I2-TEMPO as an efficient oxidizing agent for the one-pot conversion of alcohol to amide using FeCl3 as the catalyst

Article abstract of DOI:10.1016/j.catcom.2012.04.027

A high yield one-pot method for the synthesis of amides from alcohols is described. The aldehyde was generated in situ using iodine-TEMPO as oxidizing agent followed by intermediate oxime formation through reaction with NH ₂OH?HCl and finally rearrangement of oxime catalyzed by FeCl₃.

Full text of DOI:10.1016/j.catcom.2012.04.027

Catalysis Communications 26 (2012) 48–53
Contents lists available at SciVerse ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
I2-TEMPO as an efficient oxidizing agent for the one-pot conversion of alcohol to
amide using FeCl3 as the catalyst
⁎
Rima Das, Debashis Chakraborty
Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A high yield one-pot method for the synthesis of amides from alcohols is described. The aldehyde was
generated in situ using iodine-TEMPO as oxidizing agent followed by intermediate oxime formation through
reaction with NH2OH•HCl and finally rearrangement of oxime catalyzed by FeCl3.
© 2012 Elsevier B.V. All rights reserved.
Received 15 February 2012
Received in revised form 24 April 2012
Accepted 26 April 2012
Available online 7 May 2012
Keywords:
Amide
Alcohol
I2-TEMPO
FeCl3
Catalyst
1. Introduction
Many reports exist where TEMPO has been used as oxidant in
combination with Cu [23–30], Ru [31] metal or polymer support
Amides are an important class of compounds in biological and
chemical systems. Extensive studies have been done on amides by bi-
ologists and chemists over the past few decades [1,2]. Because of the
pervasive nature of the amides, it constitutes the formation of poly-
mer in a biological system through peptide linkage [3–5]. It is reg-
arded as one of the most important functional groups in organic
chemistry. Several “name reactions” and “rearrangements” exist
that are used routinely to synthesize amides. Some of these are
Schotten–Baumann reaction, Schmidt reaction, Willgerodt–Kindler
reaction, Bodroux reaction, Leuckart amide synthesis, Beckmann
rearrangement, Chapman rearrangement, etc. [6,7]. Several transition
metals are reported for the oxidative conversion of aldehydes to am-
ides [8–13]. However very few reports are present for direct alcohol
to amide synthesis. Recently our group has reported a synthetic
route for aldehyde to amide conversion using FeCl3 [14]. Recent liter-
ature documents the use of Ir [15] and Ru [16–18] complexes for the
synthesis of amides directly from alcohols. Metal free processes are
also reported for the conversion of alcohols to amides. Togo et al.
have reported the use of molecular iodine in aq. ammonia and H2O2
for alcohol to amide conversion [19]. The PhI(OAc)2–NaN3 system
was reported by Zhang et al. [20]. The selectivity of amide formation
may sometimes be hindered by the formation of side products such as
aldehyde, carboxylic acid and nitrile [21,22]. The challenge in this
area is to overcome these side reactions.
[32] although Semmelhack's report [23] indicates the inability of
Cu-TEMPO complex towards simple primary and secondary alcohols
and reactive only with allylic and benzylic alcohols. Miller et al.
have used the I2-TEMPO system for the conversion of alcohols to alde-
hydes [33]. After receiving excellent results with FeCl3 for aldehyde to
amide conversion, we were interested to explore a one-pot method
for alcohol to amide conversion using I2-TEMPO as oxidant and
FeCl3 as the catalyst and NH2OH•HCl as a nitrogen source.
2. Results and discussion
2.1. Screening of oxidant
Since the in situ oxidation of alcohol to aldehyde is critical, we first
screened various oxidants taking benzyl alcohol as a model substrate,
with FeCl3 as the catalyst, K2CO3 as the base, and NH2OH•HCl as
the nitrogen source in ethylenedichloride (EDC) solvent at 90 °C
(Table 1).
At first we have tried using a mild oxidant such as H2O2 or t-BuOOH
(solution in water), but unfortunately carboxylic acid was obtained as
the product (Table 1, Entries 1 and 2). Next, we used selective oxidants
such as MnO2/KMnO4 and KI/I2 giving benzaldehyde as the major
product along with a formation of oxime in little amount. But the reac-
tion from aldehyde to amide or oxime to amide does not proceed
further (Table 1, Entries 3 and 4) as concluded from GC studies of the
reaction mixture. Our next attempt was using I2-TEMPO which suc-
cessfully produces amide in the presence of Fe(III) (Table 1, Entry 5).
⁎
Corresponding author. Tel.: +91 44 22574223; fax: +91 44 22574202.
E-mail address: dchakraborty@iitm.ac.in (D. Chakraborty).
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2012.04.027

R. Das, D. Chakraborty / Catalysis Communications 26 (2012) 48–53
49
Table 1
Screening of oxidant.
a
Entry
Oxidant used
GC yield of products (%)
Aldehyde
Acid
Oxime
Amide
1
2
3
4
5
70% H2O2 (1 eq.)
0
0
75
72
10
92
97
0
0
0
0
0
22
25
0
0
0
0
0
75
70% t-BuOOH (water) (1 eq.)
MnO2/KMnO4 (1.5 and 0.5 mmol)
KI/I2 (25 mol%, 1 mmol)
I2-TEMPO (2 eq., 0.1 mmol)
a
Reaction performed with 10 mol% FeCl3, 3 eq. K2CO3, 1 eq. NH2OH•HCl along with above mentioned amount of oxidant in EDC at 90 °C for a period of 12 h, yield corresponds to
the GC yield obtained using internal standard.
2.2. Screening of solvent, base and iron salt
their reactivity with FeCl3 (Table 2, Entries 8–12) and we found that
K2CO3 and Cs2CO3 gave almost the same results. We have chosen
K2CO3, since it is inexpensive. We observed that KO-t-Bu, although a
very strong base, did not produce better results. Other bases such as
NaOH, KOH and Na2CO3 were less effective or ineffective (Table 2,
Entries 8–10). Among the varieties of solvents tested (Table 2, Entries
13–20), EDC was most effective. EtOAc also gave good yield, but re-
quired longer reaction time whereas reaction at lower temperature
(80 °C) with EDC produces more amide at the same time. Highly
We proceed to optimize other parameters such as the choice of
the base, solvent and iron salt taking I2-TEMPO as the oxidative sys-
tem and the results have been summarized in Table 2.
From Table 2, it is very clear that among easily available Fe(III)
salts (Table 2, Entries 1–7), FeCl3 gives good results with the forma-
tion of expected amide product. FeCl2 also produces 70% product in
22 h. Next, we screened a number of inorganic bases to compare
Table 2
Optimization of solvent, base and catalyst.
Entry
Fe-salt (10 mol%)
Base (3 eq.)
Solvent
Temp. (°C)
Time (h)a
Yield (%)b
1
2
3
4
5
6
7
8
Fe2O3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
Toluene
THF
EtOAc
EDC
CH3NO2
DMF
DMF
DMSO
DMSO
EDC
EDC
EDC
EDC
EDC
EDC
H2O
90
90
90
90
90
90
90
90
90
90
90
90
110
70
24
24
24
24
20
22
30
24
24
24
20
22
24
12
22
22
24
24
24
24
24
24
29
24
20
20
20
24
10
5
5
Fe(NO3)3·9H2O
Fe2(SO4)3
Mohr's salt
FeCl3
FeCl2
Fe powder
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
5
89
70
20
5
30
30
90
88
5
9
KOH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Na2CO3
Cs2CO3
KO-t-Bu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3 (2 eq.)
K2CO3 (4 eq.)
K2CO3
–
80
80
78
85
50
40
60
50
60
–
110
100
150
100
150
90
60
90
90
90
FeCl3
–
FeCl3
80
50
90
50
90
50
FeCl3 (5 mol%)
FeCl3 (15 mol%)
FeCl3
FeCl3
FeCl3
90
100
a
Monitored using TLC.
Isolated yield after column chromatography of the crude product.
b

50
R. Das, D. Chakraborty / Catalysis Communications 26 (2012) 48–53
polar solvents such as DMF and DMSO gave poor yield. Even when the
temperature was increased up to 150 °C, a very slight improvement in
yield was noticed (Table 2, Entries 19 and 21). Next, we have
performed a blank experiment without catalyst and no product
formation was observed (Table 2, Entry 22). Reducing the tempera-
ture from 90 °C to 60 °C leads to the increase in the reaction time
(Table 2, Entry 23). We varied the amount of catalyst from 5 mol%
to 15 mol% and 10 mol% was found to be the optimum amount
Table 3
FeCl3 catalyzed conversion of benzylic alcohols into aromatic amides.
Entry
1
Alcohol
Amide
Time (h)a
20
Yield (%)b
89
2
3
15
17
82
80
4
5
14
9
87
90
92
8
6
15
16
19
78
80
75
7
8
9
12
79
10
15
19
80
82
11
12
20
24
80
80
13
14
24
30
32
25
15
81
84
83
85
82
15
16
17
18
19
a
Monitored using TLC.
Isolated yield after column chromatography of the crude product.
b

R. Das, D. Chakraborty / Catalysis Communications 26 (2012) 48–53
51
Table 4
FeCl3 catalyzed conversion of aliphatic and allylic alcohols into amides.
Entry
1
Alcohol
Amide
Time (h)a
19
Yield (%)b
85
82
81
78
2
3
4
17
21
24
5
6
7
19
22
20
75
79
82
8
9
22
24
80
77
a
Monitored using TLC.
Isolated yield after column chromatography of the crude product.
b
(Table 2, Entries 24 and 25). Similarly, 3 eq. of base is required for
best results (Table 2, Entries 26 and 27). As our previous report on
FeCl3 uses water as solvent, here also we attempted an experiment
with H2O as solvent at 100 °C (Table 2, Entry 28) but only 50% conver-
sion was observed in 24 h.
In summary, the optimized conditions include I2-TEMPO (2 eq.,
0.1 mmol) as oxidant with NH2OH•HCl (1 equiv.) as the nitrogen
source, FeCl3 (10 mol%) as the catalyst and K2CO3 (3 equiv.) as the
base in EDC solvent at 90 °C. The grade of these various salts along
with impurities has been given in the supporting information.
converted to the corresponding amide in reasonable time with good
yield.
Long chain alcohols such as butyl, pentyl, and hexyl alcohols give
amide formation within 20–24 h under similar reaction conditions
(Table 4, Entries 3, 6, 8). Crotyl, cinnamyl and allylic alcohols result
in amide with better yields (Table 4, Entries 1, 2, 7). Propagylic and
cyclohexyl amides form within reasonable time in good yield from
the corresponding alcohols (Table 4, Entries 4, 5). Similarly, 2-
methoxyethanol also shows the same result of this reaction (Table 4,
Entry 9).
ICP-MS studies revealed that the FeCl3 used in this study con-
tained trace amounts of Cu2+ as impurity. A control experiment
was done as per the standard procedure using benzyl alcohol as the
2.3. Substrate scope
To access the capability of the reaction, various substituted alco-
hols were subjected to this reaction under the optimized condition.
Results are depicted in Tables 3 and 4.
Alcohol
Aldehyde
Amide
This method tolerates a variety of functional groups including var-
ious electron-donating and electron-withdrawing functional groups.
All the alcohols are converted to the amides giving good yields within
a reasonable time. Substrate containing electron-donating group
(Table 3, Entries 2–6) takes less time with high yields of product
whereas substrate having strong electron-withdrawing groups such
as cyano, nitro, and trifluoromethyl takes more time for completion
(Table 3, Entries 15–17). Substrates containing other functional
groups like amine and hydroxyl group (Table 3, Entries 7–11) are tol-
erated well in the reaction media, and do not affect product forma-
tion. Similar results were obtained with alcohol having a hetero
atom such as furylalcohol (Table 3, Entry 19). But in the sulphide
group containing alcohol (Table 3, Entry 18) a slightly different be-
havior is observed. Sulphide functionality also oxidizes to sulfoxide
during the conversion of alcohol to amide which has been confirmed
by ESI-MS spectroscopy.
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0
10000
20000
30000
40000
50000
Time (sec)
In addition to these, aliphatic and allyl alcohols were also sub-
jected to this methodology (Table 4). These substrates are also
Fig. 1. Concentration versus time in the conversion of p-methoxybenzyl alcohol to p-
methoxy benzamide by FeCl3.

52
R. Das, D. Chakraborty / Catalysis Communications 26 (2012) 48–53
5. Experimental
Y = - 4.08 + 2.15 X
R = 0.9986
-4.8
-4.9
-5.0
-5.1
-5.2
-5.3
-5.4
5.1. General consideration
All the reagents were purchased from Aldrich and used as received.
All the solvents were purchased from Ranchem, India and purified using
standard methods. The products were characterized by recording 1H, 13
NMR and ESI-MS by using a Bruker Avance 400 MHz instrument and
Jeol JMS GC-Mate II instrument. HPLC analysis was done with Waters
HPLC instrument fitted with Waters 515 pump and Waters 2487 dual-
wavelength absorbance detector.
C
5.2. Typical experimental procedure
-1.6
-1.4
-1.2
-1.0
log10
-0.8
-0.6
C
To a stirred solution of alcohol (1 mmol) in ethylenedichloride
(3 mL) was added I2 (507 mg, 2 mmol) and TEMPO (15 mg, 0.1 mmol)
followed by K2CO3 (414 mg, 3 mmol), NH2OH•HCl (69 mg, 1 eq.) and
anhydrous FeCl3 (16 mg, 10 mol%) and the reaction mixture was heated
to 90 °C for the appropriate time. The progress of the reaction was
monitored by TLC. After completion, the reaction mixture was cooled
and was quenched with aqueous solution of sodium sulfite and then
the organic layer was extracted in EtOAc. The organic layer was dried
over sodium sulfate and evaporated, followed by flash column purifica-
tion of the crude to obtain the pure product.
n= 2.15 and k= 8.31 × 10-5 L mol-1s-1
Fig. 2. Van't Hoff differential plot for the conversion of p-methoxybenzyl alcohol to p-
methoxy benzamide by FeCl3.
substrate along with the required concentration of CuBr2 as guided by
ICP-MS results, in the absence of FeCl3. We observed less than 5% con-
version during the required period of time. In another experiment, we
used 99.99% FeCl3 and added CuBr2 as an impurity in trace quantities,
keeping other parameters of the experiment identical. In this case the
time of reaction and the isolated yield remained almost invariant.
These experiments prove that this transformation is catalyzed by
FeCl3 alone.
Acknowledgments
This work was supported by the Department of Science and Tech-
nology, New Delhi. R.D. thanks the Council of Scientific and Industrial
Research, New Delhi for a research fellowship.
3. Kinetic studies
Appendix A. Supplementary data
We have performed the kinetic studies with the following sub-
strates namely p-methoxybenzylalcohol, p-chlorobenzylalcohol and
cinnamyl alcohol. High-Pressure Liquid Chromatography (HPLC)
was used to determine the various concentrations of starting mate-
rials and product present with respect to time. Fig. 1 shows the con-
centration vs time plot for the conversion of p-methoxybenzyl
alcohol to p-methoxy benzamide which indicates the steady decrease
in the concentration of alcohol with gradual increase in concentration
of amide with time while the intermediate aldehyde concentration
increases, achieves a steady state and finally decreases to give the
product.
The order (n) and rate constant (k) have been calculated by the
Van't Hoff differential method. The rate of the reaction at different con-
centrations has been estimated by evaluating the slope of the tangent
at each point of Fig. 1. With this data log10 (rate) vs log10 (concentra-
tion) have been plotted in Fig. 2. The order (n) and rate constant (k)
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.catcom.2012.04.027.
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