Copper-catalyzed amide bond formation from formamides and carboxylic acids

Article abstract of DOI:10.1016/j.cclet.2014.09.007

A highly efficient copper-catalyzed approach to form amide bonds from formamides and carboxylic acids was developed. This protocol shows broad substrate scopes and high yields in the presence of 1 mol% catalyst and 4.0 equiv. formamides.

Full text of DOI:10.1016/j.cclet.2014.09.007

G Model
CCLET 3088 1–4
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
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1
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Original article
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4
Copper-catalyzed amide bond formation from formamides and
carboxylic acids
a
a
Q1 Hong-Qiang Liu a, Jun Liu a, Yang-Hui Zhang a,b, , Chang-Dong Shao , Jing-Xun Yu
*
5
6
7
a Department of Chemistry, Tongji University, Shanghai 200092, China
b Key Laboratory of Yangtze River Water Environment, Ministry of Education, Tongji University, Shanghai 200092, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A highly efficient copper-catalyzed approach to form amide bonds from formamides and carboxylic acids
was developed. This protocol shows broad substrate scopes and high yields in the presence of 1 mol%
catalyst and 4.0 equiv. formamides.
Received 15 May 2014
Received in revised form 30 June 2014
Accepted 14 July 2014
Available online xxx
ß 2014 Yang-Hui Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
Amides
Formamides
Carboxylic acids
Copper
Catalysis
8
9
1. Introduction
strategy to circumvent the problems of the current amide bond 30
formation reactions is to use carboxylic acids as starting materials 31
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As one of the most common chemical linkages, the amide bond
is ubiquitous in a broad range of organic molecules. By linking
amino acids to form proteins, it represents the main chemical
bonds in biological system and plays a crucial role in the
sustenance of life [1]. Moreover, the amide bond is widely present
in drug molecules, agrochemicals, materials, and other natural
products [2]. Although a vast array of methods is available for the
formation of amide bonds, the most common one involves the
coupling reaction of activated carboxylic acids with amines [3]. For
this method, carboxylic acids should be preactivated by transform-
ing the hydroxyl groups of the acids into good leaving groups.
Unfortunately, the activation of carboxylic acids requires the use of
a stoichiometric amount of coupling reagents, and the reactions
produce large quantities of potentially hazardous chemical wastes
[4]. Due to the great drawbacks of the current methods and the
importance of amide bonds, amide bond formation is still the
subject of extensive studies and has been voted as the most
important synthetic transformation to be improved by the
American Chemical Society’s (ACS) Green Chemistry Institute
(GCI) Pharmaceutical Roundtable (PR) in 2005 [5]. One obvious
directly (Fig. 1). Although this strategy is expected to be very Q332
challenging, it has still attracted more and more attention due to its 33
great advantages and should be extensively investigated [2d,6].
34
While N,N-dimethylformamide (DMF) is primarily used as a 35
polar solvent in chemical reactions, it is a multipurpose reagent 36
and plays various roles in organic synthesis [7]. As a formamide 37
containing an aldehyde and amino group, DMF can serve as a 38
precursor to generate a wide range of intermediates in organic 39
reactions, including –CONMe2, CHO, –NMe2, –CO, O, –Me, etc. 40
[8]. Therefore, reactions involving DMF as the reaction precursor 41
has gained considerable interest recently, and its various 42
reactivities have been extensively exploited to develop a wide 43
range of novel organic reactions, especially those enabled by 44
transition metals [7,8].
45
Herein, we report a copper-catalyzed amide bond formation 46
reaction utilizing carboxylic acids and formamides as the amino 47
source [9]. It should be mentioned that several amidation reactions 48
were reported just when we almost finished this work. The Reddy 49
group disclosed the coupling reaction of carboxylic acids and 50
formamides using Cu(ClO4)2Á6H2O (10 mol%) as catalyst, tert-butyl 51
hydroperoxide (TBHP) (1.5 equiv.) as oxidant and DMF as the 52
solvent and source of the amine [10]. Subsequently, the Song and Li 53
group reported similar amide bond formation reactions under the 54
conditions consisting of CuCl2 (5 mol%), 1,4-diazabicyclo[2.2.2]oc- 55
tane (DABCO) (10 mol%), TBHP (2 equiv.), and DMF (15 equiv.) in 56
*
Corresponding author at: Department of Chemistry, Tongji University, Shanghai
200092, China.
E-mail address: zhangyanghui@tongji.edu.cn (Y.-H. Zhang).
Q2
http://dx.doi.org/10.1016/j.cclet.2014.09.007
1001-8417/ß 2014 Yang-Hui Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: H.-Q. Liu, et al., Copper-catalyzed amide bond formation from formamides and carboxylic acids, Chin.
Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.007

G Model
CCLET 3088 1–4
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H.-Q. Liu et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
presented here, only 4 equiv. of DMF and 1 mol% copper catalyst
are enough to achieve high yields.
70
71
2. Experimental
72
1H NMR and 13C NMR spectra were recorded on Bruker ARX400.
High resolution mass spectra were measured on Bruker MicroTOF
II ESI-TOF mass spectrometer. All solvents were distilled prior to
use unless otherwise noted. 1H NMR spectra were recorded in
CDCl3 and referenced to residual CHCl3 at 7.26 ppm, and 13C NMR
spectra were referenced to the central peak of CDCl3 at 77.0 ppm.
General procedure for the amidation of benzoic acids: a 50 mL
sealed tube (with a Teflon high pressure valve) equipped with a
magnetic stir bar was charged with Cu(OTf)2 (0.05 mmol),
followed by carboxylic acid (0.5 mmol), formamide (2.0 mmol),
tert-butyl peroxide (DTBP, 1 mmol), and DCE (1 mL). After the
reaction mixture was stirred at 130 8C for 12 h, it was allowed to
cool to ambient temperature. The reaction mixture was diluted
with ethyl acetate, and then filtered through a small pad of Celite.
The filtrate was washed with saturated aqueous NaHCO3 (5 mL)
and brine (5 mL, twice). The organic phase was dried (Na2SO4) and
concentrated in vacuo. The residue was purified by silica gel
preparative TLC to give the corresponding product.
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74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
Fig. 1. Two strategies for amide bond formation.
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63
64
65
66
67
68
69
1,2-dichloroethane (DCE) [11]. Coincidentally, the Kantam group
developed a similar catalysis system for the synthesis of amides
from carboxylic acids and DMF. The catalysis system consists of
CuO (10 mol%), TBHP (3 equiv.), and DMF (1.5 mL) [12]. All of these
works require the use of an excessive amount of DMF, either
15 equiv. or as the solvent. Actually, this drawback is found in
many reactions involving DMF as the reactants, which is not only
against atom-economic strategy, but also restricts the reactions to
those volatile formamides. In addition, the similar amidation of
3. Results and discussion
91
Our research started with the investigation of the amidation of
4-chlorobenzoic acid. In the presence of CuI (10 mol%) as the
catalyst and K2S2O8 (2.0 equiv.) as the oxidant, the reaction
generated desired product 1 in a very low yield in DMF at 130 8C
(Table 1, entry 1). Screening oxidants showed that DTBP was the
comparatively better oxidant than the other peroxides (entry 4),
and thus, DTBP was chosen as the oxidant for further studies.
Among the surveyed copper catalysts, Cu(OTf)2 proved to be the
most efficient, and the yield reached 89% (entry 8). It should be
92
93
94
95
96
97
98
99
100
a
-oxocarboxylic acids with formamides have been reported
[13]. Although the reactions yielded the amiation products in
good yield in the presence of only 5 equiv. of formamides in Wang’s
work [13a], 10 mol% copper catalyst was used. In our work
Table 1
Condition optimization for the amidation of 4-chlorobenzoic acid with DMF.
O
OH
O
N
catalyst
oxidant
130 oC, 12 h
O
.
+
H
N
Cl
Cl
1
0.5 mmol
Entry
Catalyst (mol%)
Oxidant (2.0 equiv.)
Solvent (1.0 mL)
Yield (%)a
1
2
CuI (10)
K2S2O8
Oxone
TBHP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
CH3CN
Dioxane
DCE
9
/
CuI (10)
3
CuI (10)
13
4
CuI (10)
45
5
CuI (10)
58
6
CuBr2 (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (5)
Cu(OTf)2 (1)
/
70
7
73
8
89
9
21b
48b
18b
45b
87b
85c
69d
84
10
11
12
13
14
15
16
17
18
DCE
DCE
DCE
DCE
84 (80e)
<5
DCE
a
The yields were determined by 1H NMR analysis of crude products using DCE as the internal standard.
b
c
DMF 10 equiv.
DMF 4 equiv.
DMF 3 equiv.
Isolated yield.
d
e
Please cite this article in press as: H.-Q. Liu, et al., Copper-catalyzed amide bond formation from formamides and carboxylic acids, Chin.
Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.007

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H.-Q. Liu et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
Table 2
Amidation of benzoic acid and its derivatives with DMF.
Cu(OTf)2 (1 mol%)
O
DTBP (2.0 equiv)
O
R
O
R
+
.
H
N
N
OH
DCE (1.0 mL)
130 °C, 12 h
0.5 mmol
Entry
2.0 mmol
Carboxylic acid
Product
Yield (%)a
Entry
Carboxylic acid
Product
Yield (%)a
1
2
Benzoic acid
2
3
71
65
72
75
72
72
56
72
80
87
81
88
80
85
78
85
60
84
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
4-Cyanobenzoic acid
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
76
68
78
72
64
85
46b
64b
75
65
75
58
55
46
72
78
68
2-Methylbenzoic acid
3-Methylbenzoic acid
4-Methylbenzoic acid
2-Methoxybenzoic acid
3-Methoxybenzoic acid
4-Methoxybenzoic acid
2-Fluorobenzoic acid
3-Fluorobenzoic acid
4-Fluorobenzoic acid
2-Chlorobenzoic acid
3-Chlorobenzoic acid
3-Bromobenzoic acid
4-Bromobenzoic acid
3-Iodobenzoic acid
4-Iodobenzoic acid
2-Cyanobenzoic acid
3-Cyanobenzoic acid
2-(Trifluoromethyl)benzoic acid
3-(Trifluoromethyl)benzoic acid
4-(Trifluoromethyl)benzoic acid
4-Acetylbenzoic acid
3
4
4
5
5
6
6
7
4-(Methoxycarbonyl)benzoic acid
2-Nitrobenzoic acid
7
8
8
9
4-Nitrobenzoic acid
9
10
11
12
13
14
15
16
17
18
19
4-Acetoxybenzoic acid
Biphenyl-2-carboxylic acid
3,5-Dimethylbenzoic acid
3-Methyl-4-nitrobenzoic acid
4-Methyl-3-nitrobenzoic acid
2-Chloro-4-nitrobenzoic acid
1-Naphthoic acid
10
11
12
13
14
15
16
17
18
2-Naphthoic acid
Octanoic acid
a
Isolated yield.
b
Cu(OTf)2 (5 mol%).
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
noted that even Cu could catalyze the amidation reaction quite
effectively (entry 5). In all of the above reactions, DMF was used as
the solvent. To circumvent this problem, we turned our attention
to reduce the quantities of DMF. To achieve this end, an
appropriate solvent should be found. Therefore, we surveyed
different solvents with 10 equiv. DMF. While polar solvents
including dimethyl acetamide (DMA), DMSO, CH3CN, and 1,4-
dioxane gave the amidation product in poor yields, fortunately, an
excellent yield was obtained when the reaction was carried out in
DCE (entry 13). Gratifyingly, the yield remained excellent even
when the amount of DMF was reduced to 4 equiv. (entry 14). The
use of 3 equiv. DMF resulted in the decrease of the yield. Notably,
only 1% of Cu(OTf)2 was enough to catalyze the reaction efficiently
and the yield almost remained unchanged (entry 17). The reaction
did not take place in the absence of Cu(OTf)2 (entry 18).
With the optimized condition in hand, we started to explore the
scope of carboxylic acids. As shown in Table 2, various aromatic
carboxylic acids reacted efficiently with DMF to produce the
corresponding amides. Benzoic acid and its derivatives bearing an
electron-donating group including methyl and methoxyl at ortho-,
meta- and para-position were smoothly transformed into corre-
sponding products in good yields (2–8). Notably, halides, including
fluoride, chloride, bromide, and even iodide, which are usually
reactive in the presence of transition metals such as copper, were
compatible with the reaction conditions and all gave excellent
results (9–17). Next, we examined the compatibility of benzoic
acids containing electron-withdrawing functionalities. A range of
electron-withdrawing substituents on aromatic rings like cyano,
trifluoromethyl, carbonyl, and ester were well-tolerated (18–25).
The presence of nitro groups resulted in diminished yields.
Gratifyingly, by increasing the quantity of catalyst Cu(OTf)2 to
5 mol%, the reactions provided the desired products in modest
yields (26, 27). The amides with acetoxy or phenyl groups could
also be prepared from corresponding aromatic carboxylic acids
(28, 29). In addition, a series of disubstituted aromatic carboxylic
acids and 1- or 2-naphthoic acid were reactive to give desired
products in moderate to good yields (30–35). Finally aliphatic
carboxylic acids could be amidated effectively under the identical
conditions (36).
The use of 4 equiv. DMF enables the amidation protocol to be 140
extended to other formamides, especially non-volatile ones. 141
Taking advantage of the strength of this protocol, we examined 142
other formamides with benzoic acids under the identical condi- 143
tions. As shown in Table 3, the formamides derived from 144
diethylamine and morpholine reacted with benzoic acids to 145
generate the corresponding amides in moderate yields (37, 38). 146
Unfortunately, N-methyl-N-phenylformamide was not reactive 147
(39).
148
Mechanistically, the carbonyl group of the amide product could 149
be from the carboxyl group of benzoic acids or the amide group of 150
formamides (Fig. 2, Eqs. (1) and (2)). To elucidate the source of the 151
carbonyl group, we carried out a 13C-isotope labeling experiment. 152
Therefore, benzoic acid was allowed to react with 13C-labeled DMF 153
Table 3
Amidation of benzoic acid with different formamides.
R1
N
Cu(OTf)2 (1 mol%)
DTBP (2.0 equiv)
O
OH
O
O
R2
R1
+
.
H
N
DCE (1.0 mL)
130 °C, 12 h
R2
0.5 mmol
2.0 mmol
Entry
1
Formamide
Product
37
Yield (%)a
53
O
N
2
3
38
39
45
0
O
O
N
O
Ph
N
a
Isolated yield.
Please cite this article in press as: H.-Q. Liu, et al., Copper-catalyzed amide bond formation from formamides and carboxylic acids, Chin.
Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.007

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Fig. 2. Investigation into the source of the carbonyl groups of the amidation
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154
155
156
157
158
under the standard conditions (Fig. 2, Eq. (3)). MS analysis showed
that the resulting N,N-dimethylbenzamide did not contain 13C,
which demonstrated that the carbonyl group should come from
the carboxyl group of benzoic acid, rather than the amide group of
formamides.
159
4. Conclusion
160
161
162
163
164
165
166
167
In summary, we disclosed a highly efficient approach to form
amide bonds from formamides and carboxylic acids. In this
protocol, only 1 mol% cheap and relatively less toxic copper
catalyst and 4 equiv. formamides were enough to facilitate the
reaction. Both aromatic and aliphatic carboxylic acids can be
transformed into corresponding amide products with high yields
under identical conditions. This reaction showed a broad substrate
scope and a wide variety of functional groups were compatible.
168
Acknowledgments
169 Q4
The work was supported by the National Natural Science
170 Q5 Foundation of China (No. 21372176), Tongji University 985 Phase
171
172
173
174
175
176
177
III funds, Pujiang Project of Shanghai Science and Technology
Commission (11 J1409800), and the Program for Professor of
Special Appointment (Eastern Scholar) at Shanghai Institutions of
Higher Learning.
We also thank Professor Xiaobing Wan in College of Chemistry,
Chemical Engineering and Material Science of Soochow University
for the generous donation of 13C-labeled DMF.
178
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Please cite this article in press as: H.-Q. Liu, et al., Copper-catalyzed amide bond formation from formamides and carboxylic acids, Chin.
Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.09.007