Copper-catalyzed oxidative coupling of carboxylic acids with formamides for the synthesis of α,β-unsaturated amides

Article abstract of DOI:10.1016/j.tetlet.2013.09.016

A novel and efficient protocol for the synthesis of α,β- unsaturated amides has been developed using catalytic amount of Cu(OAc) ₂ and TBHP as an available oxidant. Oxidative coupling of various unsaturated carboxylic acids with N,N-disubstituted formamides was examined to furnish the desired products in good yields.

Full text of DOI:10.1016/j.tetlet.2013.09.016

Accepted Manuscript
Copper-catalyzed oxidative coupling of carboxylic acids with formamides for
the synthesis of α, β-unsaturated amides
Huamin Li, Changduo Pan, Yixiang Cheng, Chengjian Zhu
PII:
S0040-4039(13)01561-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.09.016
TETL 43516
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
29 May 2013
27 August 2013
5 September 2013
Please cite this article as: Li, H., Pan, C., Cheng, Y., Zhu, C., Copper-catalyzed oxidative coupling of carboxylic
acids with formamides for the synthesis of α, β-unsaturated amides, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.09.016
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Copper-catalyzed oxidative coupling of
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carboxylic acids with formamides for the
synthesis of , -unsaturated amides
Huamin Lia, Changduo Pana,, Yixiang Chenga, Chengjian Zhua,b,*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Copper-catalyzed oxidative coupling of carboxylic acids with formamides for the
synthesis of , -unsaturated amides
Huamin Lia, Changduo Pana, Yixiang Chenga, Chengjian Zhua,b 
a School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and efficient protocol for the synthesis of , -unsaturated amides has been developed
using catalytic amount of Cu(OAc)2 and TBHP as an available oxidant. Oxidative coupling of
various unsaturated carboxylic acids with N, N-disubstituted formamides were examined to
furnish the desired products in good yields.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Unsaturated amides
Synthesis
Copper
Catalysis
Oxidative coupling
 Corresponding author. Tel./fax: +86-25-83594886; e-mail: cjzhu@nju.edu.cn

2
Introduction
absence of catalyst or oxidant (Table 1, entries 8 and 18).
Furthermore, several additives such as NaOAc, K2CO3, Ag2CO3
and HOAc were tested and the yield of 3a decreased. These
results indicated that weak acid or base could not promote the
reaction (see Table S1 in the Supporting information for details).
Consequently, the optimal reaction conditions were the
combination of 5 mol% Cu(OAc)2 and 2.0 equiv. TBHP as the
oxidant in 1.0 mL TCE at 90 oC for 12 h.
Amide compounds are of great value both in life and in
manufacture, which are widely used in kinds of fields including
pharmaceutical and chemical industry.1 At the same time, amide
linkage holds irreplaceable position in biological systems as it is
an important chemical bond which connects amino acids to form
protein.2 The research about incorporation of amide linkages into
organic molecules and following diverse transformations is one
of the most attractive subjects in the field of contemporary
organic chemistry. As an important molecular skeleton and
synthetic intermediate, the study of amide synthesis is relatively
mature.3 However, the reports covering formation of unsaturated
amides with various biochemical activities4 are few, which is still
a great challenge in the research of material synthesis.5
Table 1
Optimization of reaction conditions for the synthesis of 3aa
Transition-metal-catalyzed coupling reactions including cross
dehydrogenative coupling or oxidative coupling have become a
versatile tool for chemical bonds formation.6 Our group have
gained many achievements in this field as well.7 As we know,
carboxylic acid is a kind of ubiquitous compound in nature and
organic chemistry.8 In addition, it is stable and gained through a
lot of simple preparation methods.9 In recent years, carboxylic
acid and its derivatives are regarded as popular raw materials in
many oxidative coupling reactions, especially in the process of
decarboxylation/carbon-carbon or carbon-heteroatom bond
formation.10 Formamides are usually used as excellent solvents.
The coupling chemistry of formamides with functional groups
including aryl halides is also well known11 and we discover that
formamides are available coupling reaction reagents through
decarbonylation in our previous work.12 During preparation of
our manuscript, Reddy group finished Cu-catalyzed oxidative
coupling carboxylic acids with DMF or DEF to the synthesis of
amides.13 We noticed that their attention was focused on aliphatic
and aromatic acids. Herein, we wish to report a reaction of
copper-catalyzed oxidative coupling of carboxylic acids with
formamides for the synthesis of , -unsaturated amides
(Scheme 1).
Entry
Catalyst
Oxidant
Solvent
Yield(%)b
1
Cu
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
t-BuOOBu-t
TCEc
58
2
CuCl2
TCE
85
3
CuBr
TCE
70
4
CuI
TCE
65
5
Cu(OAc)2
AgOAc
Ag2O
TCE
86
6
TCE
46
7
TCE
35
8
-
TCE
N.D.d
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CH3CCl3
ClCH2CH2Cl
PhCH3
DMF
50
10
11
12
13
14
48
47
trace
trace
N.D.
DMSO
TCE
15
16
17
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
K2S2O8
TCE
TCE
TCE
TCE
N.D.
N.D.
N.D.
N.D.
H2O2(30%)
O2
-
Scheme 1. Cu(OAc)2 catalyzed carboxylic acids with N,
N-disubstituted formamides for the synthesis of unsaturated
amides.
18
a
Reaction conditions: 1a (0.1 mmol), 2a (0.5 mmol),
catalyst (5 mol%), oxidation (2.0 equiv.), solvent (1.0 mL),
90 oC, 12 h.
Results and Discussions
b Isolated yields.
c TCE = 1, 1, 2-trichloroethane.
d Not detected.
In our initial study, the coupling of cinnamic acid 1a with N,
N-dimethylformamide (DMF) 2a was selected as a model
reaction. The optimized results of the influence of various
parameters including reaction temperature, catalyst, oxidant and
solvent are summarized in Table 1. The results showed that the
desired product 3a was gained with 58% yield using Cu as the
catalyst and TBHP as the oxidant (Table 1, entry 1). Then we
tried other various catalysts. such as Cu(OAc)2, CuCl2, CuBr and
CuI (Table 1, entries 2-5). Among them, Cu(OAc)2 showed the
best efficiency providing 86% yield (Table 1, entry 5). AgOAc
and Ag2O were also tested, and none showed better activities than
Cu(OAc)2 (Table 1, entries 6 and 7). Afterwards, the effect of
solvents was investigated (Table 1, entries 9-13). We discovered
that CH3CCl3, ClCH2CH2Cl or toluene led to unsatisfactory
yields. Other solvents studied, such as DMF and DMSO, resulted
in meaningless yields. Other oxidants were also employed, and
3a was not detected (Table 1, entries 14-17). Besides,
experiments also demonstrated that no 3a was formed in the
With the optimized reaction conditions in hand,14 we explored
the scope of this protocol and the results are listed in Table 2.
First, the reactions of cinnamic acid 1a with a range of cyclic and
acyclic N, N-disubstituted formamides 2a-2f were examined.
Other than simple alkyl substituted formamides, the synthetically
more important benzyl-substituted and cyclic formamides were
suitable to the reaction system and also gave good yields. After
these formamides screening, a series of various substituted aryl
unsaturated carboxylic acids 1b-1h were used as reaction
partners in the transformation. The results demonstrated that
carboxylic acids with electron-donating or electron-withdrawing

3
Table 2
Synthesis of unsaturated amides from various acids and N,
N-disubstituted formamidesa
3g, 82%
3i,85%
3h, 88%
3j, 83%
3a, 86%b
3b, 78%
3d, 75%
3k, 87%
3m, 88%
3l, 80%
3n, 62%
3c, 72%
3o, 81%
3e, 76%
3f, 70%
a
Reaction conditions: 1 (0.1 mmol), 2 (0.5 mmol), Cu(OAc)2 (5
mol%), TBHP (2.0 equiv.), TCE (1.0 mL), 90 oC, 12 h.
b Isolated yields.
groups were well tolerated, affording the desired products 3g-3m
in excellent yields. We were delighted to obtain the
corresponding amide 3k with a pleased yield of 87% when
(E)-3-(4-CF3C6H4) acrylic acid 1f was subjected to the reaction
system. To the best of our knowledge, the introduction of
fluoride group into substances could change the physicochemical
and biological activities of organic molecules, which is of great
significance.15 It is worth noting that steric effects of substituents
in different positions are not obvious. Moreover, we tried the
reaction of 2-substituted allyl acid 1i with DMF and gained
product 3n in moderate yield. 3-phenylpropiolic acid and DMF
as well led to expected product 3o in a yield of 81%.
To gain insight into the mechanism of the reaction, a series of
experiments were carried out under the optimized conditions
(Scheme 2). Product 3a was not observed when radical
scavenger 2, 2, 6, 6-tetramethylpiperidin-1-yloxyl (TEMPO) or
radical inhibitor butylated hydroxytoluene (BHT) was added into
the reaction system, which indicated that the reaction might go
through a radical process (Scheme 2, a). The absence of 3a when
dimethylamine was used instead of DMF under the standard
conditions could exclude the possibility of direct coupling of
carboxylic acids with dimethylamine produced by hydrolysis of
DMF (Scheme 2, b). Then we tried to add KI, n-Bu4NI or I2
instead of Cu(OAc)2 to the reaction system as N-center radical
could be easily generated from DMF under the catalytic system
according to previous reports.16 However, the product 3a was not
detected (Scheme 2, c). Further investigation showed that 3a in a
yield of 80% was obtained when we used N,
N-dimethylmethanethioamide other than DMF as reaction
substrate, which confirmedly supports the preferential loss of the
carbonyl group from the formamide rather than the carboxylic
Scheme 2. A series of experiments for exploring the
mechanism
acid (Scheme 2, d). In the light of our present experimental
results and reported publications, a plausible mechanism is
shown in Scheme 3. Firstly, cinnamic acid 1a coupled with
t-BuOOH to form peroxybenzoate A. Then the possible
intermediate B produces from DMF 2a and A catalyzed by

4
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Organische Chemie II, 1st edn, Georg Thieme Verlag Stuttgart,
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14. General procedure for the synthesis of unsaturated amide 3a: To a
solution of cinnamic acid 1a (0.1 mmol) in TCE (1.0 mL) was
added Cu(OAc)2 (5 mol %) and N, N-dimethylformamide 2a (0.5
mmol), followed by adding a solution of TBHP (2.0 equiv.). The
resulting mixture was stirred at 90 oC until it completed. When the
reaction was finished, the reaction mixture was cooled to room
temperature and poured into saturated Na2S2O3 solution (3.0 mL),
extracted with EtOAc (3 × 8.0 mL), then washed with saturated
brine. The combined organic layers were dried over anhydrous
Na2SO4. After removing the solvents in vacuo, the residue was
purified by flash column chromatography on silica gel or
preparative TLC on GF 254 to afford the desired product 3a.
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Scheme 3. Plausible mechanism
Cu(OAc)2.17 Finally, B decomposes into the product 3a with the
loss of CO2. Another control experiment was conducted. We
observed that peroxybenzoate A with DMF led to 3a with a yield
of 80% under the standard conditions (Scheme 2, e). This result
also supports our proposed mechanism.
Conclusions
In conclusion, a practical and facile protocol for the synthesis
of unsaturated amides has been developed through a catalyzed
oxidative coupling strategy. Various easily available carboxylic
acids and N, N-disubstituted formamides can react smoothly and
result in good yields. Further studies on the mechanism and
expansion of the scope of the reaction are currently under
investigation.
Acknowledgments
We gratefully acknowledge the National Natural Science
Foundation of China (21074054, 21172106), the National Basic
Research Program of China (2010CB923303) and the Research
Fund for the Doctoral Program of Higher Education of China
(20120091110010) for their financial support.
Supplementary data
Supplementary data associated with this article: Experimental
details and the characterization data for the compounds 3a-3o.
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