Direct oxidative amidation of aromatic aldehydes using aqueous hydrogen peroxide in continuous flow microreactor systems

Article abstract of DOI:10.1039/c2gc35078e

A practical and economical protocol has been developed for the direct oxidative amidation of aromatic aldehydes with secondary amines to synthesize amides in a single operation under mild conditions within 15-40 min. The utilization of aqueous hydrogen peroxide affords a clean synthetic route. No catalysts or promoting reagents are required.

Full text of DOI:10.1039/c2gc35078e

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Volume 14 | Number 5 | May 2012 | Pages 1229–1546
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Jensen et al.
Direct oxidative amidation of aromatic aldehydes using aqueous hydrogen
peroxide in continuous flow microreactor systems

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PAPER
Direct oxidative amidation of aromatic aldehydes using aqueous hydrogen
peroxide in continuous flow microreactor systems†
Xiaoying Liu and Klavs F. Jensen*
Received 16th January 2012, Accepted 13th March 2012
DOI: 10.1039/c2gc35078e
A practical and economical protocol has been developed for the direct oxidative amidation of aromatic
aldehydes with secondary amines to synthesize amides in a single operation under mild conditions within
15–40 min. The utilization of aqueous hydrogen peroxide affords a clean synthetic route. No catalysts or
promoting reagents are required.
The amide bond is an important chemical linkage in natural pro-
ducts, synthetic polymers, and pharmaceutical compounds.
According to a recent survey on reactions used in drug discovery,
amide formation accounts for 16% of all the reported reactions
and over 50% of all drug compounds contain at least one amide
functional group.1 Additionally, the American Chemical Society
Green Chemistry Institute Pharmaceutical Roundtable has
recently identified amide formation as one of the most utilized
syntheses.2
The synthetic methods for amides are generally based on the
reaction between carboxylic acids and amines without change in
the oxidation level. It can be achieved through the amidation of
activated carboxylic acid (such as acid chlorides and anhydrides)
assisted by an acid or base, requiring an extra step and producing
waste material, or alternatively, by use of coupling reagents such
as carbodiimides which are expensive. In practice, one of the
most popular methods to synthesize carboxylic acids is the oxi-
dation of aldehydes or alcohols. Therefore, direct utilization of
aldehydes/alcohols as the starting material affords a more econ-
omical synthetic route to amides.
Only a few examples of oxidative amidation of aldehydes
have been reported. To date, this type of transformation has been
achieved through a radical-mediated process,3 with N-hetero-
cyclic carbene (NHC) as a catalyst,4 by means of Cannizzaro
reactions with lanthanide reagents,5 or in the presence of an
oxidant catalyzed by KI6 or in most cases transition metal com-
plexes such as nickel,7 rhodium,8 and palladium.9 Recently, it
has been demonstrated that heterogeneous catalytic systems are
potentially possible alternatives for this chemistry.10 Catalyst-
free oxidative amidation has also been reported by using tert-
butyl hydroperoxide11 or oxone12 as an oxidant, which affords
an attractive approach from the view point of green chemistry.
As we were preparing this manuscript, Tank et al. reported the
amidation of aromatic aldehydes by cyclic amines using hydro-
gen peroxide as the oxidant.13 Recently, homogeneously14 or
heterogeneously15 catalyzed direct amidation of alcohols with
amines has also been developed.
Our effort in developing green oxidative amidation protocols
has been focusing on utilizing clean and inexpensive oxidants.
Aqueous hydrogen peroxide is a useful candidate because it is
cheap and atomically efficient and produces water as a sole
theoretical byproduct. In our studies, we use a continuous flow
microreactor system as a platform for reaction exploration and
investigation. The use of microreactors enables continuous oper-
ation and scanning of reaction parameters and therefore renders
fast optimization of reaction conditions. Furthermore, the ability
to control the back pressure makes possible the use of standard
solvents safely at elevated temperatures (e.g., above the boiling
point) and allows for a wide selection of solvents.
We present the direct oxidative amidation of aromatic alde-
hydes with amines using aqueous hydrogen peroxide (30 wt%)
as a cheap and clean oxidant without the use of any catalysts or
other reagents. This synthetic method incorporates aldehydes
and amines in one single operation under mild conditions while
avoiding any additional cost incurred by added bases or catalytic
materials, thus providing an economical and clean route for
amide synthesis.
The diagram of the experimental setup for the oxidative trans-
formation of aldehydes and amines to form amides is shown in
Fig. 1 (see ESI† for details). A silicon–Pyrex microreactor
(230 μL) with a spiral channel was used to mix the two streams
Department of Chemical Engineering, Massachusetts Institute of
Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
E-mail: kfjensen@mit.edu; Fax: (+1)617-258-8992
†Electronic supplementary information (ESI) available: Experimental
details, experimental setup and sample analysis. See DOI: 10.1039/
c2gc35078e
Fig. 1 Experimental setup for the direct oxidative amidation of alde-
hydes with back pressure control.
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of reactants and to carry out the reaction.16 A 6-way valve was
used to collect product samples at the outlet of the reactor for
chemical analysis with minimal disturbance to the flow. Multiple
micro-metering valves were employed to adjust the back pressure
applied by N2 from a high-pressure gas cylinder. Reaction para-
meters, including reaction temperature, concentrations of starting
materials, and residence time were varied in the optimization
process.
The substrate scope of the oxidative amidation reaction was
determined by employing various aldehydes and amines as the
starting materials. Functional groups on the phenyl ring play an
important role in effecting the electron density on the carbonyl
carbon, and therefore can greatly influence the reaction kinetics,
hence the optimal conditions. For each of the aldehyde sub-
strates, the reaction parameters, including temperature, concen-
trations, and reaction time, are optimized, taking advantage of
the ability of microreactor systems to rapidly vary operating con-
ditions and change chemical parameters. Moreover, as already
mentioned the back pressure in our system allows for reactions
to be safely performed above the boiling point of the solvent,
acetonitrile (boiling point 82 °C), in the optimization of yield
and selectivity.
As shown in Table 1, electron-rich, -neutral, and -poor aro-
matic aldehydes are all readily converted to amides in
Table 1 Substrate scope of aldehydes in direct oxidative amidation with morpholine using aqueous hydrogen peroxide as the oxidant
Entry
1
Aldehyde
T (°C)
Time (min)
40
X (equiv)
Yielda (%)
86
Sel.b (%)
92
80
5.0
2
3
90
90
40
40
4.0
88
79
93
93
10.0
4
5
90
90
30
40
6.0
6.0
81
83
92
93
6
7
8
90
20
20
20
4.0
4.0
4.0
83
93
91
91
110
110
83c
88
9d
90
90
20
20
4.0
5.0
92
92
93
92
10e
11
90
40
8.0
85
92
a GC yield unless otherwise indicated. b GC selectivity. c Isolated yield. Concentration of the aldehyde substrates: d 0.25 mol L−1 and e 0.20 mol L−1
.
1472 | Green Chem., 2012, 14, 1471–1474
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Table 2 Substrate scope of aminesa
Entry
1
Aldehyde
Amine
Amine (equiv.)
6.0
Yieldb (%)
86
Sel.c (%)
92
2
3
8.0
6.0
88
79
93
93
4
8.0
5.9
81
92
5d
6d
89
89
94
95
7e
7.7
83
88
a Reaction conditions: 0.50 mol L−1 aldehyde, X equiv. of amine, and 1.2 equiv. of H2O2 in CH3CN at 90 °C with a residence time of 20 min, unless
otherwise indicated. b GC yield. c GC selectivity. d ee > 99%. e 70 °C, 15 min.
20–40 min at the temperature ranging from 80 to 110 °C. The
yields are in the range of 79–92% with the corresponding car-
boxylic acid being the main side product. Allylic aldehydes,
e.g., cinnamaldehyde (yield 71%), do not exhibit as high yields
as aromatic aldehydes. Aliphatic aldehydes, e.g., butanal (yield
23%), lead to the formation of enamines as a predominant com-
peting product to amides. In addition, we have found that other
secondary cyclic amines (Table 2), such as piperidine and pyrro-
lidine, can produce the corresponding amides with yields that are
comparable with those for morpholine. It is important to note
that this reaction can be applied to synthesize amides derived
from amino acids – D- or L-proline tert-butyl ester reacts without
racemization (Table 2, entries 5 and 6). Acyclic secondary
amines, when methyl is one of the substituent groups on N, are
also suitable for this reaction (Table 2, entry 7). Diethylamine,
however, is not well compatible with our reaction system, most
probably due to steric hindrance with ethyl being larger than
methyl, affording 16% yield for the amide when reacting with
m-anisaldehyde. Additionally, primary amines, e.g., n-hexyl-
amine and aniline, generate imines as the prevalent product, as a
result of the readily occurring dehydration pathway.
It is interesting to note that the yields for these reactions are
closely comparable with those reported by Tank et al. in batch.13
The reaction time with our microreactors is in the range of
15–40 min, while that in batch ranges from 1 to 6 h. The reaction
temperature for our experiments (70–110 °C) is slightly higher
than that used in batch (70–75 °C). Another difference between
the two methodologies is that we have used higher excess of
amines (4–10 equiv.) than that in batch (1.3 equiv.). The excess
amines, however, can be readily separated from the reaction
mixture (see ESI† for details).
Scheme 1 Isotopic labelling experiments with benzaldehyde-18
O
(90 atom% isotopic enrichment) showing virtually no incorporation of
18O into the final amide product (99 atom% for 16O-amide).
transformation: no amide formation was observed when benzoic
acid was employed as the starting material, instead of benzal-
dehyde, and combined with morpholine under the same reaction
conditions. Benzyl alcohol does not show any reactivity either.
Another question would be whether H2O2 serves as the immedi-
ate oxidant, since it is one of the weakest oxidants of a wide
range of peroxides, and a catalyst is often required to activate
it.17 In the absence of aldehydes, the reaction of morpholine and
H2O2 does not generate any morpholine-N-oxide or structurally
analogous molecules that could otherwise serve as a direct
oxidant, supporting that H2O2 directly participates in the trans-
formation without any activation steps.
Isotopic labelling experiments were carried out to further
probe the mechanistic detail of the amidation reaction. We
employed 18O-labelled benzaldehyde as a starting material to
react with morpholine. As shown in Scheme 1, isotopic scram-
bling was observed after mixing 18O-benzaldehyde with non-
labelled aqueous (30 wt%) H2O2, resulting in 18O enrichment of
75% right before the reactants were delivered into the microreac-
tor. However, the amide formed was almost solely 16O-amide
(99 atom%), showing virtually no incorporation of 18O into this
final product. This is strong evidence for the loss of carbonyl
oxygen during the transformation.
Although carboxylic acid is generated in our reactions as the
main side product, it does not participate in the amidation
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provides a clean synthetic route with water being the sole stoi-
chiometric byproduct. Furthermore, no catalytic materials or pro-
moting reagents are required in this reaction system. In addition,
our method is well applicable to the acylation of chiral amino
acid derivatives without racemization. All these advantageous
features allow for simplified workup procedures as there are no
additional hazardous waste materials (except for small quantities
of side products, carboxylic acid) to handle. Mechanistically, our
synthetic strategy involves the addition of the oxidant across the
key iminium intermediate that is derived from hemiaminal
through hydroxyl elimination, which is conceptually different
from those based on the condensation of carboxylic acids with
amines or those starting with aldehydes/alcohols and amines
facilitated by transition-metal catalysts.
Scheme 2 Proposed reaction mechanism.
Based on the observations in the above experiments, we
propose the oxidative amidation transformation as involving the
following reactive intermediates: hemiaminal → iminium →
hydroperoxide (Scheme 2). The addition of amine across the car-
bonyl is a facile process in both solution18 and vapor phases10 as
also proposed by Wolf et al. when using tert-butyl hydroperox-
ide as the oxidant.11 The resultant hemiaminal intermediate then
loses hydroxyl, as supported by the 18O-isotopic labelling exper-
iments, to form the iminium ion. The added stability by means
of π conjugation with the phenyl ring can serve as a driving
force for this step. However, when α-carbonyl protons are
present, as discussed above for the reaction with butanal, dehy-
dration becomes more favorable, generating enamine as the pre-
dominant product. We then anticipate the direct addition of H2O2
across the CvN bond of the iminium to form the hydroperoxide,
in a similar fashion as that in the Baeyer–Villiger oxidation.
Finally, the elimination of H2O leads to the formation of the
amide product.
The authors thank the Novartis-MIT Center for Continuous
Manufacturing for support of this work. We also thank Professor
Timothy Jamison for helpful discussions and Dr Wei Shu for the
help with chiral HPLC.
Notes and references
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Eur. J. Org. Chem., 2008, 3619.
It is important to note that tert-butanol has also proved to be a
suitable solvent for the oxidative amidation reactions presented
here. For example, for the reaction of 4-fluorobenzaldehyde and
morpholine under the same reaction conditions, it gives a GC
yield of 81%, comparable to that observed with acetonitrile
(Table 1, entry 6). It affords a greener and more sustainable
alternative which is highly attractive for industrial applications
where solvents make a large contribution to the environmental
impact of the manufacturing processes.19 In addition, work is
currently underway toward developing a process that is stable
and adaptable for larger-scale applications.
7 C. L. Allen, S. Davulcu and J. M. J. Williams, Org. Lett., 2010, 12, 5096.
8 A. Tillack, I. Rudloff and M. Beller, Eur. J. Org. Chem., 2001, 523.
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Ed., 2010, 49, 394; (b) L. Zhou, C. G. Freyschlag, B. J. Xu, C. M. Friend
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12 J. Gao and G. W. Wang, J. Org. Chem., 2008, 73, 2955.
13 R. Tank, U. Pathak, M. Vimal, S. Bhattacharyya and L. K. Pandey, Green
Chem., 2011, 13, 3350.
14 (a) C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007, 317,
790; (b) L. U. Nordstrom, H. Vogt and R. Madsen, J. Am. Chem. Soc.,
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9977; (b) T. Ishida and M. Haruta, ChemSusChem, 2009, 2, 538.
16 R. L. Hartman, J. R. Naber, N. Zaborenko, S. L. Buchwald and K.
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G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks and A. D. Curzons,
Green Chem., 2011, 13, 854.
In summary, we have developed a practical and economical
protocol for the direct oxidative amidation of aromatic aldehydes
with secondary amines to synthesize amides in a single operation
under mild conditions within 40 min. The use of continuous
flow microreactor systems as an investigation platform allows for
precise control and rapid scanning of reaction parameters and
hence efficient optimization of reaction conditions. The utiliz-
ation of cheap aqueous hydrogen peroxide as the oxidant
1474 | Green Chem., 2012, 14, 1471–1474
This journal is © The Royal Society of Chemistry 2012