An efficient transformation of methyl ethers and nitriles to amides catalyzed by Iron(III) perchlorate hydrate

Article abstract of DOI:10.1007/s13738-019-01615-4

An efficient and inexpensive synthesis of N-substituted amides from the reaction of nitriles with methyl ethers 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. A range of methyl ethers (benzyl, sec-alkyl and tert-butyl ethers) were reacted with nitriles to provide the corresponding amides in high–excellent yields.

Full text of DOI:10.1007/s13738-019-01615-4

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01615-4
ORIGINAL PAPER
An efficient transformation of methyl ethers and nitriles to amides
catalyzed by Iron(III) perchlorate hydrate
Guibo Yin1 · Bin Yan · Junqing Chen · Min Ji
1
2
2
Received: 19 July 2018 / Accepted: 23 January 2019
©
Iranian Chemical Society 2019
Abstract
An efficient and inexpensive synthesis of N-substituted amides from the reaction of nitriles with methyl ethers catalyzed by
Fe(ClO ) ·H O is described. Fe(ClO ) ·H O is an economically efficient catalyst for the Ritter Reaction under solvent-free
4
3
2
4 3
2
conditions. A range of methyl ethers (benzyl, sec-alkyl and tert-butyl ethers) were reacted with nitriles to provide the cor-
responding amides in high–excellent yields.
Keywords Ritter reaction · Methyl ethers · Fe(ClO ) ·H O · Amides
4
3
2
Introduction
produce active carbocation [12]. Although impactful, using
large amount of toxic and corrosive acids led to limit its
application on large scale. For this reason, to date, research-
ers have developed a lot of new catalysts (like Lewis acids)
to replace the use of acids. For example, ferric trichloride
(FeCl ) [13], Cobalt(II) chloride (CoCl ) [14], Al(HSO )
The amide compounds consists of many natural products,
polymers, pharmaceuticals and synthetic intermediates [1].
Usually, the synthesis of amides involves the acylation of
amines [2]. On the other hand, the Staudinger reaction [3–5],
the Schmidt reaction [6, 7], the Beckmann rearrangement
3
2
4 3
[15], In(OTf) [16], Cu(OTf) [17] and et al have been suc-
3
2
[
[
8, 9], the oxidative amidation of aldehydes and alcohols
10, 11] also have been explored to form amides. Although
cessfully applied in Ritter reaction.
The classical Ritter reaction is the reaction of alcohols
or alkenes with nitriles in concentrated sulfuric acid [12].
Moreover, some alternatives like ethers [18], silyl-ethers
[18], acetic esters [18], liquid carboxylate salts [12] and
halohydrocarbons [17] also were used in this reaction.
Among these alternatives, ethers are a kind of convenient
and easily obtained products [19–22]. Comparing with alco-
hols or alkenes, the reports of the ethers are relatively few
[18, 23, 24]. Exploring the literature, we found that ethers
only appeared in three papers [18, 23, 24]. First, epoxide was
used to form trifluoromethyl diamino alcohols in the pres-
ence of BF ·OEt and trifluoroethanol reported by Santos
convenient, some drawbacks like producing a stoichiometric
amount of and difficultly separated byproducts and adopting
highly hazardous reagents led to non-economy and environ-
mental pollution.
In recent years, the direct transformation of nitriles via
Ritter reaction can be a potentially elegant alternative path-
way since it employs cheap, abundant and stable starting
materials [12]. Whereas, based on the reaction mechanism, it
is necessary to use a stoichiometric amount of strong acids to
3
2
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-019-01615-4) contains
supplementary material, which is available to authorized users.
[
23]. Moreover, In 2011, methyl tert-butyl ether (MTBE)
and tert-butoxytrimethylsilane were employed into the Rit-
ter reaction to produce the N-tert-butyl amides catalyzed
by ZnCl /SiO [18]. More recently, Panduranga et al. [24]
*
Guibo Yin
2
2
guiboyin888@163.com
employed cyanamides and ethers (dibenzyl, methyl tert-
1
Institute of Pharmaceutical Engineering, Jiangsu College
of Engineering and Technology, Nantong 226000, Jiangsu,
People’s Republic of China
butyl and divinyl ethers) in the presence of BF ·Et O and
3
2
acetic acid to form N, N-disubstituted ureas. Despite con-
venience, the limitations of the expensive and relatively few
starting materials, using solvents and acids and few reports
remind us to continue to study this reaction.
2
School of Biological Sciences and Medical Engineering,
Southeast University, Nanjing 211189, Jiangsu,
People’s Republic of China
Vol.:(0
1
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Journal of the Iranian Chemical Society
In this context, we wish to report a new and efficient pro-
cedure for the transformation of nitriles with methyl ethers
by the use of Fe(ClO ) ·H O as a catalyst under solvent-free
Then the reaction mixture was heated at 100 °C for the given
time. After completion of the reaction monitored by thin
layer chromatography (TLC), 10 ml water was added into
reaction system and extracted with ethyl acetate (3×20 ml).
The organic layers were collected, combined, washed with
water (3×20 ml), dried over anhydrous Na SO , and con-
4
3
2
conditions. This report expands the scope of the ethers and
finds a new and economically efficient Fe catalyst which
was few employments in organic synthesis (Fig. 1, Path(d)).
2
4
centrated under vacuum. The pure products (1a–1k and
2
a–2p) were obtained by directly passing through a silica
Experimental
gel (200–300 mesh) column using petroleum ether/ethyl
acetate (10:1–5:1).
Materials and instruments
Analytical data for 1a–1k
All reagents were purchased from commercial sources and
used without further purification. Melting points were deter-
mined on a RY-1 hot stage microscope and are uncorrected.
N‑benzylbenzamide(1a) White powder. M.p. 97–98 °C (Lit.
1
[17] 86–97 °C). H NMR (CDCl , 400 MHz): δ 7.80(m, d,
3
1
H NMR spectra was recorded on a Bruker Avance DPX-
2H), 7.78–7.25(m, 8H), 6.51(s, 1H), 4.64(d, J=5.8 Hz, 2H).
1
3
4
00 MHz instrument in CDCl , chemical shifts (δ) were
C NMR (CDCl , 100 MHz): δ167.4, 138.2, 134.4, 131.6,
3
3
given in part per million(ppm) relative to TMS as an inter-
128.8, 128.6, 127.9, 127.6, 127.0, 44.1.
1
3
nal standard. C NMR spectra was recorded on a Bruker
Avance DPX-100 MHz instrument in CDCl , chemical shifts
N‑(2‑chlorobenzyl)benzamide(1b) White
powder.
3
1
(
δ) were given in part per million (ppm) relative to TMS as
M.p. 113–114 °C (Lit. [17] 113–114 °C). H NMR (CDCl ,
3
an internal standard. All reactions were monitored by TLC
on silica gel GF-254 glass plates (E. Merck) and viewed
under UV light at 254 nm.
400 MHz): δ 7.80–7.24(m, 9H), 6.68(s, 1H), 4.74(d,
1
3
J=6 Hz, 2H). C NMR (CDCl , 100 MHz): δ167.3, 135.6,
3
134.3, 133.7, 131.6, 130.4, 129.6, 129.1, 128.6, 127.2,
1
26.9, 42.1.
Typical experimental procedure for the reaction
of nitriles and methyl ethers
N‑(4‑nitrobenzyl)benzamide(1c) White
powder.
1
M.p. 156–157 °C (Lit. [17] 157–158 °C). H NMR
A mixture of nitriles (5 mmol), methyl ethers (6 mmol) and
Fe(ClO ) ·H O (5%mol) was placed in a round bottom flask.
(CDCl , 400 MHz): δ 8.21(m, 2H), 7.83(d, J = 7.16 Hz,
3
2H), 7.55–7.45(m, 5H), 6.70(s, 1H), 4.77(d, J = 6 Hz,
4
3
2
Fig. 1 Ritter reaction of ethers
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3

Journal of the Iranian Chemical Society
1
3
2
1
H). C NMR (CDCl , 100 MHz): δ167.6, 147.3, 145.9,
N‑(tert‑butyl)benzamide(1k) White powder. M.p. 128–
3
1
33.7, 132.0, 128.8, 128.3, 127.8, 127.0, 43.3.
129 °C (Lit. [26] 129–130 °C). H NMR (CDCl , 400 MHz):
3
δ 7.73(m, 2H), 7.47–7.39(m, 3H), 5.98(s, 1H), 1.48(s, 9H).
1
3
N‑(4‑methylbenzyl)benzamide(1d) White
powder.
C NMR (CDCl , 100 MHz): δ166.9, 135.9, 131.1, 128.5,
3
1
M.p. 129–131 °C (Lit. [17] 129–130 °C). H NMR
126.7, 51.6, 28.9.
(
CDCl , 400 MHz): δ 7.79(m, 2H), 7.49–7.39(m, 3H),
3
7
2
1
.23–7.15(m, 4H), 6.45(s, 1H), 4.61(d, J = 5.48 Hz, 2H),
Analytical data for 2a–2p
1
3
.45(s, 3H). C NMR (CDCl , 100 MHz): δ167.3, 137.4,
3
35.1, 134.4, 131.5, 129.4, 128.5, 127.9, 126.9, 43.9, 21.1.
N‑benzyl‑3‑methylbenzamide(2a) White
powder.
1
M.p. 98–99 °C (Lit. [17] 97–98 °C). H NMR (CDCl ,
3
N‑(2‑methylbenzyl)benzamide(1e) White
M.p. 112–113 °C (Lit. [25] 113–114 °C). H NMR
CDCl , 400 MHz): δ 7.78(m, 2H), 7.49–7.39(m, 3H),
powder.
400 MHz): δ 7.61–7.55(m, 2H), 7.34–7.28(m, 7H), 6.55(s,
1
13
1H), 4.62(d, J=5.64 Hz, 2H), 2.37(s, 3H). C NMR
(
(CDCl , 100 MHz): δ167.6, 138.4, 138.3, 134.3, 132.3,
3
3
7
2
1
1
.29–7.19(m, 4H), 6.33(s, 1H), 4.63(d, J = 5.2 Hz, 2H),
128.8, 128.4, 127.9, 127.7, 127.6, 123.9, 44.1, 21.3.
1
3
.36(s, 3H). C NMR (CDCl , 100 MHz): δ167.2, 136.6,
3
35.7, 134.3, 131.5, 130.6, 128.7, 128.6, 127.9, 126.9,
N‑benzyl‑2‑methylbenzamide(2b) White
powder.
1
26.3, 42.3, 19.1.
M.p. 96–98 °C (Lit. [17] 98–99 °C). H NMR (CDCl ,
3
4
00 MHz): δ 7.36–7.15(m, 9H), 6.16(s, 1H), 4.61(d,
1
3
N‑(4‑chlorobenzyl)benzamide(1f) White
powder.
J=5.76 Hz, 2H), 2.44(s, 3H). C NMR (CDCl , 100 MHz):
3
1
M.p. 138–139 °C (Lit. [25] 139–140 °C). H NMR
δ170.0, 138.1, 136.2, 133.3, 131.0, 129.9, 128.8, 127.8,
127.6, 126.7, 125.7, 43.9, 19.8.
(
CDCl , 400 MHz): δ 7.80(m, 2H), 7.51–7.41(m, 3H),
3
7
.32–7.28(m, 4H), 6.60(s, 1H), 4.61(d, J = 5.76 Hz, 2H).
1
3
C NMR (CDCl , 100 MHz): δ167.4, 136.8, 134.1, 133.4,
N‑benzyl‑4‑methylbenzamide(2c) White powder. M.p. 133–
3
1
31.7, 129.2, 128.8, 128.6, 126.9, 43.4.
134 °C (Lit. [25] 132–133 °C). 1H NMR (CDCl , 400 MHz):
3
δ 7.71(d, J=8.12 Hz, 2H), 7.36–7.21(m, 7H), 6.47(s, 1H),
1
3
N‑cyclopentylbenzamide(1g) White powder. M.p. 142–
4.65(d, J=5.52 Hz, 2H), 2.36(s, 3H). C NMR (CDCl ,
3
1
1
4
4
1
1
43 °C (Lit. [17] 143–144 °C). H NMR (CDCl ,
100 MHz): δ167.4, 142.0, 138.3, 131.5, 129.3, 128.7, 127.9,
3
00 MHz): δ 7.76(m, 2H), 7.50–7.39(m, 3H), 6.16(s, 1H),
127.6, 127.0, 44.1, 21.5.
.43–4.38(m, 1H), 2.13–2.05(m, 2H), 1.75–1.63(m, 4H),
1
3
.54–1.46(m, 2H). C NMR (CDCl , 100 MHz): δ167.2,
N‑benzyl‑4‑(trifluoromethyl)benzamide(2d) White powder.
3
1
34.9, 131.2, 128.5, 126.8, 51.7, 33.2, 23.8.
M.p. 168–170 °C (Lit. [25] 170–171 °C). H NMR (CDCl ,
3
4
00 MHz): δ 7.91(d, J=8.12 Hz, 2H), 7.71(d, J=8.2 Hz,
N‑cyclohexylbenzamide(1h) White powder. M.p. 140–
2H), 7.38–7.32(m, 5H), 6.49(s, 1H), 4.67(d, J=5.64 Hz,
1
13
1
4
1
8
1
41 °C (Lit. [17] 139–140 °C). H NMR (CDCl ,
2H). C NMR (CDCl , 100 MHz): δ166.1, 137.7, 137.6,
3
3
00 MHz): δ 7.77(m, 2H), 7.51–7.40(m, 3H), 6.05(s,
133.5 (q, JC-F=33 Hz), 128.8, 128.0, 127.9, 127.5, 125.6,
H), 4.0-3.97(m, 1H), 2.05–2.02(m, 2H), 1.74–1.23(m,
125.0 (q, JC-F=271 Hz), 44.3.
1
3
H). C NMR (CDCl , 100 MHz): δ166.6, 135.1, 131.2,
3
28.5, 126.8, 48.7, 33.2, 25.6, 24.9.
N‑benzyl‑3‑fluorobenzamide(2e) White
powder.
1
M.p. 91–92 °C (Lit. [27] 90.5–91.8 °C). H NMR (CDCl ,
3
N‑(1‑phenylethyl)benzamide(1i) White
powder.
400 MHz): δ 7.54–7.49(m, 2H), 7.46–7.16(m, 7H), 6.74(s,
1
13
M.p. 101–102 °C (Lit. [26] 103–105 °C). H NMR
1H), 4.60(d, J=5.68 Hz, 2H). C NMR (CDCl , 100 MHz):
3
(
CDCl , 400 MHz): δ 7.77–7.75(m, 2H), 7.49–7.28(m,
δ 166.3(q, JC-F=2 Hz), 163.9 (q, JC-F=246 Hz), 137.9,
136.6 (q, JC-F=7 Hz), 130.3 (q, JC-F=17 Hz), 128.8,
128.4 127.9, 127.7, 122.5 (q, JC-F=3 Hz), 118.7 (q,
JC-F=21 Hz), 114.6 (q, JC-F=22 Hz), 44.2.
3
8
3
1
H), 6.42(s, 1H), 5.37–5.30(m, 1H), 1.61(d, J=6.84 Hz,
1
3
H). C NMR (CDCl , 100 MHz): δ166.6, 143.2, 134.6,
3
31.5, 128.8, 128.6, 127.5, 126.9, 126.3, 49.2, 21.8.
N‑benzhydrylbenzamide(1j) White powder. M.p. 168–
N‑benzyl‑4‑nitrobenzamide(2f) White powder. M.p. 145–
1
1
1
4
6
1
1
69 °C (Lit. [26] 171–172 °C). H NMR (CDCl ,
146 °C (Lit. [17] 144–146 °C). H NMR (CDCl , 400 MHz):
3
3
00 MHz): δ 7.82–7.80(m, 2H), 7.50–7.28(m, 13H),
δ 8.28(d, J=8.84 Hz, 2H), 7.96(d, J=8.8 Hz, 2H), 7.38–
1
3
13
.69(s, 1H), 6.46(d, J = 7.8 Hz, 1H). C NMR (CDCl ,
7.33(m, 5H), 6.57(s, 1H), 4.67(d, J=5.64 Hz, 2H).
C
3
00 MHz): δ166.5, 141.5, 134.3, 131.7, 128.8, 128.6,
NMR (CDCl , 100 MHz): δ165.3, 149.6, 139.9, 137.4,
3
27.6, 127.5, 127.1, 57.5.
128.9, 128.2, 128.0, 123.9, 44.5.
1
3

Journal of the Iranian Chemical Society
N‑benzyl‑3‑bromobenzamide(2g) White
powder.
N‑(tert‑butyl)‑3‑methylbenzamide(2n) White
pow-
1
1
M.p. 87–88 °C (Lit. [17] 87–88 °C). H NMR (CDCl ,
der. M.p. 110–111 °C (Lit. [31] 111–112 °C). HNMR
3
4
6
00 MHz): δ 7.92(s, 1H), 7.70–7.60(m, 2H), 7.34–7.26(m,
(400 MHz, CDCl ) δ: 7.54–7.28(m, 4H), 5.95(s, 1H),
3
1
3
13
H), 6.57(s, 1H), 4.61(d, J=5.64 Hz, 2H). C NMR
2.38(s, 3H), 1.47(s, 9H). CNMR (100 MHz, CDCl ) δ:
3
(
CDCl , 100 MHz): δ166.0, 137.8, 136.3, 134.5, 130.2,
167.1, 138.3, 135.9, 131.8, 128.3, 127.5, 123.6, 51.5, 28.3,
3
1
30.1, 128.8, 127.9, 127.7, 125.6, 122.8, 44.3.
21.4.
N‑benzyl‑4‑methoxybenzamide(2h) White
powder.
N‑(tert‑butyl)‑2‑methylbenzamide(2o) White
powder.
1
1
M.p. 110–111 °C (Lit. [17] 110–112 °C). H NMR (CDCl ,
M.p. 76–78 °C (Lit. [31] 77–78 °C). HNMR (400 MHz,
3
4
6
2
1
5
00 MHz): δ 7.77(d, J = 8.76 Hz, 2H), 7.35–7.28(m, 5H),
CDCl ) δ: 7.31–7.14(m, 4H), 5.58(s, 1H), 2.42(s, 3H),
3
1
3
.91(d, J = 8.8 Hz, 2H), 6.45(s, 1H), 4.63(d, J = 5.24 Hz,
1.46(s, 9H). CNMR (100 MHz, CDCl ) δ: 169.7, 137.9,
3
1
3
H), 3.83(s, 3H). C NMR (CDCl , 100 MHz): δ166.9,
135.5, 130.8, 129.4, 126.4, 125.6, 51.7, 28.9, 19.6.
3
62.2, 138.4, 128.8, 128.7, 127.9, 127.6, 126.6, 113.8,
5.4, 44.1.
N‑(tert‑butyl)‑4‑methylbenzamide(2p) White
pow-
1
der. M.p. 111–113 °C (Lit. [31] 112–113 °C). HNMR
N‑benzyl‑2‑phenylacetamide(2i) White
powder.
(400 MHz, CDCl ) δ: 7.62(d, J=8.12 Hz, 2H), 7.19(d,
3
1
M.p. 117–118 °C (Lit. [26] 117 °C). H NMR (CDCl ,
J=7.88 Hz, 2H), 5.99(s, 1H), 2.36(s, 3H), 1.46(s, 9H).
3
1
3
4
3
1
00 MHz): δ 7.36–7.09(m, 10H), 5.77(s, 1H), 4.39(s, 2H),
CNMR (100 MHz, CDCl ) δ: 166.9, 141.3, 133.1, 129.1,
3
1
3
.62(s, 2H). C NMR (CDCl , 100 MHz): δ170.9, 138.1,
127.0, 51.6, 29.1, 21.4.
3
34.8, 129.5, 129.1, 128.7, 127.5, 127.4, 127.4, 43.8, 43.6.
N‑(4‑methylbenzyl)‑2‑phenylacetamide(2j) M.p. 139–140 °C
Results and discussion
1
(
Lit. [28] 139–139.3 °C). H NMR (CDCl , 400 MHz): δ
3
7
.35–7.28(m, 6H), 7.11–7.05(m, 4H), 5.71(s, 1H), 4.35(s,
At the outset, a model reaction of (methoxymethyl)ben-
zene and benzonitrile to form N-benzylbenzamide (1a)
was chosen to identify the catalytic system. The results
are summarized in Table 1. First, a wide range of Zn salts
like ZnO, ZnCl , Zn(OAc) ·2H O, ZnBr , Zn(OTf) and
13
2
H), 3.60(s, 2H), 2.31(s, 3H). C NMR (CDCl , 100 MHz):
3
δ170.82, 137.15, 135.11, 134.84, 129.47, 129.34, 129.05,
127.54, 127.39, 43.85, 43.40, 21.08.
2
2
2
2
2
N‑cyclopentyl‑4‑methoxybenzamide(2k) White powder.
Zn(ClO ) ·6H O were checked for the reaction since ZnCl
4 2 2 2
1
M.p. 150–151 °C (Lit. [29] 150–152 °C). H NMR (CDCl ,
[18] has been used to catalyze the reaction of methyl tert-
butyl ether and benzonitrile to form N-(tert-butyl)benza-
mide, in which only Zn(ClO ) ·6H O was found to be able to
3
4
2
2
00 MHz): δ 7.74(d, J=8.8 Hz, 2H), 6.92(d, J=8.76 Hz,
H), 6.05(s, 1H), 4.42–4.37(m, 1H), 3.85(s, 3H), 2.11–
4
2
2
1
3
.06(m, 2H), 1.73–1.63(m, 4H), 1.53–1.45(m, 2H).
C
catalyze this reaction to afford the N-benzylbenzamide (1a)
in moderate yield (46%) (Table 1, entry 6). However, cata-
lysts like ZnO, ZnCl , Zn(OAc) ·2H O, ZnBr and Zn(OTf)
NMR (CDCl , 100 MHz): δ166.7, 162.0, 128.6, 127.2,
3
1
13.7, 55.4, 51.6, 33.3, 23.8.
2
2
2
2
2
were all ineffective (Table 1, entries 1–5). For this cata-
N‑cyclohexyl‑4‑(trifluoromethyl)benzamide(2l) White
lytic result, several perchlorate salts including Ga(ClO ) ,
4
2
1
powder. M.p. 168–169 °C (Lit. [30] 167–170 °C). H NMR
Mg(ClO ) , Fe(ClO ) ·xH O, Al(ClO ) , Ni(ClO ) ·6H O,
4 2 4 3 2 4 3 4 2 2
(
CDCl , 400 MHz): δ 7.87(d, J = 8.12 Hz, 2H), 7.69(d,
Ba(ClO ) ·3H O, Mn(ClO ) ·6H O, Co(ClO ) ·6H O and
4 2 2 4 2 2 4 2 2
3
J = 8.16 Hz, 2H), 6.08(d, J = 6.24 Hz, 1H), 3.99(m, 1H),
Cu(ClO ) ·6H O were further examined for this reaction,
4 2 2
2
1
1
1
3
.06–2.03(m, 2H), 1.80–1.75(m, 2H), 1.79–1.70(m, 1H),
fortunately, Fe(ClO ) ·xH O was found to be the best
4 3 2
1
3
.45–1.42(m, 2H), 1.28–1.22(m, 3H). C NMR (CDCl ,
catalyst affording an excellent yield of the desired prod-
uct N-benzylbenzamide (1a) (91%) (Table 1, entry 9).
And the catalyst Cu(ClO ) ·6H O could also produce the
3
00 MHz): δ165.4, 138.4, 133.5 (q, JC-F = 33 Hz), 127.4,
25.6 (q, JC-F = 4 Hz), 125.1 (q, JC-F = 271 Hz), 49.0,
3.2, 25.5, 24.9.
4
2
2
N-benzylbenzamide (1a) in a good yield in 79% (Table 1,
entry 15). However, Ga(ClO ) , Mg(ClO ) , Al(ClO ) ,
4
2
4 2
4 3
N‑(tert‑butyl)‑4‑nitrobenzamide(2m) White
der. M.p. 157–158 °C (Lit. [31] 157–158 °C). HNMR
400 MHz, CDCl ) δ: 8.26(d, J = 8.72 Hz, 2H), 7.89(d,
pow-
Ni(ClO ) ·6H O, Ba(ClO ) ·3H O, Mn(ClO ) ·6H O and
4 2 2 4 2 2 4 2 2
1
Co(ClO ) ·6H O did not work for this transformation.
4
2
2
(
Accordingly, various Fe catalysts were employed to check
for this reaction again (Table 1, entries 16–22). And it was
found that FeCl and Fe(OTf) afforded the N-benzylben-
3
1
3
J = 8.72 Hz, 2H), 6.02(s, 1H), 1.40(s, 9H). CNMR
100 MHz, CDCl ) δ: 164.9, 149.4, 141.6, 127.9, 123.7,
(
3
3
3
5
2.3, 28.8.
zamide (1a) in moderate yield (Table 1, entries 12 and 16)
and FeCl ·4H O and Fe(OTf) could just give a low yield
2
2
2
1
3

Journal of the Iranian Chemical Society
Table 1 Optimization of reaction conditions
Entry
Catalyst
Amount (mol%)
T (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
ZnO
ZnCl2
Zn(OAc) ·2H O
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
5
5
NR
NR
NR
NR
NR
46
NR
NR
91
NR
NR
NR
NR
NR
79
2
2
ZnBr2
Zn(OTf)2
Zn(ClO ) ·6H O
Ga(ClO4)2
Mg(ClO4)2
Fe(ClO ) ·xH O
Al(ClO4)3
Ni(ClO ) ·6H O
Ba(ClO ) ·3H O
Mn(ClO ) ·6H O
Co(ClO ) ·6H O
Cu(ClO ) ·6H O
4
2
2
4
3
2
10
11
12
13
14
15
16
17
18
19
20
21
22
4
2
2
4
2
2
4
2
2
4
2
2
4
2
2
FeCl3
FeCl ·4H O
Fe(NO ) ·9H O
43
<10
NR
<10
51
NR
NR
2
2
3
3
2
Fe(OTf)2
Fe(OTf)3
Fe O
3
4
3
Fe O
2
Reaction conditions: benzonitrile(5 mmol), (methoxymethyl)benzene (6 mmol)
a
Isolated yield
(
Table 1, entries 17 and 19). Nevertheless, Fe(NO ) ·9H O,
Table 2 Optimization of amount of catalyst and reaction temperature
in preparation of 1a
3
3
2
Fe O and Fe O were ineffective for this transformation
3
4
2
3
(
Table 1, entries 18, 21 and 22).
Yield (%)a
Entry
Catalyst/mol%
T (°C)
Time (h)
We further studied the effect of the amount of the catalyst
1
2
3
4
5
6
7
8
9
1
2
5
10
5
5
5
5
5
5
100
100
100
100
RT
40
60
80
100
120
2
2
2
2
2
2
2
2
2
2
53
68
91
92
NR
34
61
82
91
90
and the reaction temperature. Similarly, (methoxymethyl)
benzene and benzonitrile were selected as the model sub-
strates to optimize the amount of Fe(ClO ) ·H O and the
4
3
2
results are summarized in Table 2. With 1 mol% catalyst
loading, the yield of the product decreased to 53%. When
employing with 2 mol% catalyst, the product was obtained
with the yield in 68%. Although 10 mol% of catalyst could
increase slightly the yield (92%) compared with the 5 mol%
catalyst (91%), it was noted that 5 mol% of catalyst was seen
to be sufficient to afford the best yield (Table 2, entries 3
and 4). Otherwise, it was found that the best yield obtained
indicated that the reaction should be performed at 100 °C
1
0
Reaction conditions: benzonitrile(5 mmol), (methoxymethyl)benzene
(6 mmol)
a
(
Table 2, entries 5–9).
Isolated yield
1
3

Journal of the Iranian Chemical Society
To prove the effectiveness of this transformation, in the
first place, a wide range of methyl ethers (benzyl, sec-alkyl
and tert-butyl ethers) were employed to react with benzo-
nitrile under the optimized reaction conditions. The results
are summarized in Table 3. It was observed that benzyl
ethers bearing with electron-donating groups afforded the
corresponding amides in good–excellent yields. For exam-
ple, 1-chloro-2-(methoxymethyl)benzene and 4-chloro-
Table 3 Reaction of benzonitrile and ethers (benzyl, sec-alkyl and
tert-butyl ethers)
1a–1n
a
Entry
1
R
Time (h)
Product
Yield (%)
6
C H
5
CH
2
2
91
2
1
2
1
1
4
-(methoxymethyl)benzene produced the amides 1b and
f in 85% and 87% yields, respectively (Table 3, entries
and 6). And 1-(methoxymethyl)-2-methylbenzene and
-(methoxymethyl)-4-methylbenzene afforded the amides
d and 1e in 93% and 90%, respectively (Table 3, entries
and 5). Otherwise, benzyl ethers bearing with electron-
1
a
2
2-ClC H CH
6
4
2
2
85
46
1
b
3
4-NO
2
C
6
H
4
CH
2
5
withdrawing group afforded the amide in very low yield.
For example, the 1-methoxy-4-nitrobenzene produced the
amide 1c in only 46% yield even if the reaction time was
extended to 5 h (Table 3, entry 3). When the sec-alkyl ethers
like methoxycyclopentane and methoxycyclohexane were
applied to react with benzonitrile, the corresponding amides
1c
4
5
6
4-CH
3
6
C H
4
CH
2
2
2
2
93
90
87
1
d
2-CH C H CH
3
6
4
2
1
g and 1h were obtained in 84% and 81% yields, respec-
tively (Table 3, entries 7 and 8). Methyl tert-butyl ether
was also used in this reaction, the corresponding N-(tert-
butyl)benzamide(1k) was obtained with 84% yield after 2 h
1
e
4-ClC
6
H
4
CH
2
(
Table 3, entry 11).
On the other hand, the reaction was tested with various
1f
7
8
Cyclopentyl
Cyclohexyl
2
2
84
substituted aromatic nitriles and benzyl nitriles again and
shown in Table 4. We found that the electron-withdrawing
substitutes on aromatic nitriles could afford the corre-
sponding amides in good–excellent yields. For example,
1
g
81
4
-(trifluoromethyl)benzonitrile and 4-nitrobenzonitrile
produced the amides 2d and 2f in 92% and 90% yields,
respectively(Table 4, entries 4 and 6). However, the electron-
donating groups on aryl nitriles would seriously reduce the
yields of the amides. For example, the 4-methylbenzonitrile,
1
h
9
C
6
H
5
CHCH
3
2
2
89
83
1
i
3
-methylbenzonitrile and 2-methylbenzonitrile afforded the
1
1
0
1
6 5 6 5
C H CHC H
products 2a, 2b and 2c in moderate yields (Table 4, entries
1
–3). And 4-methoxybenzonitrile just produced the amide
2
h in 27% yield (Table 4, entry 8). Furthermore, N-cyclo-
pentyl-4-methoxybenzamide (2 k) and N-cyclohexyl-4-
1
j
tert-butyl
2
84
(
trifluoromethyl)benzamide (2 l) were obtained in 23% and
8
9% yields, respectively (Table 4, entries 11 and 12). Mean-
while, methyl tert-butyl ether reacted with 4-nitrobenzoni-
trile afforded the product 2 m in 86% yield (Table 4, entry
1
K
Reaction conditions: benzonitrile(5 mmol), various methyl ethers
1
3). And it reacted with 4-methylbenzonitrile, 3-methylben-
(
6 mmol) and Fe(ClO ) ·H O (5 mol%)
4 3 2
Isolated yield
zonitrile and 2-methylbenzonitrile only afforded the prod-
ucts in moderate yields (Table 4, entries 14–16). Moreover,
benzyl nitriles could react well with benzyl ethers (Table 4,
entries 9 and 10). Unfortunately, when sec-alkyl and tert-
butyl ethers were stirred with benzyl nitriles, no reaction
was observed after 5 h (Table 4, entries 17–19).
b
electronic effects (Scheme 1). Because Fe(ClO ) ·xH O is
4
3
2
a stronger Lewis acid, therefore, the catalytic efficiency of
3
+
Fe in this reaction maybe attributed to its Lewis acidity and
oxophilicity which coordinated to oxygen atoms of methyl
ethers and urged C–O cleavage by attack of nitrile group.
On the basis of the above results and discussions, we
proposed the possible reaction mechanism according to the
1
3

Journal of the Iranian Chemical Society
Table 4 Reaction of various
nitriles and ethers
2a–2q
Entry
1
R
1
R
2
Time (h)
Product
Yield (%)a
C
6
H
5
CH
2
3-CH
3
C
6
H
4
4
2
64
2a
2
C
6
H
5
CH
2
2-CH
3
C
6
H
2
62
2b
3
4
5
6
6
C H
6
C H
6
C H
6
C H
5
CH
CH
CH
CH
2
2
2
2
4-CH
3
C
6
H
4
2
2
2
2
65
92
87
90
2
c
5
5
5
3 6 4
4-F CC H
2d
3-FC
6
H
4
2e
4-NO
2
C
6
H
4
2f
7
8
C
6
6
H
5
5
CH
2
2
3-BrC
6
H
4
2
2
61
27
2g
C
H
CH
3
4-CH OC
6
H
4
2h
9
C
6
H
5
CH
2
C
6
H
5
CH
2
2
2
2
85
87
23
2
i
1
0
1
4-CH
3
C
6
H
4
CH
2
C
6
H
5
CH
2
2j
1
Cyclopentyl
4-CH
3
OC
6
H
4
2k
1
3

Journal of the Iranian Chemical Society
Table 4 (continued)
12
Cyclohexyl
4-F CC H
2
2
89
3
6
4
2l
13
tert-butyl
4-NO
2
C
6
H
4
86
2m
14
15
16
tert-butyl
tert-butyl
tert-butyl
3-CH
2-CH
4-CH
3
3
3
6
C H
6
C H
6
C H
4
4
4
2
2
71
67
69
2
n
2
o
2
2p
17
18
19
Cyclopentyl
Cyclohexyl
tert-butyl
6
C H
6
C H
6
C H
5
5
5
CH
2
CH
2
CH
2
5
5
5
NR
NR
NR
2
q
2
r
2s
Reaction conditions: nitriles (5 mmol), various methyl ethers (6 mmol) and Fe(ClO ) ·H O
4
3
2
(
5 mol%)
Isolated yield
b
To measure the advantages of the reaction, we used differ-
ent parameters of previous methods. Table 5 shows a com-
parison of our method with previous reports. It can be seen
that our method could afford the amide 1a with the highest
yield. And it was also found that ZnCl /SiO could not cata-
2
2
lyze this transformation (Table 5, entry 3).
Conclusions
A simple and efficient catalytic system has been explored
for the Ritter reaction with methyl ethers and nitriles. The
present protocol requires inexpensive and easily available
Fe(ClO ) ·H O catalyst and starting materials for the amides
Scheme 1 Proposed mechanism for Fe(ClO ) ·xH O-catalyzed Ritter
4
3
2
reaction
4
3
2
1
3

Journal of the Iranian Chemical Society
Table 5 A comparison of our method with previous reports for the preparation of N-benzylbenzamide
Entry
1
Reaction conditions
Yields (%)a
43
BF ·Et O(1.2equivalents), Trifluoroethanol (1.2equivalents), CH Cl (10 ml),
3
2
2
2
0
–40 °C
2
3
4
BF ·Et O(30 mol%), AcOH(60 ml), 50 °C
74
NR
91
3
2
ZnCl /SiO (15 mol%), 100 °C
2
2
Fe(ClO ) ·xH O (5 mol%), 100 °C
4
3
2
Reaction conditions: benzonitrile(5 mmol), (methoxymethyl)benzene (6 mmol)
a
Isolated yield
synthesis. The developed methodology provides the respec-
tive amides products in good to high yields under the opti-
mized reaction conditions.
15. E. Karimian, B. Akhlaghinia, S.S.E. Ghodsinia, J. Chem. Sci. 128,
4
29 (2016)
6. D. Posevins, K. Suta, M. Turks, Eur. J. Org. Chem. 2016, 1414
2016)
7. G.R. Qu, Y.W. Song, H.Y. Niu, H.M. Guo, S.F. John, RSC Adv.
1
1
(
Acknowledgements We are grateful to Nantong City Science Founda-
tion (No. 2015) and Science program of Jiangsu College of Engineering
and Technology for financial support.
2
, 6161 (2012)
1
1
8. F. Tamaddon, F. Tavakoli, J Mol Catal. A. Chem. 337, 52 (2011)
9. E. Wenkert, E.L. Michelotti, C.S. Swindell, J. Am. Chem. Soc.
1
01, 2246 (1979)
2
0. E. Wenkert, E.L. Michelotti, C.S. Swindell, M. Tingoli, J. Org.
Chem. 49, 4894 (1984)
References
2
2
1. J.W. Dankwardt, Angew. Chem. Int. Ed. 43, 2428 (2004)
2. F. Kakiuchi, M. Usui, S. Ueno, N. Chatani, S. Murai, J. Am.
Chem. Soc. 126, 2706 (2004)
1
2
3
4
5
6
.
.
.
.
.
.
V.R. Pattabiraman, J.W. Bode, Nature 480, 471 (2011)
E. Valeur, M. Bradley, Chem. Soc. Rev. 38, 606 (2009)
E. Saxo, C.Z. Bertozzi, Science 287, 2007 (2000)
23. M.D. Santos, B. Crousse, D. Bonnet-Delpon, Tetrahedron Lett.
50, 857 (2009)
F. Damkaci, P.D. Shong, J. Am. Chem. Soc. 125, 4408 (2003)
Y.G. Gololobov, L.F. Kasukhin, Tetrahedron. 48, 1353 (1992)
T. Ribelin, C.E. Katz, D.G. English, S. Smith, A.K. Manukyan,
V.W. Day, B. Neuenswander, J.L. Poutsma, J. Aube, Angew.
Chem. Int. Ed. 47, 6233 (2008)
24. V. Panduranga, V.V. Basavaprabhu, Sureshbabu, Tetrahedron Lett.
54, 975 (2013)
25. F. Li, J. Ma, L. Lu, X.F. Bao, W.Y. Tang, Catal. Sci. Technol. 5,
1953 (2015)
26. K.V. Katkar, P.S. Chaudhari, K.G. Akamanchi, Green Chem. 13,
835 (2011)
7
8
.
.
S. Lang, J.A. Murphy, Chem. Soc. Rev. 35, 146 (2006)
N.A. Owston, A.J. Parker, J.M. Williams, J. Org. Lett. 9, 3599
27. H. Cheng, M.Q. Xiong, C.X. Cheng, H.J. Wang, Q. Lu, H.F. Liu,
F.B. Yao, C. Chen, F. Verpoort, Asian. J. Org. Chem. 13, 440
(2018)
(
2007)
9
.
M. Hashimoto, Y. Obora, S. Sakaguchi, Y. Ishii, J. Org. Chem. 73,
2
894 (2008)
28. D.C. Braddock, P.D. Lickiss, B.C. Rowley, D. Pugh, T. Purnomo,
G. Santhakumar, S.J. Fussell, Org. Lett. 20, 950 (2018)
29. Y.L. Tu, L. Yuan, T. Wang, C.L. Wang, J.M. Ke, J.F. Zhao, J. Org.
Chem. 82, 4970 (2017)
1
1
0. J.W.W. Chang, T.M.U. Ton, S. Tania, P.C. Taylor, P.W.H. Chan,
Chem. Commun. 46, 922 (2010)
1. S.W. Krabbe, V.S. Chan, T.S. Franczyk, S. Shekhar, J. Napolitano,
C.A. Presto, J.A. Simanis, J. Org. Chem. 81, 10688 (2016)
2. D.-H. Jiang, T. He, L. Ma, Z.-Y. Wang, RSC Adv. 4, 64936 (2014)
3. B. Anxionnat, A. Guérinot, S. Reymond, J. Cossy, Tetrahedron
Lett. 50, 3470 (2009)
30. A.R. Prosser, J.E. Banning, M. Rubina, M. Rubin, Org. Lett. 12,
3968 (2010)
1
1
31. C.L. Feng, B. Yan, W.J. Yao, J.Q. Chen, M. Ji, Chemistryselect.
3, 8501 (2018)
1
4. M. Mukhopadhyay, M.M. Reddy, G.C. Maikap, J. Iqbal, J. Org.
Chem. 60, 2670 (1995)
1
3