Copper-catalyzed oxidative condensation of α-oxocarboxylic acids with formamides: Synthesis of α-ketoamides

Article abstract of DOI:10.1039/c3ob40787j

A copper-catalyzed coupling of α-oxocarboxylic acids with formamides is reported. This simple method provides a practical approach toward the synthesis of α-ketoamides with a variety of functional groups. Mechanistic studies have shown that the reaction proceeded via a radical process and ¹³C-labeled experiments proved that the amide carbon in the products comes from the corresponding carboxylic acid, not from the DMF. is

Full text of DOI:10.1039/c3ob40787j

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Copper-catalyzed oxidative condensation of
α-oxocarboxylic acids with formamides: synthesis of
α-ketoamides†
Cite this: DOI: 10.1039/c3ob40787j
Received 18th April 2013,
Accepted 22nd May 2013
DOI: 10.1039/c3ob40787j
Hua Wang, Li-Na Guo* and Xin-Hua Duan*
www.rsc.org/obc
A copper-catalyzed coupling of α-oxocarboxylic acids with form- example, DMF can be utilized as a precursor providing
10
5d,11
amides is reported. This simple method provides a practical –CONMe2 or –NMe2
units in some reactions. However,
approach toward the synthesis of α-ketoamides with a variety of to date, the direct coupling of DMF with stable α-oxocarboxylic
functional groups. Mechanistic studies have shown that the reac- acids has not been studied. In connection with our recent
tion proceeded via a radical process and 13C-labeled experiments efforts on transition-metal catalyzed decarboxylative C–H
proved that the amide carbon in the products comes from the bond acylation,12 we envisioned that readily available form-
corresponding carboxylic acid, not from the DMF.
amides could act as potential coupling partners with α-oxocar-
boxylic acids, proceeding decarboxylative dehydrogenative
coupling under an efficient catalysis system (eqn (1)).13 DMF
can also serve as a source of amines in amination reactions,11
so, α-oxocarboxylic acids maybe also directly couple with
DMF leading to α-ketoamides (eqn (2)). During revision of
Amides are important structural motifs in a wide range of
natural products, polymers, and marketed drugs.1 For
example, α-ketoamides belong to an important class of com-
pounds because they are present in significant pharmaceuti-
cals and valuable agricultural chemicals.2 In addition, they
also serve as useful precursors for a variety of transformations
in organic synthesis.3 The synthesis of α-ketoamides has there-
fore attracted much attention and numerous synthetic
methods have been devised. Traditional strategies for acces-
sing α-ketoamides mainly involved the condensation of α-oxo-
carboxylic acids and their derivatives with amines,4 which
suffers from harsh conditions and a large amount of bypro-
ducts. Some alternative procedures including oxidative coup-
ling,5 double carbonylative amination of aryl halides,6 and
other methods7 have been developed. Very recently, the
copper-catalyzed oxidative reaction approaches to α-keto-
amides have attracted much attention in synthetic organic
chemistry.8 Although many methods are known for the syn-
thesis of α-ketoamides, development of more atom-efficient,
environmentally benign catalytic methods for α-ketoamides is
still highly desirable.
our manuscript,
a related copper-catalyzed reaction was
reported.14 However, based on 13C-labeled experiment
(vide infra), we proved that the mechanism of the reaction was
the oxidative condensation of α-oxocarboxylic acids with
formamides.
ð1Þ
ð2Þ
Our investigation commenced with a copper-catalyzed reac-
tion of phenylglyoxylic acid (1a) with DMF 2a.8 To our delight,
when 1a was treated with DMF in the presence of 20 mol% of
CuO and 2 equiv. of di-tert-butyl peroxide (DTBP) as oxidant
at 110 °C for 3 h, the desired N,N-dimethyl-2-phenylglyoxyl-
amide (3a) was isolated in 31% yield (Table 1, entry 1). Among
the Cu(II) catalysts tested, Cu(OAc)2 was the most effective cata-
lyst for this reaction (entry 4). It should be noted that CuSO4
was also effective under the present conditions (entry 5). Cu(I)
complexes such as CuCl and CuBr were also tested, and none
showed better activities than Cu(OAc)2 (entries 7 and 8).
Screening of the oxidants showed that DTBP is the best one,
while other peroxides or persulfates gave lower yields (entries
N,N-Dimethylformamide (DMF) is usually used as
a
common polar solvent for various chemical reactions. In fact,
it could also play more different roles than solvent, such as a
ligand, as a multipurpose building block and so on.9 For
Department of Chemistry, School of Science and MOE Key Laboratory for
Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong
University, Xi’an 710049, China. E-mail: duanxh@mail.xjtu.edu.cn,
guoln81@mail.xjtu.edu.cn
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40787j
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Table 1 Optimization of the reaction of DMF with phenylglyoxylic acida
Table 2 Coupling of DMF with various phenylglyoxylic acidsa
Entry
Catalyst (mol%)
Oxidant (equiv.)
Yieldb (%)
1
2
3
4
5
6
7
8
CuO (20)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
TBHP (2)
TBPB (2)
(NH4)2S2O8 (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
DTBP (2)
31
40
38
68
46
24
51
45
58
20
12
73
72
76
80
40
0
CuBr2 (20)
CuCl2 (20)
Cu(OAc)2 (20)
CuSO4 (20)
Cu(acac)2 (20)
CuCl (20)
CuBr (20)
9
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (10)
Cu(OAc)2 (5)
FeCl2 (20)
10
11
12c
13d
14c
15c
16
17
18
19
NiF2 (20)
Pd(OAc)2 (20)
—
0
0
a Reaction conditions: 20 mol% of catalyst, 1a (0.2 mmol, 1 equiv.)
DMF (1 mL), oxidant (2 equiv.), 110 °C, 3 h. b Yield of isolated
product. c DMF (2 mL). d DMF (3 mL), TBHP (tert-butyl hydroperoxide,
5–6 M in decane).
9–11). Subsequently, when the amount of DMF was increased
to 2 mL, the coupling yield could be improved to 73% (entry
12). While the amount of DMF was continuously increased to
3 mL, a similar yield was obtained (entry 13). A decrease of the
catalyst loading from 20 mol% to 5 mol% resulted in a better
a All reactions were performed with 1 (0.2 mmol) and DMF 2a (2 mL),
under the standard conditions (Table 1, entry 15) at 110 °C. Yields are
yield (entry 15). A further study revealed that the FeCl2 could of the isolated products. b N,N-Dimethyl-4-nitrobenzamide (3h′) was
also isolated in 36% yield.
also be used as a catalyst, albeit giving a lower yield (entry 16).
Interestingly, palladium and nickel catalysts did not promote
the reaction at all (entries 17 and 18), which indicated that
the type of catalyst was crucial for this reaction. Finally, no
desired product was obtained in the absence of a catalyst
(entry 19).
α-naphthyloxoacetic acid delivered the cross-coupled product
in somewhat higher yield than the corresponding β-naphthyl-
oxoacetic acid (3m vs. 3l). Satisfactorily, furoylformic acid and
We next explored the scope of the coupling reaction.
2-thienylglyoxylic acid also proceeded smoothly to give the
Various substituted α-oxocarboxylic acids furnished the
desired products 3n and 3o in 56% and 72% yields,
corresponding α-ketoamides in good to excellent yields under
respectively.
the optimized conditions (Table 2). As shown in Table 2, a
variety of phenylglyoxylic acids with p-substituted electron-
Subsequently, other N,N-disubstituted formamides for the
present coupling were examined (Table 3). Both the acyclic
rich or -withdrawing groups led to good yields, except in the
and cyclic formamides were suitable substrates for the for-
case of 4-nitrophenylglyoxylic acid (3b–h). It is noteworthy
mation of the corresponding α-ketoamides 4a–c. In the
that chloro, bromo and iodo groups included in phenyl-
present case, the reaction of N-formylmorpholine with substi-
glyoxylic acid were tolerated well and gave the desired pro-
tuted phenylglyoxylic acids provided the desired products in
ducts 3d, 3e and 3f in good yields. The results were
moderate yields (4d and 4e). Unfortunately, N-methylforma-
significant because the halo groups retained in the α-keto-
mide gave low conversion to the desired product 4f.
amides provide opportunities for further transformation
under transition metal catalytic systems. In addition to phe-
nylglyoxylic acids with substituents at the para position, the
sterically congested o-substituted substrates also participated
ð3Þ
in the desired coupling process (3i–k). Curiously, the
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Table 3 Coupling of formamides with various phenylglyoxylic acidsa
In summary, we have demonstrated the oxidative coupling
of DMF with α-oxocarboxylic acids. This operationally simple
and efficient method provides a fundamentally novel approach
toward the synthesis of α-ketoamides with a wide range of sub-
strate scopes. Both the starting materials are simple and easily
available. Based on the control experiments, an oxidative con-
densation process was suggested for the catalytic cycle. Further
studies on the mechanistic details are currently underway in
this group.
Acknowledgements
Financial support from National Natural Science Foundation
of China (Nos. 21102110, 21102111), the Doctoral Fund of the
Ministry of Education of China (No. 20110201120076), and the
Fundamental Research Funds of the Central Universities is
greatly appreciated. We also gratefully acknowledge valuable
suggestions by a reviewer for the reaction mechanism.
a All reactions were performed with 1 (0.2 mmol) and formamides 2
(2 mL), under the standard conditions (Table 1, entry 15) at 110 °C.
Yields are of the isolated products. b 3 equiv. of DTBP were used.
Notes and references
ð4Þ
ð5Þ
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