Hydrogen peroxide mediated efficient amidation and esterification of aldehydes: Scope and selectivity

Article abstract of DOI:10.1039/c1gc16041a

An efficient method for the amidation and esterification of aldehydes utilizing hydrogen peroxide as an oxidant has been developed. Cyclic amines and primary alcohols selectively reacted with aromatic aldehydes under mild conditions to yield the corresponding amides and esters.

Full text of DOI:10.1039/c1gc16041a

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COMMUNICATION
Hydrogen peroxide mediated efficient amidation and esterification of
aldehydes: Scope and selectivity†
Rekha Tank, Uma Pathak,* Manorama Vimal, Shubhankar Bhattacharyya and Lokesh Kumar Pandey
Received 23rd August 2011, Accepted 20th October 2011
DOI: 10.1039/c1gc16041a
An efficient method for the amidation and esterification
of aldehydes utilizing hydrogen peroxide as an oxidant
has been developed. Cyclic amines and primary alcohols
selectively reacted with aromatic aldehydes under mild
conditions to yield the corresponding amides and esters.
and reverts back to sp2 in the final product. Since an sp3 carbon
is more sterically crowded in comparison to an sp2 carbon, we
reasoned that the steric attributes of the amine and aldehyde
around the reaction centre (zone-A, Fig. 1) may play a crucial
role in the formation and stabilization of the carbinolamine
intermediate. Hence, we further reasoned that amines/aldehyde
having steric compatibility for this reaction could undergo amide
formation without any catalyst or derivatisation, and a simple
oxidant, such as hydrogen peroxide, should also work.
Amides and esters are valuable organic moieties and have
immense importance in organic and pharmaceutical chem-
istry. Traditionally, amides and esters are prepared from the
condensation of carboxylic acids with amines/alcohols, which
needs either coupling agents1 or conversion into more reac-
tive derivatives.2 In recent years, the direct oxidative addi-
tion of amines/alcohols to aromatic aldehydes for accessing
amides/esters has received considerable attention.3–9 Efforts are
being applied to identify a more efficient and practical method to
achieve this transformation, and, accordingly, various methods
have been reported.7 Nevertheless, many of these methods in-
volve toxic solvents, harsh oxidants, expensive reagents, difficult
to prepare transition metal catalysts etc.,10,11 thus, opening
the doors for the development of economic and eco-friendly
methods.
According to the best accepted mechanism for the direct
oxidative amidation of aldehydes with secondary amines, a
carbinolamine is initially formed as an intermediate, which is
subsequently oxidized to an amide with the help of an oxidant.
Generally the reaction is catalysed by metals, such as Cu,7a Rh,7b
Ru,7c Pd,7d Ni7c etc. Recently, utilizing tert-butyl hydroperoxide
(TBHP) as an oxidant,9 Wolf and co-workers have demonstrated
a metal free oxidative amidation of aromatic aldehydes. In this
work, active boron derivatives of dimethyl amines were reacted
with aromatic aldehydes to yield the corresponding amide but,
notably, cyclic amines reacted under these conditions without
any derivatisation.
Fig. 1
Hydrogen peroxide is a very attractive oxidant that is widely
used in laboratory scale and industrial synthesis. It is a
mild oxidant and is comparatively inexpensive. From a green
chemistry perspective, use of H2O2 has become more and more
promising with regard to the formation of water as the sole
byproduct. Surprisingly, there are no reports available of the
use of H2O2 on its own for oxidative amidation. Yutaka et al.
reported a combination of H2O2–urea and palladium catalyst12
for preparing secondary amides from aldehydes and primary
amines. But, unfortunately, this system was not applicable to
cyclic amines.
Cyclic amines are less sterically demanding in comparison to
acyclic secondary amines, which are flanked by bulkier groups.
Taking into consideration the aforementioned discussion, we
considered it worthwhile to investigate the reaction of cyclic
amines and aldehydes with H2O2 as an oxidant (Scheme 1).
Cyclic amides constitute a valuable class of amides, having
a range of biological activities, such as antimicrobial, insect
Carefully considering the reaction mechanism we noticed
that, during this transformation, the sp2 carbonyl carbon of the
aldehyde changes to sp3 in the carbinolamine, which is transitory,
Synthetic Chemistry Division, Defence R & D Establishment, Jhansi
Road, Gwalior, 474002, (M. P.). E-mail: sc_drde@rediffmail.com;
Fax: +91 751 2341148; Tel: +91 751 2390189
† Electronic supplementary information (ESI) available: General details
and characterisation data i.e. 1H NMR and mass spectrometry data for
all the compounds. See DOI: 10.1039/c1gc16041a
Scheme 1
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Table 1 The formation of amides/esters from aldehydes and cyclic amines/primary alcohols
Entry
1
Aldehyde
Amine/Alcohol
Amide/estera
Conversion (%)/Time (h)
Yield (%)b
86
96/2
2
90/6
83
3
4
98/1.5
95/1.5
90
88
5
6
99/1
90
87
97/1.5
7
8
9
96/2.5
96/2
83
88
90
98/2
10
99/1
91
11
12
99/1
99/1
89
93
13
14
15
99/1.5
98/3
92
89
88
97/2
16
17
98/1.5
97/2
90
89
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Table 1 (Contd.)
Entry
18
Aldehyde
Amine/Alcohol
Amide/estera
Conversion (%)/Time (h)
Yield (%)b
87
97/2.5
19
94/2
86
20c
21c
22
CH3OH
97/5
97/6
96/7.5
92/8
75
81
80
78
23
24c
25c
26
CH3OH
CH3OH
96/5
96/8
92/8
82
74
81
27
93/6.5
78
28
29
95/6.5
94/7
80
79
a All the products gave satisfactory spectral data. b Yield refers to isolated products. c Reaction temperature 55–60 ◦C
repellent, antihelmintic, insecticidal etc.13 They are also used
as intermediates in organic synthesis.14
(1.5 mmol) lead to the clean formation of amide along with
traces of benzoic acid within two hours. Other oxidants, like
oxone, pyridine N-oxide and peracids, such as m-CPBA, were
also attempted under different reaction conditions but these
failed to provide satisfactory results.
The protocol developed for oxidative amidation using H2O2
as an oxidant was then applied to other cyclic amines, such
as morpholine, pyrrolidine, homopiperidine etc. These cyclic
amines also responded in a similar way. A diversity of aldehydes
possessing electron donating, electron withdrawing and various
other functional groups were investigated. The results are sum-
marized in Table 1. Benzaldehydes having electron withdrawing
groups (entries 3, 4, 6, 8, 9, 12, 13) underwent amidation at a
For feasibility studies, the amidation of benzaldehyde with
piperidine was selected. 1 mmol each of amine, aldehyde, and
hydrogen peroxide were mixed together. 50% aqueous H2O2
solution was employed as an oxidant and to avoid further
dilution of the oxidant no additional ◦solvent was added. The
reaction mixture was heated at 70–75 C, and monitored after
30 min. Upon analysis by GC-MS we were happy to observe
the formation of phenyl-piperidin-1-yl-methanone, which was
the desired product, and the reaction was found to progress
satisfactorily with time. On further optimization, employment
of a slightly higher quantity of piperidine (1.3 mmol) and H2O2
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faster rate than those having electron donating groups (entries 2,
14). This may be due to the electronic and mesomeric factors that
increase the electron deficiency of the carbonyl group of aldehy-
des, thus making nucleophilic attack by amines more facile. Even
thiophene-2-carboxaldehyde, a heterocyclic aldehyde (entries
5, 10), which was earlier reported as a nonreactive substrate
with the H2O2–urea/palladium system,12 underwent neat and
fast conversion to give the corresponding amide in very good
yield.
Conclusions
In conclusion, aqueous H2O2, a green oxidant without any
additive/metallic catalyst or organic solvent, has been utilized
for the efficient amidation and esterification of benzaldehyde and
its derivatives. Cyclic amines and primary alcohols selectively
reacted with aldehydes under mild conditions to yield the cor-
responding amides and esters, respectively. An environmentally
benign and simple protocol, the clean reaction and easy isolation
of the final products render this newly developed reaction
practical.
When we switched to acyclic amines, like diethylamine,
dipropylamine, diisopropylamine etc., no appreciable amide
formation occurred (2–3%). This indicated that the protocol is
selective for cyclic amines. But, acyclic secondary amines having
a small N-alkyl group, such as N-methylpropylamine, reacted
with benzaldehyde to produce N-methyl-N-propylbenzamide
with 52% conversion; the other product was benzoic acid,
produced from a competing oxidation reaction of benzaldehyde.
To further study the influence of steric factors in this reaction we
investigated the reaction of aldehydes that were sterically more
crowded near the reaction site, such as o-bromobenzaldehyde
and 2,4,6-trimethylbenzaldehyde, and also amines, such as 2-
methylpiperidine. We assumed that crowding near the reac-
tion centre may retard the formation of the carbinolamine
intermediate or destabilize it. Indeed, this was found to be
the case and only 10% conversion was achieved in three
hours when o-bromobenzaldehyde was reacted with piperidine.
After 20 h, 80% conversion was seen. In the case of the
reaction of 2,4,6-trimethylbenzaldehyde with piperidine, in three
hours only 5% conversion was obtained, which could not be
progressed further, even after long hours of reaction. Similarly,
no appreciable product formation (<2%) occurred by reacting 2-
methylpiperidine with p-nitrobenzaldehyde. Substitution at the
meta position did not affect the outcome of the reaction, which
was indicated by the smooth formation of (3-methoxy-phenyl)-
piperidin-1-yl-methanone from 3-methoxybenzaldehyde and
piperidine. Additionally, we reasoned that if our presumption is
correct then primary alcohols with appropriate nucleophilicity
should also provide esters. Carboxylic esters are widespread in
nature and are widely used in the pharmaceutical industry,
materials science, organic and bioorganic synthesis etc.15 To
examine the possibility of H2O2 mediated oxidative esterification
of aldehydes, reaction of benzaldehyde with methanol was
attempted. The formation of methyl benzoate revealed that the
developed protocol can also be extended for the esterification
of aldehydes. A variety of esters were then prepared from the
reaction of various primary alcohols with different aldehydes
(Table 1, entries 20–29). However, esterification was found to
be comparatively slower than amidation. Longer reaction times
led to the degradation of H2O2, therefore a higher amount (3–5
mol equivalents) of H2O2 was required for completion of the
reaction. In addition, for low boiling alcohols, such as methanol
and ethanol, 2.5 mol equivalents of alcohol were required.
Similar to acyclic secondary amines, reaction with secondary
alcohols was very slow and incomplete (for iso-propanol 26%
conversion was obtained after 3 h). Tertiary alcohols did
not react due to steric reasons. Aromatic alcohols were also
found to be unreactive under these conditions, which was
presumably due to the lower nucleophilicity of aromatic hydroxy
groups.
Experimental
A typical experimental procedure for phenyl-piperidine-1-yl-
methanone: 6.5 mmol (642 ml) of piperidine was added to 5
mmol (508 ml) of benzaldehyde and mixed thoroughly. To this,
7.5 mmol of hydrogen peroxide (50% aqueous solution) was
added with gentle stirring and the reaction mixture was heated
at 70–75 ◦C, until the reaction was complete. The contents were
cooled and neutralized with 5% sodium bicarbonate solution.
A yellow oil was separated, which was extracted with ethyl
acetate. Solvent removal under vacuum yielded the crude amide,
which was further purified by column chromatography. Data for
1
phenyl-piperidin-1-yl-methanone (1): Yellow oil; H NMR (400
MHz, CDCl3): d 7.31–7.27 (m, 2H), 6.95–6.91 (m, 3H), 3.70 (br,
s, 2H), 3.34 (br, s, 2H), 1.67–1.51 (m, 6H); EIMS: m/z 189 [M+],
188, 160, 105, 77, 84, 51.
Acknowledgements
We thank Mr. Ajay Pratap for NMR analysis. We also thank
Dr R. Vijayaraghavan Director, DRDE for his keen interest and
encouragement. Dr Rekha Tank thanks to CSIR, New Delhi for
providing Research Associate Fellowship.
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