Cu(ii)-catalyzed decarboxylative acylation of acyl C-H of formamides with α-oxocarboxylic acids leading to α-ketoamides

Article abstract of DOI:10.1039/c3cc41188e

CuBr₂-catalyzed decarboxylative acylation of the acyl C-H of N-monosubstituted and N,N-disubstituted formamides with α-oxocarboxylic acids leading to α-ketoamides was developed, which generated the corresponding products in good yields. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41188e

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Cu(II)-catalyzed decarboxylative acylation of acyl C–H
of formamides with a-oxocarboxylic acids leading
to a-ketoamides†
Cite this: Chem. Commun., 2013,
49, 3640
Received 13th February 2013,
Accepted 12th March 2013
Dengke Li,a Min Wang,*a Jie Liu,a Qiong Zhaoa and Lei Wang*ab
DOI: 10.1039/c3cc41188e
www.rsc.org/chemcomm
CuBr2-catalyzed decarboxylative acylation of the acyl C–H of Pd-catalyzed decarboxylative acylation of o-methyl ketoximes and
N-monosubstituted and N,N-disubstituted formamides with phenylacetamides with a-oxocarboxylic acids.10 Meanwhile, Tan et al.
a-oxocarboxylic acids leading to a-ketoamides was developed, also described Pd-catalyzed decarboxylative ortho-acylation of
which generated the corresponding products in good yields.
o-methyl oximes with phenylglyoxylic acids.11
a-Ketoamides are very important and frequently found in natural
In recent years, transition metal-catalyzed decarboxylative cross- products, pharmaceuticals and synthetic intermediates.12 The
coupling has been a rapidly growing area of research for carbon– synthesis of a-ketoamides has been the subject of intense research,
carbon and carbon–heteroatom bond formations.1 This method and several methods have been developed. These methods can
accesses reactive organometallic intermediates through the roughly be divided into four categories with regard to substrates or
release of CO2 from the metal carboxylates instead of toxic metal reagents in the reactions; condensation reactions,13 double carbonyla-
salts used in traditional cross-coupling methods. Meanwhile, tion reactions,14 oxidative reactions,15 and others.16 Among oxidative
protodecarboxylation achieves the site-specific generation of approaches, Cu-catalyzed oxidative amidation/diketonization of term-
reactive organometallic species without requiring the use of inal alkynes with anilines,15a Cu-catalyzed oxidative coupling of aryl
directing groups, which is often necessary for regioselective acetaldehydes,15b and aryl methyl ketones and amines15c have pre-
formation of specific intermediates via C–H functionalization.
sented the most attractive strategies. Most recently, TBHP-promoted
Moreover, carboxylic acid derivatives, as cross-coupling compo- oxidative coupling of acetophenones with amines and dialkylforma-
nents, are non-toxic, low cost, structurally diverse and can be mides under metal-free conditions have been developed.17
obtained both from natural and synthetic sources.2 Since the
Of course, formamides can be used as amide sources via acyl
decarboxylative Heck-type reactions reported by Myers et al.,3 exten- C–H activation of formamides.18 Nevertheless, to the best of our
sive studies on decarboxylative couplings of carboxylic acids (salts) knowledge, using formamides as amide sources for the preparation
have been carried out by Gooßen et al.,4 Liu et al.,5 Forgione et al.,6 of a-ketoamides has not been reported. With regard to atom
and Tunge et al.7,8 In particular, the recently developed decarboxyl- efficiency and environmentally benign features, and in our ongoing
ative C–H bond functionalization, which combines decarboxylation synthesis of a-ketoamides, herein, we wish to report a Cu(II)-catalyzed
and direct C–H bond (sp, sp2 and especially sp3 C–H bonds) direct decarboxylative cross-coupling reaction between acyl C–H of
functionalization, would allow chemists to exploit organic com- formamides with a-oxocarboxylic acids using DTBP as the oxidant.
pounds in previously unimaginable ways.9 Representative examples The reactions generated a-ketoamides in good yields (Scheme 1).
include the Pd-catalyzed reaction of carboxylic acids with saturated
At the beginning of our investigation, 2-oxo-2-phenylacetic acid
propiophenones by Su et al.,9a Cu-catalyzed reaction of cinnamic (1a) and DMF (2a) were chosen as model substrates to optimize the
acids with benzylic molecules by Mao et al.,9b and Cu-catalyzed reaction parameters and the results are summarized in Table 1. When
coupling of vinylic carboxylic acids with alcohols, ethers, and hydro- the reaction of 1a and 2a was carried out in the n-Bu4NI–TBHP or
carbons by Liu et al.9c Most importantly, Ge’s group has reported a I2–TBHP system,17 the desired product 3aa was notobtained. As listed
Pd-catalyzed decarboxylative acylation of arenes with a-oxocarboxylic in Table 1, among the tested catalysts, CuBr2 was found to be the most
acids as acylating agents.9d,e Most recently, Kim et al. developed effective together with 2 equiv. of DTBP (di-tert-butyl peroxide) and
2 equiv. of PivOH in toluene at 110 1C under an air atmosphere, and
a Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000,
3aa was isolated in 81% yield (Table 1, entry 1). Other copper catalysts,
including Cu(I)andCu(II), were less effective (Table 1, entries 2–8). The
attempts with other catalysts, such as FeCl3 and Pd(OAc)2, led tolower
yields of 3aa (Table 1, entries 9 and 10). 3aa was not detected in the
P. R. China. E-mail: leiwang@chnu.edu.cn; Fax: +86-561-309-0518;
Tel: +86-561-380-2069
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc41188e absence of a transition-metal catalyst (Table 1, entry 11).
c
3640 Chem. Commun., 2013, 49, 3640--3642
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Scheme 1
Table 1 Optimization of the catalysta
Scheme 2 The scope of formamides (2). Reaction conditions: 1a (0.50 mmol), 2
(5.0 equiv.), CuBr2 (10 mol%), DTBP (2.0 equiv.), PivOH (2.0 equiv.), toluene
(1.5 mL), air atmosphere, 110 1C, 18 h. aIsolated yields.
Entry
Catalyst
Oxidant
Additive
Yieldb (%)
1
2
3
4
5
6
7
8
CuBr2
CuCl2
Cu(acac)2
CuSO4
CuI
CuCl
Cu(OAc)2
CuO
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
81
51
31
29
25
13
o5
Trace
34
good yields of the corresponding products. N-Methylformamide,
N-ethylformamide, and N-tert-butylformamide reacted with 1a to
generate the desired products (3af, 3ag and 3ah) in 61, 64, and 57%
yields.
Next, the scope of a-oxocarboxylic acids was examined and
a variety of 2-oxo-2-arylacetic acids bearing substituents on the
benzene rings were well tolerated (Scheme 3). In general, 2-oxo-
2-arylacetic acids possessing an electron-withdrawing group on the
benzene ring gave better yields than those having an electron-
donating group on the benzene ring. For example, 2-oxo-2-arylacetic
acids with F, Br, and Cl on the para-positions of benzene rings
reacted with DMF efficiently, and the corresponding products (3ea,
3fa and 3ga) were isolated in 77–85% yields. However, 2-oxo-
2-arylacetic acids with Me, t-Bu, and MeO on the para-positions of
benzene rings gave the desired products (3ba, 3ca and 3da) in 75%,
69%, and 47% yields respectively. But 2-(4-nitrophenyl)-2-oxoacetic
acid is an exception, and only 31% yield of 3na was obtained.
Meanwhile, 2-oxo-2-arylacetic acids, bearing a sterically hindered
group, such as Cl or Br on their ortho/meta-positions, also underwent
decarboxylative coupling with DMF, providing the corresponding
products (3ha, 3ia, 3ja and 3ka) in slightly lower yields (61–74%)
compared with their corresponding para-substituted ones.
Additionally, 2-(naphthalen-1-yl)-2-oxoacetic acid and 2-(furan-2-yl)-
2-oxoacetic acid also proceeded through the reaction smoothly with
DMF to generate 3la and 3ma in 53% and 51% yields.
Although the reaction mechanism is not clear at this stage, on
the basis of previous publications, it is believed that this transforma-
tion proceeds via a combination of C–H activation of formamide by
a radical step17,18a and a transition-metal catalyzed decarboxylation
of a-oxocarboxylic acid.9d–f As anticipated, the addition of a radical
inhibitor blocked the reaction. The desired product 3aa was not
detected when 0.25 equiv. of TEMPO (2,2,6,6-tetramethylpiperidine-
N-oxyl) was added to the model reaction. A plausible catalytic cycle is
presented in Scheme 4. Firstly, homolysis of DTBP produces the tert-
butoxy radical, which traps H from DMF to generate a radical
intermediate A. On the other hand, 2-oxo-2-arylacetic acid reacts
with Cu(II) catalyst to form a salt of Cu(II) carboxylate B, and then
organometallic species C is produced via extrusion of CO2 from B.
The obtained intermediate A couples with organometallic species C
to generate intermediate D, which was followed by a reductive
elimination process to form the desired product and Cu(I).
9
10
11
FeCl3
Pd(OAc)2
—
o5
NR
a
Reaction conditions: 1a (0.50 mmol), 2a (5.0 equiv.), catalyst (10 mol%),
DTBP (2.0 equiv.), PivOH (2.0 equiv.), toluene (1.5 mL), air atmosphere,
110 1C, 18 h. Isolated yields.
b
The oxidant also plays an important role in the reaction and
DTBP exhibited the highest reactivity among the tested oxidants,
including H2O2, TBHP, TBPB, BQ, K2S2O8 and O2 (Table S1, ESI†).
When the reaction was carried out under an air atmosphere without
an additional oxidant, only 20% yield of 3aa was obtained. Mean-
while, a significant influence of additive on the model reaction was
observed. PivOH was the best additive because it can inhibit the side
reactions and improve the yield of 3aa.
Other additives, whether acids (TFA, HOAc, PhCO2H, and
CF3SO3H), or bases (pyridine, NEt3, K2CO3, and K3PO4), were
ineffective (Table S1, ESI†). The absence of additive resulted in a
decreased yield of 3aa to 43%. The solvent was also an important
factor in this transformation and the results are shown in Table S1
(ESI†). Of the tested solvents, toluene was found to be the best choice.
Other solvents, such as t-AmOH (tertiary amyl alcohol), dioxane,
CH2ClCH2Cl, CH3OCH2CH2OCH3, CH2Cl2 and benzene, were less
effective, and NMP, CH3NO2, DMSO, HOAc and H2O shut down the
reaction completely. During further investigation of the reaction
conditions, the model reaction was completed at 110 1C for 18 h.
In order to study the potential and general applicability of this
methodology, the representative formamides with 2-oxo-2-phenyl-
acetic acid (1a) were screened. The results are shown in Scheme 2.
Besides DMF, other dialkylformamides, such as N,N-diethylform-
amide and N,N-dibutylformamide, were well tolerated, and the
product yield decreased along with the increase in chain length of
formamides owing to the steric hindrance (3ab and 3ac). However
cyclic formamides, such as 1-formylpiperidine and 4-formylmorpho-
line, reacted smoothly with 1a, furnishing high yields of the desired
products (3ad, 87%; 3ae, 85%). It is important to note that
N-monosubstituted formamides were also well tolerated, providing
c
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Scheme 4 Proposed reaction mechanism.
Finally, oxidation of Cu(I) by DTBP regenerates Cu(II) to complete this
catalytic cycle.
In conclusion, we have developed a CuBr2-catalyzed decarboxyla-
tive acylation of acyl C–H of formamides with a-oxocarboxylic acids.
The reactions of N-monosubstituted and N,N-disubstituted form-
amides with a variety of a-oxo-2-arylacetic acids proceeded smoothly
to generate the corresponding a-ketoamides in good yields.
This method can provide a useful strategy for the synthesis of
a-ketoamides, which are key units of many biological active com-
pounds, and it is the first example to use formamides as an amide
source for the preparation of a-ketoamides. The reaction is highly
efficient and has a broad substrate scope. Further investigation on
the reaction is ongoing in our laboratory.
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This work was financially supported by the National Science
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c
3642 Chem. Commun., 2013, 49, 3640--3642
This journal is The Royal Society of Chemistry 2013