Copper-catalyzed bis-arylations of alkenes leading to oxindole derivatives

Article abstract of DOI:10.1039/c4ob00576g

A simple and practical copper-catalyzed approach to oxindole derivatives by copper-catalyzed bis-arylation of N-alkyl-N-phenylacrylamides with diaryliodonium triflates has been developed under mild conditions, and the method is of tolerance towards some functional groups in the substrates. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00576g

Organic &
Biomolecular Chemistry
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Copper-catalyzed bis-arylations of alkenes leading
to oxindole derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 4070
Liangliang Shi, Yuyuan Wang, Haijun Yang and Hua Fu*
Received 17th March 2014,
Accepted 27th March 2014
DOI: 10.1039/c4ob00576g
www.rsc.org/obc
A simple and practical copper-catalyzed approach to oxindole great progress has been made in the transition metal-catalyzed
derivatives by copper-catalyzed bis-arylation of N-alkyl-N-phenyl- difunctionalization of alkenes,6 such as dioxygenation,7
acrylamides with diaryliodonium triflates has been developed aminooxygenation,8 diamination,9 aminohalogenation10 and
under mild conditions, and the method is of tolerance towards fluoroamination,11 and various interesting and useful oxindole
some functional groups in the substrates.
derivatives were constructed via the difunctionalization strat-
egy12 (very recently, Fu and co-workers reported the visible-
light-mediated diarylation of N-arylacrylamides with aryl diazo-
nium salts with a Ru(bpy)3 catalyst12o).
Oxindoles widely occur in natural products with unique bio-
logical activity, they are privileged scaffolds for the design and
discovery of drugs, and many of them exhibit potent biological
activities, such as anticancer, antibacterial, antifungal, anti-
viral and antiangiogenic properties.1 As shown in Fig. 1, the
cyclopropane-containing oxindole (A) is a potent HIV-1 non-
nucleoside reverse transcriptase inhibitor,2 and Sunitinib
(SU11248, B) is used as the orally active receptor tyrosine
kinase (RTK) inhibitor marketed by Pfizer as Sutent.3 The
3-amino-substituted oxindole AG-041R (C) exhibits a variety of
interesting biological properties including the induction of sys-
temic cartilage hyperplasia in rats,4 and the 3-hydroxy oxindole
SM-130686 (D) is a growth hormone secretagogue.5 Recently,
On the other hand, diaryliodonium salts have attracted
much attention as powerful electrophilic arylation
reagents,13,14 and they have been used in metal-catalyzed15
and metal-free arylation reactions.16 Recently, copper-catalyzed
organic reactions have attracted considerable attention
because of the low cost, low toxicity and high efficiency of
copper-catalysts,17,18 and some efficient copper-catalyzed
methods for the synthesis of heterocycles has been developed
by us19 and other groups.20 Herein, we report an easy copper-
catalyzed bis-arylation of alkenes leading to oxindole deriva-
tives via reactions of N-alkyl-N-phenylacrylamides with diaryl-
iodonium triflates.
Reaction conditions, including catalysts, ligands, solvents
and temperature were first investigated for the synthesis of
3-benzyl-1,3-dimethylindolin-2-one (3a) via the copper-cata-
lyzed reaction of N-methyl-N-phenylmethacrylamide (1a) with
diphenyliodonium triflate (2a). As shown in Table 1, six
ligands (20 mol% amount relative to 1a) were screened,
applying 10 mol% of CuI as the catalyst, and dichloroethane
(DCE) as the solvent at 100 °C under a nitrogen atmosphere
(Table 1, entries 1–6), and 2-(pyridin-2-yl)pyridine provided
the highest yield (Table 1, entry 1). It is worthwhile noting that
the reaction gave a similar yield to entry 1 (Table 1) in the
absence of ligand (Table 1, entry 7). Other copper salts were
attempted (Table 1, entries 8–13), and they afforded lower
yields than CuI. No target product was observed without the
addition of a copper catalyst (Table 1, entry 14). The effect of
solvents were investigated, and DCE was suitable (Table 1,
compare entries 7, 15–19). A lower reactivity was observed
when the temperature was changed (Table 1, compare entries
7, 20 and 21).
Fig. 1 Representative examples for pharmacologically active com-
pounds with the oxindole framework.
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua University, Beijing 100084,
P. R. China. E-mail: fuhua@mail.tsinghua.edu.cn; Fax: (+86) 10-62781695
†Electronic supplementary information (ESI) available: Full experimental
details, characterization and NMR spectra of the target products are provided.
See DOI: 10.1039/c4ob00576g
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Table 1 Investigation of the reaction conditions for the synthesis of
3-benzyl-1,3-dimethylindolin-2-one (3a) via the copper-catalyzed reac-
tion of N-methyl-N-phenylmethacrylamide (1a) and diphenyliodonium
triflate (2a)a
Table 2 Copper-catalyzed synthesis of oxindole derivativesa
2 (Time, Yieldb)
Entry
Cat.
Ligand
Solvent
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
Cu2O
CuSCN
Cu(OAc)2
Cu(OTf)2
—
CuI
CuI
CuI
CuI
L-1
L-2
L-3
L-4
L-5
L-6
—
—
—
—
—
—
—
—
—
—
—
—
—
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
Dioxane
MeCN
THF
DMSO
DCE
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
70
48
62
17
56
66
71
57
60
68
64
56
46
0
51
45
Trace
61
Trace
49
66
9
10
11
12
13
14
15
16
17
18
19
20
21
CuI
CuI
CuI
—
—
DCE
120
a Reaction
conditions:
N-methyl-N-phenylmethacrylamide
(1a)
(0.25 mmol), diphenyliodonium triflate (2a) (0.75 mmol), catalyst
(0.025 mmol), ligand (0.05 mmol), solvent (2.5 mL), temperature
(80–120 °C) under nitrogen atmosphere. Reaction time (24 h).
b Isolated yield.
a Reaction conditions: N-alkyl-N-phenylacrylamide (1) (0.25 mmol),
diaryliodonium triflate (2) (0.75 mmol), CuI (0.025 mmol), DCE
(2.5 mL), temperature (100 °C) under nitrogen atmosphere. Reaction
time (24–48 h). b Isolated yield.
The substrate scope of the copper-catalyzed bis-arylation of
N-alkyl-N-phenylacrylamides (1) was investigated under our
optimized conditions (using 10 mol% of CuI as the catalyst
and DCE as the solvent at 100 °C under a nitrogen atmos-
phere). As shown in Table 2, the tested substrates gave mode-
rate to good yields. For N-alkyl-N-phenylacrylamides (1), the
reactivity of the substrates decreased when the R1 substituents
were at the ortho-site of nitrogen on the phenyl (3l, 3m and 3t),
so a long time was required. The substrates containing elec-
tron-donating groups (R1) provided higher yields than those
with electron-withdrawing groups. When R2 was phenyl the
substrate displayed a higher reactivity (3h). However, the sub-
strate with phenyl for R3 afforded a low yield due to the steric
hindrance (see 3j). The reactivity decreased when R4 was ethyl
(3v and 3w), and a pair of diastereoisomers were observed by
1H NMR for the presence of a new chiral carbon during the
first arylation. For diaryliodonium triflates, the substrates con-
taining electron-withdrawing groups exhibited a lower reactive
activity than those with electron-donating groups. The bis-aryl-
ation above could tolerate some functional groups including
C–F bonds (3c, 3o and 3q), C–Cl bond (3d and 3r), C–Br bond
(3s and 3t), ether (3p and 3w), N-heterocycle (3u) and amide
(3a–w) in the substrates.
A possible mechanism for the synthesis of oxindole deriva-
tives is proposed as shown in Scheme 1, according to the
results above and the literature.6d,12p First, treatment of diaryl-
iodonium triflate (2) with Cu(I) salt gives Cu(III) complex (II)
leaving ArI (I), then arylation of the alkenyl in 1 with II yields
intermediate III, and intramolecular arylation of III provides
IV. Finally, desorption of CuI and HOTf from IV affords the
target product (3).
In summary, we have developed a simple and efficient
copper-catalyzed method for the synthesis of oxindole deriva-
tives. The protocol uses inexpensive CuI as the catalyst, readily
available N-alkyl-N-phenylacrylamides and diaryliodonium tri-
flates as the starting materials, and the bis-arylations of
N-alkyl-N-phenylacrylamides were performed well under mild
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The authors wish to thank the National Natural Science
Foundation of China (grant no. 21172128, 21372139 and
21221062), and the Ministry of Science and Technology of
China (grant no. 2012CB722605) for financial support.
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