Iodine-catalyzed one-pot synthesis of amides from nitriles via Ritter reaction

Article abstract of DOI:10.1016/j.tetlet.2010.03.057

Ritter reactions of alcohols and tert-butyl acetate with various nitriles were performed using iodine as a mild and effective catalyst under heating conditions to afford the corresponding amides in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.03.057

Tetrahedron Letters 51 (2010) 2813–2819
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Iodine-catalyzed one-pot synthesis of amides from nitriles via Ritter reaction
b
Palani Theerthagiri a,b, Appaswami Lalitha a, , Pirama Nayagam Arunachalam
*
a Department of Chemistry, Periyar University, Salem 636 011, India
b Syngene International Ltd, Biocon Park, #2 and 3, Bommasandra, Jigani Link Road, Bangalore 560 099, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Ritter reactions of alcohols and tert-butyl acetate with various nitriles were performed using iodine as a
mild and effective catalyst under heating conditions to afford the corresponding amides in good to excel-
lent yields.
Received 3 December 2009
Revised 10 March 2010
Accepted 16 March 2010
Available online 20 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ritter reaction
Iodine-catalyzed
Nitriles
Alcohols
Amides
Modification of already existing synthetic methodologies has
received greater attention in recent years from both industrial
and academic research communities. The construction of carbon–
nitrogen bond is one of the most important fundamental processes
in organic and bioorganic chemistry as peptides and proteins are
formed by amide bonds. The N-tert-butyl amides are pharmaceuti-
cally important compounds in pharmaceutical industries1,2 and
serve as precursors to the corresponding amines. Therefore there
is a great deal of interest in the synthesis of amides. Earlier, amides
were prepared by the condensation of carboxylic acids with
amines using various coupling agents.3 Ritter reported efficient
protocol for the synthesis of amides by the reaction of nitriles with
substituted alkenes or alcohols using concentrated sulfuric acid.
However, as an alternative to sulfuric acid, now other acid cata-
lysts,4–7 Bronsted acids,8 Nafion,9 Fe-montmorllonite K-1010 are
employed in the Ritter reaction. Ritter reaction using tert-butyl
acetate instead of alcohol was also reported to be catalyzed by sul-
furic acid,11 or Bi(OTf)3.6 Ritter reaction involving benzylic alcohols
or tert-butyl acetate with various nitriles has been reported using
FeCl3Á6H2O,12 as a catalyst. Ritter-type amidation of alkyl boron
derivatives with nitriles has been described.13 However, most of
these methods have several disadvantages such as (i) usage of cor-
rosive acid catalysts, (ii) usage of toxic and moisture sensitive cat-
alysts, and (iii) usage of more expensive metal triflates. Moreover
the recently reported FeCl3Á6H2O catalyzed Ritter reaction protocol
was not successful to produce N-tert-butyl amides from tert-buta-
nol. To circumvent the disadvantages, we wish to introduce molec-
ular iodine as a mild and efficient catalyst for this transformation.
Currently iodine has received considerable attention as a mild cat-
alyst because of its non-toxic nature coupled with cheap and ready
availability making iodine as a promising catalyst for Ritter reac-
tion under mild and neutral conditions. In addition to this, no strin-
gent dry condition is necessary in this reaction.
Recent studies indicate that iodine can be effectively used as a
catalyst for acetylation,14 protections and deprotections, oxida-
tions, three-component synthesis of protected homoallylic
amines,15 direct oxidative conversion of alkyl halides into nitriles,
synthesis of bis(indolyl) methanes,16 alkylation of active methy-
lene compounds,17 synthesis of amidophenol,18 etc., surprisingly,
to the best of our knowledge there are no previous examples of io-
dine being used as a catalyst for the Ritter reaction.
The activation of alcohols to generate the carbocation is thought
to be difficult due to the poor leaving ability of the –OH group in
the absence of any catalyst. In the present study, alcohols I–IV
and the tert-butyl acetate were used with a variety of aromatic/ali-
phatic nitriles for the synthesis of the corresponding amides.
Reaction of 1-phenylethanol (I) with acetonitrile was taken as a
model reaction to optimize the reaction conditions (Scheme 1).
OH
NHAc
I2 , H2O
MeCN
1
I
* Corresponding author. Tel.: +91 427 2345271; fax: +91 427 2345124.
E-mail address: lalitha2531@yahoo.co.in (A. Lalitha).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.057

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P. Theerthagiri et al. / Tetrahedron Letters 51 (2010) 2813–2819
Table 1
After several trials, iodine with 2 equiv of water was found to be
the best to provide the desired amide in good yield. To optimize
other reaction conditions, the reaction was performed using differ-
ent solvents and toluene was found to be superior to others. The
reaction was also monitored to find out the influence of different
concentrations of the catalyst using toluene as a solvent and
20 mol % of iodine was found to be the optimum. To find out the
optimum temperature, the reaction was carried out at different
temperatures and even at reflux conditions the conversion was
found to be only 50% and this prompted us to study the reaction
Iodine-catalyzed Ritter reaction of I with MeCN in different solvents
Entry
Solventa
Temp (°C)
Time (h)
Conversionb (%)
Yieldc (%)
1
2
3
4
5
MeNO2
MeNO2
Toluene
Xylene
THF
100
50
110
150
80
8
8
4
4
6
50
10
100
100
30
—
—
85
80
—
a
b
c
Alcohol I (1 mmol), nitrile (1.1 mmol), solvent (10 volume), sealed tube.
Conversion of I monitored by LC–MS.
Isolated yield.
Table 2
Ritter reaction of various alcohols and nitriles catalyzed by iodine
Entrya
Alcohol
Nitrile
Amide
Timeb (h)
Yieldc (%)
OH
O
O
HN
1
MeCN
4.0
8512
I
1
OH
CN
HN
2
3
4.0
4.0
8412
I
2
OH
CN
O
HN
HN
HN
60d
I
3
O
OH
CN
4
5
5.0
5.0
6219
Br
N
I
Br
N
4
O
OH
CN
6420
I
5
OH
CN
O
HN
6
4.0
7521,22
I
6
Br
OH
CN
O
Br
7
8
3.0
6.0
91d
HN
I
7
Br
OH
O
HN
Br
MeCN
4423
II
8

P. Theerthagiri et al. / Tetrahedron Letters 51 (2010) 2813–2819
2815
Table 2 (continued)
Entrya
Alcohol
Nitrile
Amide
Timeb (h)
Yieldc (%)
Br
OH
OH
CN
O
HN
Br
9
4.0
66d
II
9
O
Br
Br
CN
Br HN
10
11
4.0
6.0
88d
II
OH
10
O
CN
Br HN
82d
II
11
OH
O
HN
12
MeCN
5.0
8012
III
12
OH
CN
O
O
HN
13
14
15
6.0
5.0
6.0
8512
6024
70d
III
13
OH
CN
Cl
HN
Cl
III
14
OH
CN
O
N
H
III
15
OH
CN
O
N
N
HN
16
6.0
6624,25
III
16
OH
O
CN
HN
17
5.0
9526
III
17
(continued on next page)

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P. Theerthagiri et al. / Tetrahedron Letters 51 (2010) 2813–2819
Table 2 (continued)
Entrya
Alcohol
Nitrile
Amide
Timeb (h)
Yieldc (%)
OH
Br
CN
O
HN
Br
18
6.0
4024
III
18
F
OH
CN
O
F
HN
19
20
7.0
76d
III
19
O
OH
CN
N
H
8.0
8.0
6011
IV
20
OH
H
N
CN
21
6311
O
IV
21
a
Alcohol (1 mmol), nitrile (1.1 mmol), solvent (10 volume), 110 °C, sealed tube.
Reactions were monitored by LC–MS.
Isolated yield.
Novel compounds.
b
c
d
using sealed tubes. The reaction worked in a much better way at
110 °C in a sealed tube (Table 1).
The conditions described in the entry 3 of Table 1 were found to
be suitable for the synthesis of various other amides in good yields,
and the results are summarized in Tables 2 and 3.
The generality and scope of this protocol were evaluated for
both aromatic and aliphatic alcohols, and a variety of nitriles.30
In all these cases, the Ritter reaction proceeded and yielded the de-
sired amides in good to excellent yields including some novel
amides (entries 3, 7, 9, 10, 11, 15, and 19). When secondary benzyl
Table 3
Ritter reaction of various nitriles with tert-butyl acetate catalyzed by iodine
O
I2 (20 mol %)
t-Bu
Ar-CN
N
Ar
t-BuOAc (2 equiv), H2O (2 equiv)
H
Toluene, 110 o
C
Entrya
Nitrile
Amide
Timeb (h)
Yieldc (%)
CN
O
N
H
1
6.0
6511
20
CN
Cl
O
N
H
2
3
6.0
5.0
4429
Cl
22
CN
O
N
H
87d
23

P. Theerthagiri et al. / Tetrahedron Letters 51 (2010) 2813–2819
2817
Table 3 (continued)
Entrya
Nitrile
Amide
Timeb (h)
Yieldc (%)
O2N
CN
CN
O
O2N
N
H
4
5
7.0
81d
24
O
N
H
MeO
N
NO2
6.0
86d
MeO
N
NO2
25
CN
O
N
6
7
6.0
6.0
7227
H
26
CN
CN
O
N
H
8611
F3C
CF3
27
O
N
H
MeO
8
9
4.0
8311
MeO
28
H
CN
N
6.0
5.0
80d
O
F
F
29
H
N
CN
Br
10
8228
O
Br
30
a
Nitrile (1.1 mmol), tert-butyl acetate (2 mmol), solvent (10 volume), 110 °C.
Reactions were monitored by LC–MS.
Isolated yield after column chromatography.
Novel compounds.
b
c
d
or tert-butyl alcohols are used as substrates, amides are produced
in good yields. On the other hand primary benzyl alcohol on treat-
ment with phenyl cyanide under the same conditions, disappoint-
ingly, results in a very low conversion (10%).
OH
I2 (20 mol %)
MeCN, 60 oC
O
B
In the mechanism proposed, we invoke the formation of ether
as suggested in the Ritter reaction of alcohols catalyzed by
FeCl3Á6H2O.12 The ether leads to the formation of carbocation
which attacks the nitrile to give the amide. When the reaction
was carried out in the absence of water, it has been observed that
ether B was the major product and no amide was formed. While
ether formation was observed at low temperatures (60 °C), at high-
er temperatures (110 °C) amide was found to be the only product
(Scheme 2). In one of the experiments, ether B was isolated and
confirmed by NMR. The plausible mechanism for the iodine-cata-
lyzed Ritter reaction is given in Scheme 3. It is presumed that io-
dine catalyzes the reaction as a mild Lewis acid.18 The molecular
iodine is believed to activate the alcoholic OH to give intermediate
I
I2 (20 mol%),
H2O (2 equiv)
MeCN,
110 oC
NHAc
1
Scheme 2.
A, which on combination with another alcohol molecule yields the
ether B. In the presence of iodine, B may afford C which may then
be converted to the carbocation D. The attack of the carbocation on
the nitrile followed by water addition may provide the amide.
Next, we turned our attention to the synthesis of N-tert-butyl
amides from tert-butyl acetate and nitriles under the reflux condi-
tions. As the yields with the tert-butyl alcohol are less, tert-butyl

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P. Theerthagiri et al. / Tetrahedron Letters 51 (2010) 2813–2819
I2
Ph
O
Ph
I
I2
I2
OH
B
OH
Ph
Ph
Ph
O
Ph
I
A
I2
Ph
D
C
MeCN
O
HN
Me
Ph
H2O
N
C
Me
Ph
1
E
Scheme 3.
O
O
I2 (20 mol %), H2O (2 equiv)
ArCN, 110 oC
Ar
N
O
H
Scheme 4.
acetate has been used as the carbocationic source. In an earlier Let-
ter, synthesis of tert-butyl amides has been achieved using H2SO4
and acetic acid at room temperature11 where they describe the
convenient synthesis of only the tert-butyl amides but the present
protocol can be effectively used for the synthesis of both benzyl
and tert-butyl amides. Though the reaction is carried out at high
temperature (110 °C), our method avoids the use of corrosive
H2SO4 and uses only catalytic amount of iodine (Scheme 4). There-
fore this is an eco-friendly reaction. This reaction is useful to pre-
pare bulky amides, which may be useful in the preparation of the
hindered amines by hydrolysis.6
The scope of this reaction was investigated by examining a vari-
ety of nitriles and in most of the cases, using the same conditions,
the reaction proceeded smoothly in a few hours with good yields
and the results are summarized in Table 3.31
The formation of amides in good yields as seen from Table 3, is
sufficient to show that tert-butyl acetate served as a better source
of tert-butylcarbocation. The reaction of PhCN with t-BuOAc in tol-
uene at 110 °C in the presence of molecular iodine (20 mol %) pro-
duced the amide (20) in 65% isolated yield. The yields of most of
the other amides are more than 80%, whereas only 45% amide 22
was obtained using around 30 mol % of iodine and 3 equiv of
tert-butyl acetate.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.057.
References and notes
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Table 2. After completion of the reaction (monitored by TLC), saturated sodium
thiosulfate in water was added and extracted with ethyl acetate. The organic
layer was separated and washed with water and brine and dried over sodium
sulfate, concentrated to furnish the desired amides. When necessary, the
obtained amides were purified by crystallization using petroleum ether/ethyl
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30. General experimental procedure for synthesis of amides: A mixture of alcohol
(1 mmol), nitrile (1.1 mmol), iodine (20 mol %), and water (2 equiv) was placed
in a sealed tube and heated to 110 °C for the appropriate time as mentioned in
31. General experimental procedure for synthesis of tert-butyl amides: A mixture of
tert-butyl acetate (2 equiv), nitrile (1 mmol), iodine (20 mol %), and water
(2 equiv) were placed in a RB flask and heated to110 °C for the appropriate
time as mentioned in Table 3. After completion of the reaction (monitored by
TLC), saturated sodium thiosulfate in water was added and extracted with
ethyl acetate, the organic layer was separated and washed with water and
brine and dried over sodium sulfate and concentrated. The obtained tert-butyl
amides were purified by flash chromatography.