Copper-catalyzed oxidative cascade coupling of N-alkyl-N-phenylacrylamides with aryl aldehydes

Article abstract of DOI:10.1039/c3ra46915h

An oxidative cascade coupling reaction was developed between N-alkyl-N-phenylacrylamides and aryl aldehydes using CuCl₂/TBHP (tert-butyl hydroperoxide) as a catalyst and oxidant. The reaction involves oxidative cross coupling of the activated alkene Csp²-H from the N-alkyl-N-phenylacrylamide with the aldehyde Csp²-H bond (-CHO), followed by metal-mediated direct aryl Csp²-H functionalization/ cyclization to afford 3-(2-oxo-2-arylethyl)indolin-2-ones in good yields under mild reaction conditions without organic solvents involved.

Full text of DOI:10.1039/c3ra46915h

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Copper-catalyzed oxidative cascade coupling of
N-alkyl-N-phenylacrylamides with aryl aldehydes†
Cite this: RSC Adv., 2014, 4, 6854
a
a
a
b
a
c
Weiwei Gong, Lei Xu, Tao Ji, Ping Xie, Xueyong Qi, Charles U. Pittman, Jr.
a
and Aihua Zhou*
Received 21st November 2013
Accepted 6th January 2014
DOI: 10.1039/c3ra46915h
www.rsc.org/advances
7
An oxidative cascade coupling reaction was developed between K u¨ ndig. Recently, more fascinating results were obtained when
2
N-alkyl-N-phenylacrylamides and aryl aldehydes using CuCl
2
/TBHP aryl C(sp )–H cyclization/functionalization was combined with
(
tert-butyl hydroperoxide) as a catalyst and oxidant. The reaction oxidative cross couplings of activated alkenes. Zhu and Liu
2
involves oxidative cross coupling of the activated alkene Csp –H from independently used N-arylacrylamides as reactants for the
the N-alkyl-N-phenylacrylamide with the aldehyde Csp –H bond oxindole syntheses by Pd(OAc) -catalyzed oxidative difunction-
2
2
2
8
(–CHO), followed by metal-mediated direct aryl Csp –H functionali- alization (Scheme 1). Li developed a novel FeCl -catalyzed
3
zation/cyclization to afford 3-(2-oxo-2-arylethyl)indolin-2-ones in oxidative coupling reaction of the alkene function substrate
2
good yields under mild reaction conditions without organic solvents from N-arylacrylamide with either an aryl Csp –H bond or a
3
involved.
Csp –H bond adjacent to a heteroatom to afford oxindole
9
derivatives (Scheme 1). Yang reported the preparation of
3
various diphenylphosphoryl oxindoles by AgNO -catalyzed
Transition-metal-catalyzed oxidative cross coupling of activated
alkenes has attracted a lot of attention, because these kinds of
difunctionalization of the alkene function on N-arylacrylamides
through a carbon phosphorylation and C–H functionalization
1
reactions are normally atom-economic, highly efficient and
10
cascade (Scheme 1). Here, we report a copper-catalyzed
2
environment friendly. When these substrates are carefully
2
oxidative cross coupling reaction of the double bonds' Csp –H
designed, the reactions will not stop at the oxidative coupling
stage. Instead, it will subsequently undergo metal-mediated
functionalization/cyclization catalyzed by the same metal cata-
2
of N-alkyl-N-phenylacrylamides with an aryl aldehyde Csp –H
2
bond, followed by a Cu-mediated direct aryl Csp –H function-
alization/cyclization to produce the ketone oxindole derivatives,
2
3
lyst in one pot. For example, direct aryl C(sp )–H or alkyl C(sp )–
H cyclization/functionalization can occur. In this way, the
cascade reaction can generate a complex product skeleton in a
3-(2-oxo-2-arylethyl)indolin-2-ones. This cascade reaction pro-
ceeded under mild, atom-economical and environmental
friendly conditions. An inexpensive copper catalyst and
aqueous tert-butylhydroperoxide (TBHP) were used without any
organic solvents involved.
3
highly efficient way. N-Alkyl-N-phenylacrylamides, which
2
contain both an activated double bond (Csp –H) and an elec-
2
tron-rich aryl substrate (Csp –H) in one molecule, is a suitable
Very recently, Lei reported oxidative cross coupling reactions
synthetic substrate for planning this kind of cascade reaction.
Reports exist of using N-alkyl-N-arylacrylamides as reactants for
carrying out cascade reactions to synthesize oxindole deriva-
11
between phenyl-substituted alkenes with aldehydes. We have
extended this chemistry using the electron-decient alkene
functions from N-alkyl-N-phenylacrylamides in contrast to a
phenyl-substituted alkene. By introducing an arylamide
substrate into the reactant structure, a one-pot cascade reaction
generating ketone oxindoles in good yield was developed. An
inexpensive copper catalyst and aqueous tert-butylhy-
drogenperoxide (TBHP) were used without any organic solvents
involved.
4,8–11
tives,
but these transformations are still quite rare.
It is known that N-aryl amide substrates are suitable for
2
5
C(sp )–H cyclization/functionalization. Early work was repor-
6
ted by Hennessy and Buchwald, and later extended by Jia and
a
Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang, Jiangsu 212013,
Reaction conditions were screened to search for cascade
Scientic Information Research Institute, Jiangsu University (Library), Xuefu Road promoting features. Benzaldehyde and N-methyl-N-phenyl-
People's Republic of China. E-mail: ahz@ujs.edn.cn
b
3
01, Zhenjiang, Jiangsu 212013, People's Republic of China
methacrylamide were selected and various catalysts, solvents,
reaction times and yields were screened. Based on previous
research, catalyst screening focused mainly on copper
c
Mississippi State University, Mississippi State, MS 39762, USA
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c3ra46915h
12
1
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a
Table 2 Oxidative cascade coupling reaction
1
b
Entry
1
R
R
Product
Yield (%)
H
Me
70
72
Scheme 1 Transition-metal catalyzed cascade reactions of using
N-aryklacrylamide as one of reactants.
2
3
Me
Me
Me
catalysts which are capable of promoting oxidative coupling of
arylamide via single-electron transfer. There is no prior litera-
ture report of using a copper catalyst for this type of cascade
reaction.
The synthesis starts with the reaction between benzaldehyde
and N-methyl-N-phenyl-methacrylamide (Table 1). Excess
benzaldehyde (3.5 equiv.) and aqueous TBHP (70% in water, 2.5
equiv., added in two portions) as an oxidant were used to
MeO
62
86
promote conversion. When CuBr , CuI, CuBr (20% mol) were
2
4
t-Bu
Me
used as catalysts in the absence of solvent (entries 1, 3 and 4),
none or only trace amounts of desired product 3a was detected.
Using CuO gave only about 5% of 3a. Using solvents DCE,
2
toluene or DMF (entries 5, 6 and 8) with CuCl as the catalyst
afforded none or only trace amounts of 3a in acetonitrile
5
6
H
Et
Et
70
69
a
Table 1 Optimization of reaction conditions
Me
b
7
8
9
MeO
t-Bu
Et
64
84
80
Entry
Cat. (mol%)
CuBr (20)
CuO (20)
CuI (20)
CuBr (20)
Solvent
Reaction time
Yield (%)
1
2
3
4
5
6
7
8
2
—
—
—
—
DCE
Toluene
3
CH CN
DMF
—
—
18
18
18
18
18
18
18
18
18
18
10
18
Trace
5%
Trace
Trace
—
Trace
40
Trace
56
Et
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
—
2
2
2
2
2
2
2
(20)
(20)
(20)
(20)
(10)
(20)
(20)
c
9
1
1
1
0
1
2
70
50
52
MeO
i-Pr
d
—
—
a
Reaction conditions: benzaldehyde (3.5 equiv.), N-methyl-N-phenyl-
methacrylamide (1 equiv.), aqueous TBHP (70 wt% in water, 2.5
equiv.), copper catalyst (10 mol%, or 20 mol% of 2a); yield is based on
b
c
reactant 2a. Yield of isolated 3a. The reaction was run with
d
1
0 mol% catalyst CuCl
2
.
The reaction was run for 10 hours.
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Table 2 (Contd.)
radical adds to the double bond of the N-alkyl-N-phenyl-
acrylamide to give radical 4 which cyclizes to give product 3 via
intermediate 5.
In summary, we have developed a novel Cu-catalyzed
oxidative cascade coupling reaction between N-alkyl-N-phe-
nylacrylamides and aryl aldehydes using CuCl /TBHP as
2
catalyst and oxidant respectively. The reaction undergoes
oxidative cross coupling reactions of the activated alkenes
1
b
Entry
R
R
Product
Yield (%)
2
Csp –H of the N-alkyl-N-phenylacrylamides with aldehyde
2
Csp –H bonds, this is subsequently followed by metal-medi-
2
ated direct aryl Csp –H functionalization/cyclization process
to afford 3-(2-oxo-2-arylethyl)indolin-2-ones in good yields
under mild reaction conditions.
1
0
m-NO
2
Me
Trace
Acknowledgements
a
Reaction conditions: aldehyde (3.5 equiv.), N-alkyl-N-phenylacryl-amide
(
(
1 equiv.), aqueous TBHP (70 wt% in water, 2.5 equiv.), copper catalyst
20 mol% of 2a–i), yield calculation is based on reactant 2a–i. Yield
This investigation was generously supported by funds
b
(1281290006) provided by Jiangsu University.
of isolated 3a–i.
Notes and references
(
entry 7), the reaction produced a moderate 40% yield of 3a.
Using CuCl (10% mol) as the catalyst without solvent (entry 9)
gave 3a in 56% yield aer 18 h. Increasing the amount of CuCl
1
9
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one electron transfer from low valent copper species A to give
the tBuOc radical and the cOH radical, which coordinates to
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atom from the aldehyde 1 to generate the acyl radical. This
2
3
4
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(
2
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