Direct use of dioxygen as an oxygen source: Catalytic oxidative synthesis of amides

Article abstract of DOI:10.1039/c1cc14640h

The first transition-metal-catalyzed direct oxidative synthesis of amides by using dioxygen as an oxygen source has been developed under mild conditions, in which DBU was used as the key additive. The present methodology, which utilizes dioxygen as an oxidant and oxygen source and cheap copper salts as catalysts, opens up an interesting and attractive avenue for the synthesis of amide functionality.

Full text of DOI:10.1039/c1cc14640h

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COMMUNICATION
Direct use of dioxygen as an oxygen source: catalytic oxidative synthesis
of amidesw
Wei Wei,ab Xiao-Yu Hu,ab Xiao-Wei Yan,ab Qiang Zhang,ab Ming Chengab and Jian-Xin Ji*a
Received 28th July 2011, Accepted 7th November 2011
DOI: 10.1039/c1cc14640h
The first transition-metal-catalyzed direct oxidative synthesis of amides
by using dioxygen as an oxygen source has been developed under mild
conditions, in which DBU was used as the key additive. The present
methodology, which utilizes dioxygen as an oxidant and oxygen source
and cheap copper salts as catalysts, opens up an interesting and
attractive avenue for the synthesis of amide functionality.
key additive. To the best of our knowledge, this is the first
example of transition-metal-catalyzed direct oxidative synthesis
of amides from simple and readily available materials by
employing O2 as the oxidant and oxygen source.4
The synthesis of diverse oxygen-containing blocks is one of the
most fundamental and significant subjects in organic chemistry.
From the viewpoint of green and sustainable chemistry,
employing dioxygen as the oxidant and oxygen source for
functionalization of organic substrates represents one of the
most ideal methodologies for producing oxygenated com-
pounds. During the past several decades, considerable efforts
have been made in this area1 and some important oxygen-
containing compounds such as alcohols, aldehydes, ketones,
carboxylic acids, and epoxides have been successfully obtained
through the catalytic oxidation reaction using dioxygen. Never-
theless, there is still a great demand for the development of a
new and selective aerobic oxidation system to afford other
important and useful oxygenated building blocks.
ð1Þ
In general, traditional approaches for amide synthesis rely
heavily on the use of activated carboxylic acids and amines,
which often require stoichiometric amounts of coupling reagents
and produce toxic chemical waste.5 Recently, catalytic oxidative
methods have become a powerful tool for the construction of
amide complexes, in which oxygen atoms of amides generally
originate from oxone/H2O26 or oxygen-containing carbonyl pre-
cursors including aldehydes7 and alcohols.8 Nevertheless, such
well developed oxidative reactions usually require stoichiometric
oxidants such as TBHP7a,b and oxone,6,7c expensive or relatively
complex transition metal catalysts such as Ru,8a–c Rh,7d,8d and
Mn6 complexes. The present methodology, which utilizes dioxygen
as an oxidant and oxygen source and cheap copper salts as
catalysts, opens up a new and attractive window for the synthesis
of amide functionality.
As an extremely valuable oxygen-containing functional
group, the amide functionality strongly attracts synthetic
pursuit of chemists in both academic and industrial commu-
nities, since it is one of the most vital structural motifs in life
and materials sciences.2 The direct incorporation of an oxygen
atom from dioxygen into organic substrates for the formation
of amide bonds has been observed in some biological oxyge-
nase systems.3 For example, cytochrome P450 catalyzed
oxidative biotransformation of amidoximes and nitriles to the
corresponding amides in liver microsomes.3b,c Although biomi-
metic studies of such enzymes catalyzed oxidative amidation
reactions using dioxygen have been investigated, it is still challen-
ging to develop non-biomimetic aerobic oxidation systems
employing simple metal salts as catalysts to conveniently access
amides. Herein, we present a novel copper-catalyzed direct
oxidative synthesis of amides from alkynes, amines, and dioxygen
under mild conditions (eqn (1)), in which DBU was used as the
Initially, under an oxygen atmosphere, the reaction of
phenylacetylene 1a with piperidine 2a was performed to
examine the catalytic activity of various transition metal
complexes including Ru, Rh, Pd, Ti, Au, Ag, Cu, Fe, Ni,
and Zr salts. As shown in Table 1, among those metal catalysts
examined (entries 1–3), copper salts especially CuBr was found
to be able to catalyze the formation of amide 3aa, albeit in low
yield (entry 3). Preliminary exploration using CuBr as catalyst
led to a discovery that the base was the critical additive for
improving this amidation reaction. Among various bases
examined, DBU turned out to be the best choice, while others
such as Cs2CO3, Na2CO3, DBN, Et3N, iPr2NEt, and pyridine
were less effective (entries 4–7). After an extensive screening of
the reaction parameters (see Table 1 and ESIw), the best yield
of 3aa (68%) was obtained by employing phenylacetylene
(2.5 mmol), piperidine (0.5 mmol), CuBr (5 mol%), and
DBU (0.6 mmol) in THF at 55 1C (entry 7). The high loading
of alkynes might be caused by the side reaction of the
dimerization of alkynes (Glaser reaction), which easily occurred
with copper catalyzed reactions of alkynes with amines in the
a Chengdu Institute of Biology, Chinese Academy of Sciences,
Chengdu 610041, China. E-mail: jijx@cib.ac.cn
b Graduate University of the Chinese Academy of Sciences,
Beijing 100049, China
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c1cc14640h
c
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Chem. Commun., 2012, 48, 305–307 305

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Table 1 Oxidative amide synthesis under various conditionsa
alkynes such as 3-ethynylthiophene and 3-ethynylpyridine were
also compatible with this reaction, providing the corresponding
products in 61% and 60% yields, respectively (3ia and 3ja).
1-Ethynylnaphthalene could also be used in the reaction to give
the expected product 3ka in 64% yield. Nevertheless, when
aliphatic alkynes such as 1-hexyne and 4-phenyl-1-butyne were
used as the substrates, the corresponding products were obtained
in relatively low yields (3la and 3ma).
Yieldb
(%)
Entry Catalyst
1
RuCl3, or RhCl3, or Pd(OAc)2, or AuBr3, or AgOTf, 0c
In order to obtain clear mechanistic insight into the function
of molecular oxygen, labeling experiments using 18O2 and
H218O were conducted in the reaction of phenylacetylene 1a
with n-butylamine 2f, respectively (eqn (2)), and the results
showed that the oxygen atom of the amide originated from
molecular oxygen (HRMS, see ESIw).
or NiCl2, or Ti(OiPr)4, or (C5H5)2ZrCl2, or FeBr3
CuI, or CuCl, or CuCl2, or CuBr2, or Cu(OTf)2
CuBr
2
3
4
5
6
7
8
9
10
Trace
4
i
CuBr/Na2CO3, or Et3N, or Pr2NEt, or pyridine
o5
21
55
68
35
0
CuBr/Cs2CO3
CuBr/DBN
CuBr/DBU
CuBr/DBU, air
CuBr/DBU, N2
–/DBU
0
a
Reaction conditions: 1a (2.5 mmol), 2a (0.5 mmol), catalyst
(5 mol%), base (0.6 mmol except entries 1–3), THF (1.0 mL), O2
b
(balloon). Isolated yields based on 2a. The same results were
c
obtained in the presence of DBU (0.6 mmol).
presence of a base and dioxygen.9 This amidation reaction could
also proceed smoothly under the air atmosphere (entry 8). No
conversion was observed in the absence of copper catalyst or O2
(entries 9 and 10).
ð2Þ
Oxirene and ketene were proposed as the key intermediates in
the oxidative amidation of alkynes using oxone by Che, and the
corresponding mechanism was proved by the conversion of
phenylacetylene to phenylacetic acid under aqueous NaHCO3
conditions (eqn (3)).6 However, in our standard reaction conditions,
when amine was replaced with aqueous NaHCO3, no conversion of
phenylacetylene to phenylacetic acid was observed (eqn (3)). So we
considered that the oxirene and ketene intermediates might not be
involved in this oxidation process.
Under the optimized conditions, the scope of this reaction was
tested with various combinations of alkynes and amines
(Table 2). In general, when 1a was employed, both primary
and secondary amines (including cyclic and acyclic amines)
afforded the corresponding amides 3aa–3ah in moderate to good
yields. With respect to alkynes, both electron-rich and electron-
deficient aromatic alkynes in our cases could be transformed into
the desired products (3ba–3ha). In addition, heteroaromatic
Table 2 Results for the reaction of the oxidative amidation of
alkynesa,b
ð3Þ
The exact mechanism of the direct oxidative amidation of
alkynes using dioxygen is unclear at the present stage. However,
related experimental phenomena and previous reports10–14 provide
some helpful information for our tentative understanding of this
process.
Firstly, it is known that phenylethynyl-copper(I) species as a
precipitate could be obtained from the reaction of phenyl-
acetylene with copper salts in the presence of a base.10 In the
present reaction system of phenylacetylene 1a and piperidine
2a, a yellow insoluble precipitate of the phenylethynyl-
copper(I) was formed in the absence of DBU,11 which might
be explained by the weak base effect of 2a. After DBU was
added to the above reaction mixture, this precipitate of the
phenylethynyl–copper(I) completely dissolved and the corres-
ponding product 3aa could be detected by TLC (Thin-layer
Chromatography). Based on these observations and previous
studies about using DBU as ligand in other copper catalyzed
reactions,12 we assumed that in our reaction system, DBU might
act not only as an organic strong base to promote the generation of
a
Reaction conditions: 1 (2.5 mmol), 2 (0.5 mmol), CuBr (5 mol%),
b
DBU (0.6 mmol), THF (1.0 mL), 4–24 h, O2 (balloon). Isolated
c
yields based on 2. DBN (0.6 mmol). Neat conditions, 24 h.
d
c
306 Chem. Commun., 2012, 48, 305–307
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copper acetylides, but also as a ligand to chelate with copper(I)
acetylide and enhance the solubility and reactivity of copper species.
accomplished in a single operation. The present methodology
opens up an interesting and attractive avenue for the synthesis of
amide functionality due to the following features: easily available
materials, cheap catalyst, and environmentally benign oxygen
source. Studies of the detailed mechanism of this process and its
application are ongoing.
We thank the Natural Science Foundation of China
(20802072) for financial support and Professor Albert S. C. Chan
for helpful discussions and suggestions.
ð4Þ
Notes and references
Subsequently, when the reaction of 1a with 2a was conducted
in the absence of dioxygen, enamine intermediate 10aa was
detected by NMR (see ESIw) (eqn (4)). Nevertheless, enamine
intermediate 10aa could not be detected in the presence of
dioxygen (eqn (4)). According to the general process of the
anti-Markovnikov hydroamination of alkyne,9d,13 we envisioned
that a-aminovinylcopper(I) complex 5aa, the hydroamination
product of copper acetylide 4aa, might be involved in the present
reaction system. In the absence of dioxygen, 5aa underwent
protonation to afford enamine intermediate 10aa, which was
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1
proved by H NMR. On the basis of the growing amount of
information about copper–dioxygen reactivity,14,15 we speculated
that 5aa might react more readily with dioxygen to generate the
corresponding copper–oxygen complex under an oxygen atmo-
sphere, which would lead to the formation of the C–O bond in
subsequent reactions.14d
Based on the above information and previous studies,10–16 we
propose a postulated reaction pathway shown in Scheme 1. The
LCu(I)-acetylide species 4 (L = DBU) was formed by the
reaction of the Cu(I) species with alkyne in the presence of
DBU and amine. Then, the reaction of the acetylide species with
amine would lead to the formation of the key intermediate
a-aminovinyl–Cu(I) complex 5. Subsequently, complex 5 was quickly
oxygenated by dioxygen to form more active m-peroxo dicopper(II)
complex 6,14 which underwent the O–O bond cleavage,15 single
electron transfer,16 protonation, followed by reductive elimination of
copper species to deliver the corresponding a-aminoenol complex 11
and Cu(I) species. Finally, the desired amide 3 was generated by the
isomerization of 11.
In conclusion, we have developed the first transition-metal-
catalyzed direct oxidative synthesis of amides by employing O2
as the oxidant and oxygen source. In this process, anti-
Markovnikov hydroamination of alkyne and subsequent oxidation
by copper activated dioxygen into the resulting amide could be
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Scheme 1 Postulated reaction pathway.
c
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Chem. Commun., 2012, 48, 305–307 307