1
Product, t (h), yield (%)b
O
O
N
H
C6H5CH2
CH3
N
H
18
tert-butyl
3-CH3C6H4
1p, (24), (n.r.)
a Reaction conditions: the reaction of nitriles (5 mmol) and acetic esters (6
mmol) was carried out in the presence of Fe(ClO4)3·H2O (5 mol%) at 80 °C
for 3–8 h.
1e, (5), (91)
O
b Isolated yields; n.r. = no reaction.
N
19
20
21
tert-butyl
tert-butyl
tert-butyl
2-CH3C6H4
4-CH3OC6H4
3-FC6H4
H
1f, (5), (86)
Furthermore, the developed catalytic system was also
applied to react with di-tert-butyl malonate and the results
are shown in Table 4. Obviously, reactions with various aryl
nitriles and benzyl nitriles proceeded well and furnished
the corresponding N-tert-butyl amides in 88–97% yield af-
ter two hours. When the system was applied to sec-alkyl ni-
triles, the target compounds were also obtained in excellent
yields. For example, cyclopentyl cyanide and cyclopropyl
cyanide afforded the N-tert-butyl amides 1s and 1t in 97
and 95% yield, respectively (Table 4, entries 14 and 15).
O
N
H
MeO
1g, (5), (94)
O
F
N
H
1h, (5), (90)
O
Table 4 Reaction of Various Nitriles and di-tert-Butyl Malonatea
N
22
tert-butyl
4-CH3C6H4
H
O
O
O
Fe(ClO4)3⋅H2O
R–CN
+
1i, (5), (91)
R
N
O
O
H
80 °C, 2 h
j, 1d–1m and 1q–1t
O
23
24
25
tert-butyl
tert-butyl
tert-butyl
C6H5CH2
N
H
Entry
1
R
Product, yield (%)b
1j, (5), (87)
O
Cl
N
H
O
C6H5
4-ClC6H4CH2
2-CH3C6H4CH2
N
H
j, (93)
1k, (5), (89)
O
O
N
2
3
4-NO2Ph
3-MePh
H
N
H
O2N
1d, (90)
1l, (5), (90)
O
Cl
Cl
N
H
O
3,4-
Cl2C6H3CH2
26
tert-butyl
N
H
1e, (95)
1m, (5), (84)
O
O
N
H
4
5
2-MePh
27
28
isopropyl
ethyl
C6H5CH2
C6H5CH2
N
H
1f, (92)
1n, (24), (n.r.)
O
O
N
4-MeOPh
H
N
H
MeO
1g, (97)
1o, (24), (n.r.)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

F
C. Feng et al.
Letter
Synlett
Table 4 (continued)
In addition, to expand the scope of this system, benzoic
esters (benzyl, sec-alkyl, and tert-butyl esters), formic es-
ters (benzyl and sec-alkyl esters) and carbonic esters (ben-
zyl, sec-alkyl, and tert-butyl esters) were also employed to
produce the corresponding amides. The results indicate
that the reaction proceeded well and afforded the products
in good to excellent yields (Scheme 2).
Entry
R
Product, yield (%)b
O
F
N
H
6
3-FPh
1h, (94)
O
O
O
CN
R
R
N
H
Fe(ClO4)3⋅H2O (5 mol%)
7
4-MePh
O
N
+
H
80 °C
1i, (95)
(5 mmol)
(6 mmol)
O
a: 89%, 5 h
i: 86%, 5 h
j: 94%, 2 h
m: n.r., 24 h
R: benzyl
isopropyl
tert-butyl
ethyl
8
9
PhCH2
N
H
1j, (93)
O
Cl
O
O
R
CN
Fe(ClO4)3⋅H2O (5 mol%)
N
4-ClPhCH2
2-MePhCH2
R
+
H
N
H
H
O
80 °C
1k, (92)
(6 mmol)
R: benzyl
isopropyl
(5 mmol)
a: 84%, 5 h
i: 90%, 5 h
O
O
10
N
O
CN
H
Fe(ClO4)3⋅H2O (5 mol%)
R
R
R
N
+
1l, (94)
O
O
H
80 °C
(3 mmol)
(5 mmol)
Cl
a: 94%, 5 h
i: 89%, 5 h
j: 97%, 2 h
m: n.r., 24 h
R: benzyl
isopropyl
tert-butyl
ethyl
Cl
O
11
12
3,4-Cl2PhCH2
N
H
1m, (91)
Scheme 2 Ritter reaction of benzoic esters, formic esters, and carbonic
esters
O2N
O
4-NO2C6H4CH2
N
H
In addition, the catalytic system was applied to alcohols,
namely benzyl alcohol and tert-butyl alcohol (Scheme 3).
We found that benzyl alcohol could not react with nitrile
(path a) and tert-butyl alcohol afforded the corresponding
N-(tert-butyl)benzamide in only 21% yield after 24 hours
(path b).
1q, (88)
1r, (91)
1s, (97)
13
14
15
C6H5CHCH3
cyclopentyl
cyclopropyl
NH
O
O
HN
O
CN
Fe(ClO4)3 H2O
80 °C, 24 h
OH
N
H
a)
b)
+
+
O
HN
Fe(ClO4)3 H2O
80 °C, 24 h
CN
N
H
OH
(21%)
O
1t, (95)
Scheme 3 The reaction of benzonitrile (5 mmol) and alcohols (6
mmol) was carried out in the presence of Fe(ClO4)3·H2O (5 mol%) at 80
°C for 24 h.
a Reaction conditions: the reaction of nitriles (5 mmol) and di-tert-butyl
malonate (3 mmol) was carried out in the presence of Fe(ClO4)3·H2O (5
mol%) at 80 °C for 2 h.
b Isolated yields.
A reaction in the absence of catalyst did not proceed
(Scheme 4). On the other hand, we found that N-benzylben-
zamide (a) could also be obtained by a one-pot reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

G
C. Feng et al.
Letter
Synlett
O
O
HCl
K2CHO3
AcOEt
O
+
NaBH4
Ac2O
CN
N
OH
N
N
H
Cl
+
O
HO
EtOH
80 °C, 12 h
2
a
O
O
Scheme 4 A reaction of benzonitrile (5 mmol), benzyl alcohol (6
mmol), and acetic anhydride (6mmol) did not work in the absence of
catalyst.
OH
Ac2O, TEA
AcOEt
N
N
O
O
4
3
O
CN
O
with benzyl alcohol, acetic anhydride, benzonitrile, and
Fe(ClO4)3·H2O (Scheme 5). Therefore, this result indicated
that a one-pot raction with alcohols, acetic anhydride, ni-
triles, and Fe(ClO4)3·H2O could be applied to synthesize am-
ides.
O
N
H
O
N
Ritter reaction
O
O
itopride
87%
Scheme 7 Ritter reaction for the synthesis of itopride
O
CN
Ac2O, Fe(ClO4)3⋅H2O
OH
N
functional groups and provides the respective amide prod-
ucts in good to excellent yields under the optimized reac-
tion conditions.
+
H
80 °C, 5 h
a
84%
Scheme 5 The reaction of benzonitrile (5 mmol), benzyl alcohol (6
mmol), and acetic anhydride (6 mmol) was carried out in the presence
of Fe(ClO4)3·H2O (5 mol%) at 80 °C for 5 h.
Funding Information
The financial support for this work was provided by Nantong City Sci-
ence Foundation (No. 2015) and the Science Program of Jiangsu Col-
lege of Engineering and Technology.
)(
The mechanism for this sequential reaction can be ex-
plained by the already established mechanisms of the Ritter
reaction,26 involved in this new method (Scheme 6). In the
end, the explored catalytic system was successfully applied
to synthesize the prokinetic drug itopride (Scheme 7).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610658.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Fe3+
N
R
O
O
Fe3+
References and Notes
O
R1
O
R1
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O
hydrolysis
R
N
R1
R
N
H
R1
Scheme 6 Proposed mechanism for the Fe(ClO4)3·H2O-catalyzed Ritter
reaction
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range of electron-donating as well as electron-withdrawing
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H

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After completion of the reaction monitored by thin layer chro-
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mixture was extracted with ethyl acetate (3 × 20 mL). The
organic layers were collected, combined, washed with water
(3 × 20 mL), dried with anhydrous Na2SO4, and concentrated
under vacuum. The pure product was obtained by directly
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Compound a
1H NMR (CDCl3, 400 MHz): δ = 7.80 (m, 2 H), 7.78–7.25 (m, 8 H),
6.51 (s, 1 H), 4.64 (d, J = 5.8 Hz, 2 H) ppm. 13C NMR (CDCl3, 100
MHz): δ = 167.4, 138.2, 134.4, 131.6, 128.8, 128.6, 127.9, 127.6,
127.0, 44.1 ppm.
(31) Typical Experimental Procedure for the Reaction of Various
Nitriles and Acetic Esters
A mixture of 3-methylbenzonitrile (5 mmol), benzyl acetate (6
mmol), and Fe(ClO4)3·H2O (5 mol%) was placed in a round-bot-
tomed flask. Then, the reaction mixture was heated at 80 °C for
5 h. After completion of the reaction monitored by thin layer
chromatography (TLC), water (10 mL) was added, and the reac-
tion mixture was extracted with ethyl acetate (3 × 20 mL). The
organic layers were collected, combined, washed with water (3
× 20 mL), dried with anhydrous Na2SO4, and concentrated under
vacuum. The pure product was obtained by directly passing
through a silica gel (200–300 mesh) column to give a white
powder n (0.96 g, 86% yield).
Compound n
1H NMR (CDCl3, 400 MHz): δ = 7.61–7.55 (m, 2 H), 7.34–7.28 (m,
7 H), 6.55 (s, 1 H), 4.62 (d, J = 5.64 Hz, 2 H), 2.37 (s, 3 H) ppm. 13
C
NMR (CDCl3, 100 MHz): δ = 167.6, 138.4, 138.3, 134.3, 132.3,
128.8, 128.4, 127.9, 127.7, 127.6, 123.9, 44.1, 21.3 ppm.
(32) Typical Experimental Procedure for the Reaction of Nitriles
and di-tert-Butyl Malonate
A mixture of 2-(3, 4-dichlorophenyl)acetonitrile (5 mmol), di-
tert-butyl malonate (3 mmol), and Fe(ClO4)3·H2O (5 mol%) was
placed in a round-bottomed flask. Then, the reaction mixture
was heated at 80 °C for 5 h. After completion of the reaction
monitored by thin layer chromatography (TLC), water (10 mL)
was added and the reaction mixture was extracted with ethyl
acetate (3 × 20 mL). The organic layers were collected, com-
bined, washed with water (3 × 20 ml), dried over anhydrous
Na2SO4, and concentrated under vacuum. The pure product was
obtained by directly passing through a silica gel (200–300
mesh) column to give a white powder 1m (1.08 g, 84% yield).
Compound 1m
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(30) Typical Experimental Procedure for the Reaction of Benzoni-
trile and Esters (Benzyl, sec-Alkyl and Primary Alkyl Esters)
A mixture of benzonitrile (5 mmol), benzyl acetate (6 mmol),
and Fe(ClO4)3·H2O (5 mol%) was placed in a round-bottomed
flask. Then, the reaction mixture was heated at 80 °C for 5 h.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.35 (m, 2 H), 7.12–7.10 (m,
1 H), 5.31 (s, 1 H), 3.40 (s, 2 H), 1.32 (s, 9 H) ppm. 13C NMR (100
MHz, CDCl3): δ = 168.9, 135.6, 132.7, 131.2, 131.2, 130.6, 128.6,
51.6, 43.5, 28.7 ppm. HRMS: m/z calcd for C12H15Cl2NO [M + H]+:
259.0531; found: 259.0533.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–H