Tandem oxidative amidation of benzyl alcohols with amine hydrochloride salts catalysed by iron nitrate

Article abstract of DOI:10.1016/j.tetlet.2013.07.005

A tandem process for the oxidative amidation of benzyl alcohols with amine hydrochloride salts has been developed using inexpensive Fe(NO₃) ₃ as the catalyst, air and aqueous t-butyl hydroperoxide as oxidants. A wide range of benzamides have been synthesized under mild conditions. This greener amide formation method provides an economical and practical assess to benzamides from readily available and inexpensive starting materials.

Full text of DOI:10.1016/j.tetlet.2013.07.005

Tetrahedron Letters 54 (2013) 4922–4925
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tandem oxidative amidation of benzyl alcohols with amine
hydrochloride salts catalysed by iron nitrate
Subhash Chandra Ghosh a,b, Joyce S. Y. Ngiam a, Abdul M. Seayad a, Dang Thanh Tuan a,
Charles W. Johannes a, Anqi Chen a,
⇑
a Institute of Chemical and Engineering Sciences, Agency for Science, Technology and Research (AÃSTAR), 8 Biomedical Grove, Neuros #07-01, 138665, Singapore
b Current address: Discipline of Inorganic Materials and Catalysis, Central Salt & Marine Chemicals Research Institute (CSIR-CSMCRI), G.B. Marg, Bhavnagar, Gujarat 364002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A tandem process for the oxidative amidation of benzyl alcohols with amine hydrochloride salts has been
developed using inexpensive Fe(NO3)3 as the catalyst, air and aqueous t-butyl hydroperoxide as oxidants.
A wide range of benzamides have been synthesized under mild conditions. This greener amide formation
method provides an economical and practical assess to benzamides from readily available and inexpen-
sive starting materials.
Received 26 April 2013
Revised 26 June 2013
Accepted 1 July 2013
Available online 6 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Oxidative amidation
Benzyl alcohol
Amides
Iron(III) nitrate
Tandem oxidation
The amide bond is a ubiquitous functionality found in peptides,
natural products, polymers, fine chemicals and pharmaceuticals.1
Consequently, amide bond formation has been one of the most
important transformations in organic synthesis and a plethora of
methods have been reported.2 Amongst these, direct amidation
of alcohols with amines catalysed by transition metals is highly
attractive owing to its high atom-efficiency and environmental
friendliness.3 This type of amide formation can be achieved by
either dehydrogenative or oxidative amidation, depending on
whether an oxidant is required (Scheme 1).
In dehydrogenative amidation, alcohols and amines are directly
coupled to form amides without the presence of an oxidant and
molecular hydrogen is formed as the by-product. Several catalyst
systems based on homogenous ruthenium,4 rhodium,5 iridium6
complexes and supported silver or gold nanoparticles7 have been
developed. Oxidative amidation, on the other hand, requires an
oxidant to affect the coupling of alcohols and amines to form
amides. Heterogeneous catalysts such as gold or its bimetallic
nanoparticles,8 manganese oxide octahedral molecular sieves
(OMS-2)9 have been shown to promote this type of amide
formation.
These novel methods represent important advances toward
environmentally benign and atom-efficient amide formation that
could circumvent the poor efficiency and hazardous problems
associated with the existing acid halide or coupling reagent based
methods. However, the high cost of noble metal catalysts and their
potential toxicity in pharmaceutical products10 continue to pro-
mote exploration of more economical and safer catalysts for amide
formation. For example, very recently CuO11a and FeCl3
have
11b
also been reported for the formation of benzamides from benzyl
alcohols. In continuation of our efforts in developing atom-efficient
and environmentally benign amide formation methodologies,12 we
report herein our extended work on iron-catalysed tandem oxida-
tive amidation of benzyl alcohols with amine HCl salts.
A tandem oxidative amidation process of alcohol requires the
catalyst to affect the oxidation of both the alcohol to aldehyde
and the hemiaminal intermediate12,13 formed between aldehyde
and amine to the amide (Scheme 2). Iron compounds are particu-
O
larly attractive catalysts for such
they are inexpensive and low toxic (permitted daily exposure
a transformation because
R2
metal catalyst
R2
R1
N
R1
HN
+
OH
R3
with or without oxidant
R3
O
OH
R3R2NH
R2
O
Catalyst
Oxidant
Catalyst
Oxidant
R1
N
R2
Scheme 1. Metal-catalysed dehydrogenative and oxidative amidation.
R1
R1
N
OH
R1
H
R3
R3
⇑
Corresponding author. Fax: +65 64642102.
E-mail address: chen_anqi@ices.a-star.edu.sg (A. Chen).
Scheme 2. Tandem oxidative amidation of alcohols with amines.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.005

S. C. Ghosh et al. / Tetrahedron Letters 54 (2013) 4922–4925
4923
limit >13 mg).10 In addition, they have been shown to catalyse the
oxidation of alcohols to aldehydes14 and aldehydes to amides as
demonstrated in our previous work.12a
issues,15 we examined the feasibility of using air (atmospheric
oxygen) as a more practical and safer oxidant for our tandem oxi-
dative amidation. This indeed proved feasible with the desired
amide being formed in essentially the same yield (entry 9). Control
experiments revealed that sodium chloride was not necessary (en-
try 10) whereas in the absence of TEMPO, the yield of amide de-
creased to 57% (entry 11), and without iron nitrate, only 12% of
the amide product was formed (entry 12), indicating the crucial
role of the iron catalyst in the reaction. Increasing the amount of
amine salt to 1.5 equiv further improved the yield to 85% (entry
13). Furthermore, shortening the reaction time of step A to ca.
2 h did not affect the reaction (entries 14 and 15). However, addi-
tion of all the reagents at the beginning resulted in a significant de-
crease in yields (entry 16). This could be due to the known
competitive oxidation of the amine under the reaction conditions16
which could lead to ineffective oxidation of the alcohol as well as
premature consumption of the amine. The performance of other
TEMPO co-catalysts such as 4-hydroxy and 4-acetamido TEMPO
(entries 16 and 17) was not as good as TEMPO itself.
Our investigation of tandem amidation began with the screen-
ing of a number of inexpensive and readily available iron catalysts
based on the reaction of benzyl alcohol and glycine methyl ester
hydrochloride as a test reaction (Table 1). The reaction was carried
out in a tandem fashion by firstly oxidizing the alcohol to benzal-
dehyde using an iron catalyst in conjunction with TEMPO as a co-
catalyst and molecular oxygen as an oxidant (step A), followed by
oxidative amidation of the aldehyde by the addition of the amine
salt, calcium carbonate (as the base) and a second oxidant T-hydro
(70% aqueous TBHP).12a The initial results from two reported cata-
14a
lytic systems, that is, FeCl3-TEMPO-NaNO2
and Fe(NO3)3-TEM-
PO-NaCl14b for alcohol oxidation showed only low to moderate
activity for the amidation reaction in dichloroethane (DCE) (Table 1,
entries 1 and 2).
We reasoned that the lower yields could be due to poor solubil-
ity of the amine salt in the low polarity solvent DCE. Indeed,
switching the solvent to more polar acetonitrile gave a much im-
proved yield of 79% (entry 3). Further screening of a wide range
of other iron salts concluded that Fe(NO3)3Á9H2O was superior over
others (entries 4–8). Since the use of pure oxygen could pose safety
In order to better understand the reaction profile, the conver-
sion of benzyl alcohol alone (step A) was monitored (Fig. 1A).
At ca. 2 h, almost 50% of the alcohol was converted into the alde-
hyde and the oxidation was completed at 6 h. The reaction course
after the addition of glycine methyl ester HCl salt (step B) was also
followed (Fig. 1B). The amidation reaction in the first 2 h was faster
Table 1
Screening of iron catalysts and optimization of reaction conditionsa
Step A
O
OH
Fe salt (5 mol%), TEMPO (5 mol%)
conditions (see Table)
100
80
60
40
20
0
Alcohol
Aldehyde
N
H
CO2Me
Step B
+
TBHP (1.1 equiv.), CaCO3 (1.1 equiv.)
60 oC, 16 h
MeO2C
NH2. HCl
(1.2 equiv)
(A)
Entry Catalyst
Oxidant Additive Solvent Timeb
(h)
Yieldc
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
FeCl3Á6H2O
O2
O2
O2
NaNO2
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
—
—
—
—
—
—
—
—
—
DCE
DCE
6
6
6
6
6
6
6
6
6
6
6
6
6
4
2
0
2
2
2
2
15
45
79
33
27
22
30
47
76
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Fe(III)oxalate.6H2O O2
Fe(II)oxalateÁ2H2O
O2
O2
O2
O2
FeF3Á6H2O
Fe(acac)3
0
1
2
3
4
5
6
FeSO4Á7H2O
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
—
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Time (h)
77
57d
12
100
80
60
40
20
0
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
Fe(NO3)3.9H2O
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
85e
85e
86e
38e
68e,f
74e,g
48e,h
69e,i
Alcohol
Aldehyde
Amide
—
—
(B)
a
The reaction in step A was carried out with benzyl alcohol (1.0 mmol), TEMPO
(5 mol %), additive (10 mol %), Fe catalyst (5 mol %) and solvent (1 mL) at room
temperature for the indicated time. Subsequently, glycine methyl ester HCl salt
(1.2 mmol unless otherwise mentioned), TBHP (70% aq solution, 1.1 mmol) and
CaCO3 (1.1 mmol) were added and the reaction was heated at 60 °C for a further
16 h.
b
Time for step A.
c
Yields were determined by quantitative GC analysis using dodecane as an
internal standard.
0
2
4
6
8
10
Time (h)
12
14
16
18
d
In the absence of TEMPO.
1.5 mmol amine salt was used.
4-Hydroxy-TEMPO was used.
4-Acetamido-TEMPO was used.
1 mol % Fe-catalyst was used.
3 mol % Fe-catalyst was used.
e
f
Figure 1. Reaction progress monitored by GC: (A) Oxidation of benzyl alcohol to
benzaldehyde. (B) Oxidative amidation of benzyl alcohol and glycine methyl ester
hydrochloride to methyl-2-benzamidoacetate. Amine salt was added after 2 h of
alcohol oxidation.
g
h
i

4924
S. C. Ghosh et al. / Tetrahedron Letters 54 (2013) 4922–4925
Table 2
Amide formation from benzyl alcohols and amine saltsa,b
O
Fe(NO3)3. 9H2O (5 mol%)
R3R2NH. HCl (1.5 equiv)
TEMPO (5 mol%)
R2
2
R1
OH
R1
N
CH3CN, air, rt, 2 h
TBHP (70% aq solution,1.1 equiv)
CaCO3 (1.1 equiv), 60 oC, 16 h
R3
1
3
O
O
Ph
O
O
N
H
Ph
N
H
CO2Et
N
H
CO2Me
N
H
CO2Me
3d, 78%
3a, 80%
3b, 78%
3c, 81%
O
O
O
O
N
CO2Et
N
CO2Me
N
H
N
H
H
H
F
Cl
F
Br
3f, 65 %
3g, 77%
3e, 72 %
3h, 64 %
O
O
O
O
N
N
H
Ph
N
N
H
MeO
MeO2C
3k, 58%
3j,45%
3i, 67%
3l,74%
O
O
N
O
N
O
N
CO2Me
N
CO2Me
O
O
F
3o, 76%
3m, 71%
3n, 56%
3p, 79%
O
O
O
N
CO2Me
N
CO2Me
N
CO2Me
Ph
MeO
Cl
3q, 76%
3r, 73%
3s, 78%
a
Reaction conditions: A vial containing a solution of benzyl alcohol (1.0 mmol), TEMPO (0.05 mmol) and Fe(NO3)3Á9H2O (0.05 mmol) in acetonitrile (1 mL) was stirred
under open air at room temperature for 2 h. Subsequently, amine hydrochloride salt (1.5 mmol), calcium carbonate (1.1 mmol) and TBHP (70% aq solution, 1.1 mmol) were
added and the reaction mixture was capped and stirred for additional 16 h at 60 °C.
b
Yields in the table refer to isolated yields.
(46% of amide formed) due to significant amount of aldehyde al-
ready present in the reaction. Subsequently, the reaction pro-
gressed more slowly and essentially leveled off at ꢀ11 h with
80% yield of amide formed.
reaction of aliphatic alcohols gave inseparable mixtures. These lim-
itations in substrate scope are likely due to undesired reactions un-
der the reaction conditions, such as ring-opening of furan under
acidic conditions,17 aza-Michael reaction of amines with
a,b-unsat-
With the optimized conditions in hand, the scope of this
tandem amidation reaction was investigated with various benzyl
alcohols and amine hydrochloride salts. In general, amides were
obtained in good yields (Table 2). Electronic effects were not
significant as both electron-donating (3d, 3i, 3p and 3r) and elec-
tron-withdrawing groups (3f–h, 3o and 3r) on benzyl alcohols
gave similar yields of amide products. Several functional groups
such as ester, halides, ketone and ether were compatible with
the reaction conditions. This method worked well with both pri-
mary and secondary amines to form the corresponding secondary
and tertiary amides. Chiral amine salts derived from amino acids
urated aldehydes18 formed and aldol condensation of enolizable
aldehydes produced in the first step. The limitation of aliphatic
alcohols11 and aldehydes12,13,19 in oxidative amidation has been
observed previously. Hence, the development of catalyst systems
R1
R1
OH
O
Fe(III)-TEMPO
H2O
1/2O2
Fe(II) + TEMPOH
R2
R2
NH
CaCO3
such as L-phenylalanine and L-proline underwent smooth amida-
NH. HCl
R3
R3
tion providing the corresponding amides without detectable race-
mization (3c and 3l). Nevertheless, the reaction appeared to be
sensitive to steric hindrance of the amine as bulky t-butyl amine
HCl salt gave reduced yield (3j).
Other alcohols, including heterocyclic, allylic and aliphatic ones,
were also examined for this oxidative amidation. However, most of
these alcohols either gave low yields of the respective amide prod-
ucts or failed to provide the desired products. For example, amida-
tion of furfuryl alcohol and cinnamyl alcohol with primary amine
hydrochlorides provided <40% of the desired amides whereas the
FeLn
tBuO
tBuOOH
R2
tBuOOH
OH
R1
O
OH
R2
R2
N
N
R1
N
R1
R3
R3
R3
tBuOH
tBuO + H2O
Figure 2. A proposed mechanism for (Fe-TEMPO)-catalysed tandem oxidative
amidation of alcohols with amine hydrochloride salts.

S. C. Ghosh et al. / Tetrahedron Letters 54 (2013) 4922–4925
4925
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Based on a reported iron-TEMPO mediated alcohol oxidation, a
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reacts with amine generated in situ to form a hemiaminal interme-
diate12,13,19 which is further oxidized to the amide by Fe(III)-TBHP
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tyl-4-methylphenol (BHT, 1 equiv) which resulted in complete
inhibition of amide formation.
In conclusion, we have developed a tandem oxidative amidation
of benzyl alcohols with amine hydrochloride salts using inexpensive
Fe(NO3)3Á9H2O-TEMPO as the catalyst, air and aqueous TBHP as the
oxidants. Both secondary and tertiary benzamides can be prepared
under mild conditions and without using any noxious reagents.
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Acknowledgements
This work was supported by the GlaxoSmithKline (GSK), Singa-
pore Economic Development Board (EDB) for Green and Sustain-
able Manufacturing (GSM) and the Agency for Science,
Technology and Research (AÃSTAR), Singapore.
Supplementary data
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Supplementary data associated with this article can be found, in
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