Direct amidation of carboxylic acids with tertiary amines: Amide formation over copper catalysts through C-N bond cleavage

Article abstract of DOI:10.1002/ejoc.201402332

A copper-catalyzed system for the amidation of carboxylic acids with tert-amines through C-N bond cleavage was developed. This protocol is practical and represents a simple way to produce functionalized amides from basic starting materials in moderate to good yields. A plausible mechanism is proposed for the reaction. Copyright

Full text of DOI:10.1002/ejoc.201402332

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402332
Direct Amidation of Carboxylic Acids with Tertiary Amines: Amide Formation
over Copper Catalysts through C–N Bond Cleavage
Biquan Xiong,[a] Longzhi Zhu,[a] Xiaofeng Feng,[a] Jian Lei,[a] Tieqiao Chen,[a]
Yongbo Zhou,*[a] Li-Biao Han,[a] Chak-Tong Au,[a,b] and Shuang-Feng Yin*[a]
Keywords: Synthetic methods / Cleavage reactions / Amidation / Carboxylic acids / Amines / Copper
A copper-catalyzed system for the amidation of carboxylic
acids with tert-amines through C–N bond cleavage was de-
veloped. This protocol is practical and represents a simple
way to produce functionalized amides from basic starting
materials in moderate to good yields. A plausible mechanism
is proposed for the reaction.
found in natural products and are easily available, it is en-
visaged that the use of tertiary amines as substrates is an
attractive alternative for the formation of amides.[4,5]
Introduction
Amides are important compounds for the synthesis of
pharmaceuticals and bioactive molecules.[1] Owing to their
broad applications, a variety of methods have been devel-
oped for their production.[2,3] Makitra et al. first reported
the acylation of amines (N–H contained) for the prepara-
tion of amides in 1975 (Scheme 1, path A).[2a] Later in 1979,
Grieco et al. disclosed the direct conversion of carboxylic
acids into amides by using primary or secondary amines as
starting materials (Scheme 1, path b).[2b] In 2010, Troisi
et al. published the one-pot synthesis of amides over a
palladium catalyst through the carbonylation of alkyl or
benzyl halides with amines (Scheme 1, path c).[2c] Later,
Chen et al.[2d] and Rieke and Kim[2e] demonstrated the
preparation of amides by using substituted alkynyl brom-
ides and organozinc reagents as starting materials
(Scheme 1, paths d and e). Recently, Xie et al. reported the
direct generation of amides through the activation of alkane
C–H bonds with CO and primary or secondary amines
(Scheme 1, path f).[2f] Kumar,[2g] Li,[2h] and Priyadarshini[2i]
further disclosed the oxidative coupling of carboxylic acids
with formamides for the synthesis of amides over copper
catalysts.[2j,2k] All these methods generally employ primary
and secondary amines or formamides as the nitrogen
source.[3] In view of the fact that tertiary amines are widely
Scheme 1. General methods for the synthesis of amides.
In 2013, Zhang et al.[5a] first reported the amidation of
benzoylformic acids with tertiary amines through C–N
bond cleavage over a silver catalyst. They reported that
both oxidant and catalyst were used in large amounts, and
the amidation of α-keto acids was low in conversion as well
as in product selectivity. It is apparent that these shortcom-
ings limit the application of the method.
Herein, we report the copper-catalyzed amidation of ac-
ids with tertiary amines through C–N bond cleavage. The
system can accommodate a wide range of substituted acids
and gives the desired amides in moderate to good yields.
To the best of our knowledge, such a convenient and facile
method for the synthesis of amides from acids and tertiary
amines has not been previously disclosed.
[a] State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering, Hunan
University,
Changsha 410082, P. R. China
E-mail: zhouyb@hnu.edu.cn
sf_yin@hnu.edu.cn
http://cc.hnu.cn/index.php?option=com_content&task=view&
id=374&Itemid=227
Results and Discussion
[b] Department of Chemistry, Hong Kong Baptist University,
Kowloon Tong, Hong Kong, China
We first investigated the reaction of phenylacetic acid
(1a) and triethylamine (2a) by using CuI as the catalyst, and
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402332.
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Y. Zhou, S.-F. Yin et al.
SHORT COMMUNICATION
desired amidation product 3a was generated in 55% yield
As shown in Table 2, this amidation reaction was applied
(Table 1, entry 1). Then, we screened a number of catalysts to a variety of substituted acids, and the yields of the corre-
[i.e., CuBr, CuCl, Cu2O, Cu(OAc)2, CuO, Cu powder, sponding amides varied from moderate to good under the
NiCl2·6H2O, AgBF4, Ag2CO3] for the amidation reaction mild conditions. Upon treating 2-(naphthalen-6-yl)acetic
(Table 1, entries 1–10), and it was found that CuI was the acid (1b) and 3-phenylpropanoic acid (1c) with triethyl-
best catalyst for the reaction. Given that both the selectivity amine (2a), corresponding products 3b and 3c were ob-
and conversion were unsatisfactory, we embarked to opti- tained efficiently in 95 and 77% yield, respectively. Further-
mize the reaction conditions. As shown in Table 1, increas- more, upon using para-substituted 2-phenylacetic acids 1d–
ing the temperature within the 40–60 °C range was benefi- f, desired amides 3d–f were isolated in 74–94% yield. In
cial, but a further increase from 60 to 100 °C resulted in a the case of 2-(1H-indol-3-yl)acetic acid (1g), there was no
decrease in the product yield (Table 1, entries 11–13). With formation of the expected amidation product. Interestingly,
the reaction optimized at 60 °C, we investigated the effect with a change in the solvent from DMF to toluene, amid-
of additives such as Cs2CO3, K3PO4, Na2CO3, K2CO3, and ation product 3g was obtained in 79% yield. In addition,
NaHCO3. In the presence of additives, the reaction pro- para-substituted cinnamic acids 1h–j reacted efficiently with
ceeded efficiently, and the desired product was obtained in 2a under the adopted optimized conditions to afford the
yield at or above 73% (Table 1, entries 14–18). It is found products in 62–81% yield. Notably, if benzoic acids 1k–l
that K2CO3 and Na2CO3 were effective additives that gave were used as substrates, the yields of corresponding prod-
the product in 99% yield. We hence adopted Na2CO3 as an ucts 3k–l were in the 46–69% range. For most cases, elec-
additive. As for the concentration of the catalyst, if the tron-donating groups and electron-withdrawing group on
amount of CuI was reduced from 10 to 5 mol-%, the prod- the acids did not have a significant effect on the yield of the
uct yield remained at 99%, but a further decrease to 1 mol- products (Table 1, see 3d–f, j–l). Moreover, the amidation
% caused a decline in the product yield to 45% (Table 1, of picolinic acid (1m) and (2E,4E)-hexa-2,4-dienoic acid
entries 1, 19, and 20). Therefore, the optimal reaction con- (1n) with 2a gave products 3m and 3n in moderate yields.
ditions are as follows: acid (1.0 mmol), amine (2.0 mmol),
Phenylacetic acids with α-substituted functional groups
CCl4 (3.0 mmol), Na2CO3 (2.0 equiv.), and CuI (5 mol-%) were also tested in the reaction, including 2,2-diphenyl-
in DMF (3 mL) at 60 °C under an air atmosphere.
acetic acid (1o), 2-bromo-2-phenylacetic acid (1p), and 2-
hydroxy-2-phenylacetic acid (1q). The reaction of 2,2-di-
phenylacetic acid with 2a produced the expected product of
N,N-diethyl-2,2-diphenylacetamide (3o) in 91% yield, but
the use of 2-bromo-2-phenylacetic acid (1p) and 2-hydroxy-
2-phenylacetic acid (1q) did not yield the corresponding
amidation product under the reaction conditions, which
may be ascribed to the lower stability of α-hydroxy-substi-
tuted phenylacetic acids. In addition, an amino acid [e.g., l-
proline (1r)] was examined in the reaction, but the expected
product was not detected during the reaction. 2-(Dimeth-
ylamino)-N,N-diethylacetamide (3s) was only produced in
trace amount through the reaction of 2-(dimethylamino)-
acetic acid (1s) with 2a. However, upon applying 3-(dimeth-
ylamino)propanoic acid (1t) in this reaction, there was no
product generated after the reaction. Thus, it is deduced
that such compounds (including amino acids) containing
N,N-dialkyl-substituted groups possibly decompose or co-
ordinate with the cooper salts under the reaction condi-
tions.
As depicted in Table 3, we investigated the reactions of
phenylacetic acid (1a) with amines 2 under the optimized
conditions. It is clear that both tributylamine and trioctyl-
amine reacted with 1a efficiently to give products 4a and 4b
in 61 and 83% yield, respectively. Nonetheless, upon using
secondary amines such as dipropylamine and N-ethylphen-
ylamine, products 4c and 4d were obtained in only 28–43%
yield. It is clear that tertiary amines show better reactivity
than secondary amines in the present system. It is deduced
that the secondary amines coordinate with the copper salts
more easily than tertiary amines, which leads to low yields
of these types of compounds. Moreover, the reaction of N-
ethyl-N-isopropylpropan-2-amine with phenylacetic acid
Table 1. Catalyst and additive screening and optimization of the
temperature and catalyst concentration.[a]
Entry Catalyst
Temp. [°C] Base
Yield[b] [%]
1
2
3
4
5
6
7
8
CuI
60
60
60
60
60
60
60
60
60
60
40
80
100
60
60
60
60
60
60
60
none
none
none
none
none
none
none
none
none
none
none
none
55
47
45
52
48
13
5
CuBr
CuCl
Cu2O
Cu(OAc)2
CuO
Cu powder
NiCl2·H2O
AgBF4
Ag2CO3
CuI
CuI
CuI
CuI
CuI
2
3
9
10
11
12
13
14
15
16
17
18
19
20
11
38
43
41
94
73
99
99
78
45
99
none
Cs2CO3
K3PO4
Na2CO3
K2CO3
NaHCO3
Na2CO3
Na2CO3
CuI
CuI
CuI
CuI[c]
CuI[d]
[a] Reaction conditions: phenylacetic acid (1.0 mmol), Et3N
(2.0 mmol), CCl4 (3.0 mmol), catalyst (0.1 mmol, 10 mol-%), addi-
tive (2.0 equiv.), DMF (3 mL), in air, 60 °C, 16 h. [b] Yield was de-
termined by GC analysis by using dodecane as an internal stan-
dard. [c] CuI (0.01 mmol, 1 mol-%) was used. [d] CuI (0.05 mmol,
5 mol-%) was used.
2
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Direct Amidation of Carboxylic Acids with Tertiary Amines
Table 2. Scope of the acids.[a]
[a] Reaction conditions: acid 1a–o (1.0 mmol), Et3N (2a, 2.0 mmol), CCl4 (3.0 mmol), CuI (0.05 mmol, 5 mol-%), Na2CO3 (2.0 mmol,
2.0 equiv.), DMF (3 mL), in air, 60 °C, 16 h. [b] Yields of the isolated products are given. [c] Toluene (3 mL). [d] DMSO (3 mL). [e] n.d.:
not detected.
Table 3. Scope of the amines.[a]
(1a) gave products N,N-diisopropyl-2-phenylacetamide (4e,
61% selectivity) and N-ethyl-N-isopropyl-2-phenylacet-
amide (4eЈ, 39% selectivity) in 56 and 36% yield, respec-
tively. In contrast, there was no formation of the expected
amidation products upon using N,N-dimethylbenzenamine,
N,N-dimethyl(phenyl)methanamine, and tribenzylamine as
the substrates (see 4f–h). It is plausible that as a result of
their low reactivity, they do not undergo oxidation by CCl4
under the adopted reaction conditions.
Under the optimized reaction conditions, we performed
the reaction of phenylacetic acid with triethylamine under
a N2 atmosphere, and it was found that desired amidation
product 3a was generated in 98% yield by using CCl4
(3.0 equiv.) as the oxidant (Scheme 2). Thus, it is deduced
that CCl4 plays a key role in the reaction as an oxidant.
Scheme 2. The control reaction performed under a N2 atmosphere.
On the basis of the presented results, a mechanism is pro-
posed for the amidation reaction (Scheme 3). Tertiary
amine A first combines with CCl4 to give quaternary
ammonium salt B. In the presence of the selected base, in-
[a] Reaction conditions: phenylacetic acid (1a, 1.0 mmol), amine
2a–h (2.0 mmol), CCl4 (3.0 mmol), CuI (0.05 mmol, 5 mol-%),
Na2CO3 (2.0 mmol, 2.0 equiv.), DMF (3 mL), in air, 60 °C, 16 h.
[b] Yields of the isolated products are given. [c] n.d.: not detected.
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Y. Zhou, S.-F. Yin et al.
SHORT COMMUNICATION
termediate B decomposes to generate CHCl3 and intermedi-
ate imine C. Subsequently, C undergoes oxidative C–N
bond cleavage to give copper salt intermediate D with the
aid of the Cu salt, H2O, and CCl4. Finally, D combines
with an acid molecule to produce corresponding amide E
by regenerating the Cu salt as a catalytically active species.
Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China (NSFC) (grant numbers U1162109, 21273066,
21273067), the Program for New Century Excellent Talents in Uni-
versities (grant number NCET-10-0371), the Fundamental Re-
search Funds for Central Universities (Hunan University), and the
Canon Foundation. C. T. A. thanks Hunan University (HNU) for
an adjunct professorship. The authors thank the reviewers for their
useful suggestions on the mechanism for the reaction.
Conclusions
In summary, we successfully synthesized a variety of
functional amides through the direct amidation of acids
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Scheme 3. Plausible reaction mechanism.
with tertiary amines over a copper catalyst by C–N bond
cleavage under mild reaction condition. Unlike the known
strategies for amide preparation, we used cheap copper salts
as catalysts and tertiary amines as the nitrogen source. Fur-
ther mechanistic studies on this kind of amidation reaction
are being conducted in our laboratory.
Experimental Section
1H NMR (400 MHz), 13C NMR (100 MHz), and 31P NMR
(162 MHz) spectra were recorded with a 400 MHz spectrometer in
CDCl3. 1H NMR chemical shifts are reported relative to tetrameth-
ylsilane as an internal standard. 13C NMR chemical shifts are re-
ported relative to CDCl3 as an internal standard. The electron ion-
ization method was used as the ionization method for the HRMS
measurements, and the mass analyzer type was double focusing.
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Typical Procedure for the Preparation of Amides: The amine
(2.0 mmol) was added in air to a mixture of the acid (1.0 mmol),
CCl4 (3.0 mmol), Na2CO3 (2.0 mmol), and CuI (5 mol-%) in DMF
(3 mL), and the resulting mixture was stirred at 60 °C for 16 h.
Upon completion of the reaction, the mixture was concentrated
under vacuum, and EtOAc (20 mL) was added to the crude mix-
ture. Then, the mixture was washed with saturated aqueous NH4Cl
(2ϫ 5 mL) and dried with Na2SO4. The solvent was removed under
reduced pressure to give the crude product; pure product was ob-
tained by passing the crude product through a short silica gel col-
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Supporting Information (see footnote on the first page of this arti-
cle): Optimization protocols, analytical data, and copies of the
1H NMR, 13C NMR, and 31P NMR spectra.
Received: March 31, 2014
Published Online: ᭿
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Direct Amidation of Carboxylic Acids with Tertiary Amines
Amides
B. Xiong, L. Zhu, X. Feng, J. Lei,
T. Chen, Y. Zhou,* L.-B. Han, C.-T. Au,
S.-F. Yin* .......................................... 1–5
Direct Amidation of Carboxylic Acids with
Tertiary Amines: Amide Formation over
Copper Catalysts through C–N Bond
Cleavage
A copper-catalyzed system for the amid-
ation of carboxylic acids with tert-amines
through C–N bond cleavage is developed.
The protocol can accommodate a wide
range of substituted acids and gives the de-
sired amides in moderate to good yields. It
thus represents a simple and practical way
to produce functionalized amides from
basic starting materials.
Keywords: Synthetic methods / Cleavage re-
actions / Amidation / Carboxylic acids /
Amines / Copper
Eur. J. Org. Chem. 0000, 0–0
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