FeCl3-catalyzed Ritter reaction. Synthesis of amides

Article abstract of DOI:10.1016/j.tetlet.2009.02.208

A safe and inexpensive synthesis of amides, from benzylic alcohols and nitriles and from t-butyl acetate and nitriles, using a Ritter reaction catalyzed by FeCl₃·6H₂O is described.

Full text of DOI:10.1016/j.tetlet.2009.02.208

Tetrahedron Letters 50 (2009) 3470–3473
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FeCl3-catalyzed Ritter reaction. Synthesis of amides
*
*
Bruno Anxionnat, Amandine Guérinot, Sébastien Reymond , Janine Cossy
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10, Rue Vauquelin, 75231 Paris Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A safe and inexpensive synthesis of amides, from benzylic alcohols and nitriles and from t-butyl acetate
and nitriles, using a Ritter reaction catalyzed by FeCl3Á6H2O is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 21 January 2009
Revised 26 February 2009
Accepted 26 February 2009
Available online 4 March 2009
Keywords:
Ritter reaction
Nitriles
Amides
Iron
OH
The Ritter reaction is a well-known Name Reaction in which
nitriles react with an in-situ generated carbocation to produce
amides.1 In recent examples, the Ritter reaction involving benzylic
alcohols was found to be catalyzed by Brønsted acids,2 Nafion3 or
Fe-Montmorillonite K10.4 Furthermore, the Ritter reaction involv-
ing tert-butyl acetate was reported to be catalyzed by sulfuric acid5
or bismuth triflate.6 As it was recently demonstrated that FeCl3 is
able to activate benzylic alcohols to produce carbocation interme-
diates,7–11 we have envisaged to synthesize amides from benzylic
alcohols or t-butyl acetate by using a Ritter reaction catalyzed by
FeCl3.
When 1-phenylethanol (1) was treated with FeCl3Á6H2O
(10 mol %) in MeCN at 150 °C for 30 min in the presence of water,
amide 2 was produced. The best yield in 2, 77%, was obtained when
2 equiv of water was added to the reaction medium (see Scheme 1).
The reaction is general and various benzylic amides were ob-
tained using different nitriles and benzylic alcohols. The results
are reported in Table 1. The reaction of 1 with PhCN led to the ex-
pected amide 6 in 54% isolated yield (Table 1, entry 1). Acrylonitrile
appeared to be a suitable nitrile as 1 was transformed to the corre-
sponding amide 7 in 66% yield (Table 1, entry 2). Benzhydrol 3 can
also react smoothly with MeCN, PhCN and acrylonitrile to produce
the corresponding amides 8–10 in 96%, 75% and 87% isolated
yields, respectively (Table 1, entries 3–5). In the case of 1-phe-
nyl-but-3-en-1-ol (4) (Table 1, entries 6 and 7), the FeCl3-catalyzed
Ritter reaction involving MeCN and acrylonitrile led to the ex-
pected amides in moderate yields (49% yield for 11 and 41% yield
NHAc
FeCl3 6H2O (10 mol %)
H2O (2 equiv)
MeCN, 150 °C
1
2
77%
Scheme 1.
for 1212) for a 90% conversion of 4. It is worth noting that the for-
mation of amide 13 from 5 and MeCN was only possible at 50 °C,
and at higher temperatures, a complex mixture was observed (Ta-
ble 1, entry 8).
In order to use nitriles as reagents, the Ritter reaction was
examined in solvents such as MeNO2, dioxane, toluene or cumene.
The results are reported in Table 2. In MeNO2 the transformation of
1 to 2, by using 10 equiv of MeCN, in the presence of FeCl3Á6H2O
(10 mol %) and water (2 equiv), at 110 °C or 50 °C was sluggish
and the formation of many by-products was observed (Table 2, en-
tries 1 and 2). On the contrary, when the reaction was performed at
110 °C in toluene or dioxane, a full conversion of 1 was observed
after 6 h and 2 was isolated in 72% and 74% yields, respectively (Ta-
ble 2, entries 3 and 4). Furthermore, when the reaction was
achieved in cumene at 150 °C, after 1 h, the conversion of 1 was
complete allowing the isolation of 2 in 73% yield (Table 2, entry 5).
The formation of ethers from benzylic alcohols in the presence
of FeCl310,11 or Fe(NO3)314 was previously observed. Similarly, dur-
ing the course of the Ritter reaction involving 1, the formation of
ether 14 was observed at 70 °C, whereas at 150 °C, only amide 2
was produced. Furthermore, when ether 14 was treated at
150 °C under the previous established conditions [MeCN,
* Corresponding authors. Tel.: +33 1 40 79 46 59; fax: +33 1 40 79 46 60 (J.C.).
E-mail addresses: sebastien.reymond@espci.fr (S. Reymond), janine.cossy@
espci.fr (J. Cossy).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.208

B. Anxionnat et al. / Tetrahedron Letters 50 (2009) 3470–3473
3471
Table 1
Ritter reaction of various alcohols and nitriles catalyzed by FeCl3Á6H2O13
O
R
R'CN
OH
HN
Ar
R'
FeCl3 6H2O (10 mol %)
H2O (2 equiv), 150 °C
Ar
R
Entrya
Alcohol
Nitrile
PhCN
Amide
Time (h)
1.0
Yieldb (%)
NHCOPh
1
1
54
6
O
HN
2c
1
1.0
0.5
66
CN
7
OH
NHAc
3
MeCN
PhCN
96
8
3
NHCOPh
4
3
3
0.5
75
9
O
HN
5c
1.0
87
CN
10
OH
NHAc
6
MeCN
4.5
49e
41e
52e
11
4
O
HN
7c
4
2.0
CN
12
NHAc
OH
8d
MeCN
15.0
5
13
a
Alcohol (1 mmol), nitrile (1 mL), 150 °C, sealed tube.
Isolated yield.
Alcohol (1 mmol), nitrile (3 equiv), cumene (1 mL), 150 °C, sealed tube.
At 50 °C.
b
c
d
e
90% conversion.
FeCl3Á6H2O (10 mol %), water (2 equiv), 150 °C], amide 2 was iso-
According to these results, it can be speculated that amide 2 can
come from ether 14 as the latter can be polarized by FeCl3 to gen-
lated in 75% yield (Scheme 2).

3472
B. Anxionnat et al. / Tetrahedron Letters 50 (2009) 3470–3473
Table 2
RCN
FeCl3
O
FeCl3Á6H2O-catalyzed Ritter reaction of 1 with MeCN in different solvents
t-Bu
R
N
H
OH
NHAc
FeCl3 6H2O (10 mol %)
E
MeCN (10 equiv), H2O (2 equiv)
solvent, T °C
1
2
Scheme 4.
Entrya
Solvent
T (°C)
Time (h)
Conversionc (%)
Yieldd (%)
Table 3
1
2
3
MeNO2
MeNO2
Toluene
Dioxane
Cumene
110
50
110
110
150
5.0
5.0
6.0
6.0
1.0
50
6
100
100
100
—
—
72
74
73
Ritter reaction of various nitriles with t-butyl acetate catalyzed by FeCl3Á6H2O16
O
FeCl3 6H2O (10 mol%)
4
5b
t-Bu
RCN
R
N
t-BuOAc (3 equiv.), H2O (2 equiv.)
cumene, 150 °C
H
a
Alcohol 4 (1 mmol), solvent (1 mL), sealed tube.
b
c
Alcohol 4 (1 mmol), solvent (0.5 mL), sealed tube.
Conversion of 4 determined by GC/MS.
Isolated yield.
Entrya
Nitrile
Amide
Time (h), yieldb (%)
d
O
t-Bu
N
H
1
PhCN
1.5, 69
OH
15
FeCl3 6H2O (10 mol %)
O
O
CN
t-Bu
MeCN, H2O (2 equiv), 70 °C
N
H
2
3
1.0, 61
14
1
Br
Br
NHAc
16
19
FeCl3 6H2O (10 mol %)
O
MeCN, H2O (2 equiv), 150 °C
14
2
75%
H
N
CN
CN
t-Bu
t-Bu
1.0, 65
6.0, 45
O
17
18
Scheme 2.
20
H
N
N
N
4c
erate the benzylic carbocation C which can be trapped by MeCN.
However, we cannot exclude that A or B can be attacked by MeCN
to produce D, or that A can generate the carbocation C directly
(Scheme 3).11b
O
21
a
Nitrile (1 mmol), t-Bu-OAc (3 equiv), cumene (0.6 mL), 150 °C, sealed tube.
Isolated yield.
Nitrile (1 mmol), t-Bu-OAc (6 equiv), FeCl3Á6H2O (20 mol %), 150 °C, sealed tube.
b
c
Ph
As tert-butyl amides of type E can be valuable synthetic inter-
O
mediates as they can be deprotected to the corresponding primary
amides,15 we turned our attention to the possible FeCl3-catalyzed
synthesis of amides E from nitriles and from a synthetic equivalent
of the tert-butyl carbocation (Scheme 4).
1
Ph
Ph
14
FeCl3
OH
HO
Ph
FeCl3
O
Cl3Fe
At first, the generation of the tert-butyl cation from t-BuOH was
examined. Disappointingly, when PhCN was treated with t-BuOH
in the presence of FeCl3Á6H2O (10 mol %), a low conversion of PhCN
was observed. However, t-butyl acetate appeared to be a better
source of t-butyl carbocation (Table 3). The reaction of PhCN with
t-BuOAc in cumene at 150 °C in the presence of FeCl3Á6H2O
(10 mol %) produced amide 15 in 69% isolated yield (Table 3, entry
1), the reaction was stopped after 1 h (89% conversion of PhCN) as
for longer reaction times, the degradation of amide 15 was ob-
served. In the case of nitriles 16 and 17 (Table 3, entries 2 and
3), the expected amides 19 and 20 were isolated in 61% and 65%
yields, respectively, and with nitrile 18, the reaction was still pos-
sible but required 20 mol % of FeCl3Á6H2O and 6 equiv of t-BuOAc
to produce 21 in 45% yield after 6 h (Table 3, entry 4).
In conclusion, we have described that FeCl3Á6H2O catalyzes the
Ritter reaction of nitriles with benzylic alcohols as well as the
Ritter reaction of nitriles with t-BuOAc producing, respectively,
benzylic amides and t-butyl protected primary amides. This cata-
lytic reaction is an inexpensive and eco-friendly process allowing
the preparation of various amides that can be useful synthons.
B
Ph
A
Ph
1
Ph
Ph
C
Me
C
N
Me
C N
Me
C N
Me
N
D
H2O
O
HN
Ph
Me
2
Scheme 3.

B. Anxionnat et al. / Tetrahedron Letters 50 (2009) 3470–3473
3473
11. (a) Jana, U.; Maiti, S.; Biswas, S. Tetrahedron Lett. 2008, 49, 858; (b) Jana, U.;
Biswas, S.; Maiti, S. Eur. J. Org. Chem. 2008, 5798; (c) Jana, U.; Biswas, S.; Maiti,
S. Tetrahedron Lett. 2007, 48, 4065; (d) Jana, U.; Maiti, S.; Biswas, S. Tetrahedron
Lett. 2007, 48, 7160.
12. It is worth noting that an amide of type 12 is a suitable substrate for Ring
Closing Metathesis (RCM). See: Fiorelli, C.; Savoia, D. J. Org. Chem. 2007, 72,
6022.
Acknowledgement
One of us (A.G.) thanks the CNRS for a grant (2007–2010).
References and notes
13. Typical experimental procedure: A mixture of alcohol (1 mmol), nitrile (1 mL)
and FeCl3Á6H2O (10 mol %, 27 mg) was placed in a sealed tube and warmed to
150 °C. The reaction medium was concentrated and diluted with AcOEt (4 mL)
and H2O (0.5 mL). Celite was added and the mixture was filtered and dried over
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A mixture of nitrile (1 mmol), t-Bu-OAc
(3 mmol), cumene (0.6 mL) and FeCl3Á6H2O (10 mol %, 27 mg) was placed in
a sealed tube and warmed to 150 °C. The reaction medium was concentrated
and diluted with AcOEt (4 mL) and H2O (0.5 mL). Celite was added and the
mixture was filtered and dried over Na2SO4. The obtained t-butyl amides were
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