Synthesis of primary Amides via Copper-Catalyzed Aerobic Decarboxylative ammoxidation of Phenylacetic Acids and α-Hydroxyphenylacetic acids with Ammonia in water

Article abstract of DOI:10.1021/ol403586c

A Cu₂O-catalyzed aerobic oxidative decarboxylative ammoxidation to primary benzamides from phenylacetic acids and a-hydroxyphenylacetic acids is developed. A variety of primary benzamides could be prepared smoothly, in good to excellent yields, by means of a one-pot domino protocol combining decarboxylation, dioxygen activation, oxidative C-H bond functionalization, and amidation reactions.

Full text of DOI:10.1021/ol403586c

Letter
pubs.acs.org/OrgLett
Synthesis of Primary Amides via Copper-Catalyzed Aerobic
Decarboxylative Ammoxidation of Phenylacetic Acids and
α‑Hydroxyphenylacetic Acids with Ammonia in Water
Qiuling Song,* Qiang Feng, and Kai Yang
Institute of Next Generation Matter Transformation, College of Chemical Engineering at Huaqiao University, 668 Jimei Boulevard,
Xiamen, Fujian, 361021, P. R. China
S
* Supporting Information
ABSTRACT: A Cu2O-catalyzed aerobic oxidative decarboxylative ammoxidation to primary benzamides from phenylacetic acids
and α-hydroxyphenylacetic acids is developed. A variety of primary benzamides could be prepared smoothly, in good to excellent
yields, by means of a one-pot domino protocol combining decarboxylation, dioxygen activation, oxidative C−H bond
functionalization, and amidation reactions.
Scheme 1. Synthesis of Primary Amides from Carboxylic
Acids
romatic primary amides are regarded as an important class
Aof compounds in organic synthesis, pharmaceutical
chemistry, and chemical engineering.1−3 They are also present
in numerous biologically active molecules.4 In synthetic
chemistry, primary amides are very good functional groups
which can be easily transformed into nitriles, primary amines, and
heterocycles. For these reasons, numerous methodologies have
been developed for their synthesis. Some examples are the
ammonolysis of carboxylic acids,5,6 the rearrangement of
benzaldoximes,7 the palladium-catalyzed carbonylation of
organo halides with ammonia,8 the direct oxidation of benzyl
amines9 or benzyl alcohol10 to the corresponding benzamides,
and the hydration of the corresponding nitriles.11−13 Of these
methods, the ammonolysis of activated carboxylic acid species is
still the traditional method for synthesis of primary amides.5,6
However, this procedure requires preactivation of the free
carboxylic acid with stoichiometric activating reagents, and
corrosive byproducts are often generated during the reaction
(Scheme 1). Thus, the development of greener and more
efficient methods to prepare amides from readily available
carboxylic acids is still a big challenge for synthetic organic
chemistry.
Currently, transition-metal-catalyzed decarboxylative cou-
plings have attracted much attention due to readily accessible
starting materials, simple operation, and clean byproduct (CO2
as the only byproduct). Among the decarboxylative couplings
reactions, palladium-catalyzed methods are well studied and
provided novel protocols for C−C or C−heteroatom bond
formation.14−19 However, those palladium-mediated or cata-
lyzed methods suffer from some drawbacks: (a) palladium is
quite expensive; (b) air or moisture-sensitive, and very expensive,
bulky phosphines are always required for the success of the
reactions; (c) other additives, such as stoichiometric silver salts,
are frequently encountered in the reactions. In light of the recent
demands for environmentally benign and economically attractive
organic syntheses, much cheaper copper salts have many
advantages and remarkable progress has been made with
copper-catalyzed coupling reactions;20−22 yet copper-only
catalyzed decarboxylative coupling reactions21,23−25 are relatively
rare compared to well-developed palladium-catalyzed ones.
Molecular oxygen is an ideal terminal oxidant for oxygenation,
because of its abundance, negligible cost, and high atom
efficiency. To the best of our knowledge, there is no known
reaction that encompasses the decarboxylation of C(sp3) with
simultaneous formation of C(sp2)(CO)−N bonds via copper-
catalysis with O2 as the sole terminal oxidant. As part of our
ongoing research into the development of oxidative decarbox-
ylation reactions at C(sp3),26 we herein report a novel aerobic
decarboxylative ammoxidation of readily available phenylacetic
Received: December 10, 2013
© XXXX American Chemical Society
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acids and α-hydroxyphenylacetic acids to primary amides in
aqueous ammonia solution in ligand-, acid- or base-free patterns.
Our initial investigation commenced with phenylacetic acid
(1) in aqueous ammonia in the presence of Cu(OAc)2 at 130 °C
under oxygen atmosphere. To our delight, benzamide (2) was
obtained in 38% isolated yield (Table 1, entry 1). Catalyst
Scheme 2. Copper-Catalyzed Aerobic Oxidative
Decarboxylative Ammoxidation of Phenylacetic Acids to
a
Benzamides
a
Table 1. Optimization of the Reaction Conditions
b
temp
(°C)
yield
(%)
entry
catalyst
oxidant
solvent
1
Cu(OAc)2 (10 mol %) O2
Cu(OAc)2 (20 mol %) O2
Cu(TFA)2 (20 mol %) O2
Cu(OTf)2 (20 mol %) O2
130
130
130
130
130
130
130
130
130
130
130
130
130
100
120
130
130
130
130
130
130
11
38
trace
trace
32
26
47
83
47
0
2
3
4
5
CuCl2 (20 mol %)
CuBr (20 mol %)
CuSO4 (20 mol %)
Cu2O (20 mol %)
CuO (20 mol %)
Fe(acac)2 (20 mol %)
FeCl3 (20 mol %)
Cu2O (20 mol %)
Cu2O (20 mol %)
Cu2O (20 mol %)
Cu2O (20 mol %)
Cu2O (20 mol %)
Cu2O (20 mol %)
Cu2O(10 mol %)
Cu2O (20 mol %)
Cu2O (20 mol %)
O2
6
O2
7
O2
8
O2
9
O2
10
11
12
13
14
15
16
17
18
19
20
21
O2
O2
0
air
9
N2
0
O2
20
80
63
30
52
28
31
0
O2
O2
DMF
a
O2
DMSO
Reaction conditions: phenylacetic acid (0.5 mmol), Cu2O (20 mol
b
O2
%), ammonia in water (1.5 mL), O2. This reaction was carried out at
150 °C. This reaction was carried out at 95 °C. These reactions were
carried out at 140 °C. This reaction was carried out at 100 °C. This
reaction was carried out at 110 °C.
c
d
TBHP
DTBP
O2
e
f
a
Reaction conditions: phenyl acetic acid (0.5 mmol), catalyst,
ammonia in aqueous water (1.5 mL) in a sealed tube under
corresponding atmosphere. Isolated yield.
usually giving lower yields of the benzamides when compared to
meta- and para-substitution, probably as a result of steric
hindrance. It is noteworthy that most halo-substituted aryl
groups survived well, leading to halo-substituted aromatic
carboxamides which could be used for further transformations
(Scheme 2, 5−9). In addition, 1-naphthylacetic acid and 2-
naphthylacetic acid also reacted well to give the corresponding
naphthyl carboxamides in 71% and 80% yields (Scheme 2, 17 and
18). Nitro groups also survived under the standard conditions
(Scheme 2, 19), and heteroaromatic acetic acids were trans-
formed well into corresponding primary amides (Scheme 2, 20,
21, and 22).
Inspired by the above results, we applied the same conditions
to α-hydroxyphenylacetic acids. To our delight, when α-
hydroxyphenylacetic acid (24) was treated with aqueous
ammonia under standard conditions, benzamide was obtained
in 58% isolated yield (Scheme 3, entry 1). Without further
optimization, the standard conditions were applied to various α-
hydroxyphenylacetic acids to explore the tolerance of the
reaction, and the results are shown in Scheme 3. The reaction
worked well with diverse α-hydroxyphenylacetic acids to give the
corresponding benzamides in 45−72% isolated yields.
b
screening showed that Cu2O gave the best isolated yield of the
desired product (83%, Table 1, entry 8). Notably, CuO only gave
47% of desired product even though it was considered that Cu2O
should be oxidized into CuO under oxidative conditions. Further
investigation indicated that oxygen plays a crucial role in the
reaction (Table 1, entries 1, 12, 13, 19, and 20). This
transformation is sensitive to temperature: when the temperature
was dropped to 120 and 100 °C, the isolated yields dropped to
80% and 20%, respectively (Table 1, entries 14 and 15). Solvent
screening showed water to be the best solvent, and addition of
other solvents gave lower yields of the desired products (Table 1,
entries 16 and 17). When catalyst loading was dropped to 10 mol
%, only 52% of the desired product was afforded (Table 1, entry
18). Without copper catalyst, there is no reaction at all (Table 1,
entry 21), which demonstrates that copper is vital for the success
of the reaction.
A variety of substituted phenylacetic acids were subjected to
the optimized conditions to evaluate the scope of the
decarboxylative ammonoxidation reaction. As shown in Scheme
2, phenylacetic acids with both electron-rich and electron-
deficient substituents on the aromatic ring could be smoothly
converted into the desired products. The position of the
substituents on the aromatic rings had some effect on yields
(Scheme 2, 3−4, 5−7, 8−9, and 14−15), with ortho-substitution
In order to understand the reaction mechanisms, several
control experiments were performed. Since the reaction involves
oxygen, radical trapping experiment was conducted by employ-
ing 2,2,6,6-tetramethyl-1-piperidinyloxy (BHT) with phenyl-
acetic acid. The result showed that the reaction was totally
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Information , eqs S1 and S2), showing that benzyl alcohol and
benzoic acid are not intermediates for this reaction. However,
benzaldehyde and 2-oxo-2-phenylacetic acid gave 29% and 45%
of benzamide, respectively (Scheme 4, eq 2 and eq 3); when
phenylacetic acid was directed heated at 130 °C without
ammonia under standard conditions, 10% of benzaldehyde was
obtained (Supporting Information, eq S3). Interestingly, during
condition screening, we observed benzonitrile generated during
the reaction. Benzonitrile was formed after 2 h of heating under
the standard conditions with some starting material remaining,
and 4 h later, the benzamide peak appeared upon GC analysis
with the benzonitrile peak shrinking. After about 24 h, the
benzamide peak is the major component and the benzonitrile
peak almost completely disappeared. In order to verify whether
benzonitrile is the key intermediate or not, two control
experiments were employed: one is under the standard
conditions (Scheme 4, eq 4) and another one is treated only in
water (Scheme 4, eq 5). The former reaction gave 83% of the
desired product, but the latter one gave no product at all. The
experiments clearly showed that ammonolysis, not just
hydrolysis, occurred in the conversion of benzonitrile to
benzamide under the standard conditions and the two protons
of amides in product were from ammonia, not water. In order to
determine the oxygen source of the product, 18O label
experiment was also carried out under the standard conditions
(Scheme 4, eq 6) with 18O2. After purification, no 18O was
observed or detected in final product by LCMS, thus ruling out
that the oxygen in product was from molecular oxygen;
eventually, there is only one source that the oxygen can come
from: the water. Based on all of the above control experiments,
we gave a plausible reaction mechanism (Scheme 5): phenyl-
Scheme 3. Copper-Catalyzed Aerobic Oxidative
Decarboxylative Ammoxidation of α-Hydroxyphenylacetic
a
Acids to Benzamides
a
Reaction conditions: 1 (0.5 mmol), Cu2O (20 mol %), ammonia (1.5
b
mL), O2. Isolated yield.
Scheme 5. Plausible Mechanism of Benzamide Formation
from Phenylacetic Acid and Ammonia in H2O
inhibited by BHT (Scheme 4, eq 1), so the reaction should be a
radical pathway. The reactions of benzyl alcohol, benzaldehyde,
benzoic acid, and 2-oxo-2-phenylacetic acid with ammonia under
standard conditions were also explored. Both benzyl alcohol and
benzoic acid afforded no desired benzamide at all (Supporting
Scheme 4. Control Experiments
acetic acid was oxidized into 2-oxo-2-phenylacetic acid and then
decarboxylated to an organocopper species, which was in turn
converted into benzonitrile, and after ammonolysis and
hydrolysis of the benzonitrile, benzamide was obtained.
In conclusion, a Cu2O-catalyzed decarboxylative ammoxida-
tion of phenylacetic acids and α-hydroxyphenylacetic acids with
ammonia in water has been developed. These reactions
combined decarboxylation, dioxygen activation, oxidative C−H
bond functionalization, and amidation reactions in a one-pot
synthesis to generate primary aromatic amides in a practical and
easy way.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*Email: qsong@hqu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Science
Foundation of China (21202049), the Recruitment Program of
Global Experts (1000 Talents Plan), and Research Funds of
Huaqiao University.
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