Copper-catalyzed oxidative electrophilic carbofunctionalization of acrylamides for the synthesis of oxindoles

Article abstract of DOI:10.1055/s-0034-1378354

A novel and efficient copper-catalyzed tandem oxidative cyclization of arylacrylamides with diaryliodonium salts is reported. This reaction provides a novel approach for the synthesis of oxindoles and various functional groups were well tolerated.

Full text of DOI:10.1055/s-0034-1378354

LETTER
▌2009
lCettoerpper-Catalyzed Oxidative Electrophilic Carbofunctionalization of Acryl-
amides for the Synthesis of Oxindoles
Copper-Catalyzed Tandem Oxidative Cyclization of Arylacrylamides
Xueqin Li,a Jian Xu,a Pengbo Zhang,a Yuzhen Gao,a Ju Wu,a Guo Tang,*a Yufen Zhaoa,b
a
Department of Chemistry, College of Chemistry and Chemical Engineering, and the Key Laboratory for Chemical Biology of Fujian Province,
Xiamen University, Xiamen, Fujian 361005, P. R. of China
Fax +86(592)2185780; E-mail: t12g21@xmu.edu.cn
b
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua
University, Beijing 100084, P. R. of China
Received: 05.04.2014; Accepted after revision: 27.05.2014
Abstract: A novel and efficient copper-catalyzed tandem oxidative
Table 1 Optimization of Reaction Conditionsa
cyclization of arylacrylamides with diaryliodonium salts is report-
ed. This reaction provides a novel approach for the synthesis of ox-
indoles and various functional groups were well tolerated.
N
O
Key words: copper-catalyzed, acrylamides, diphenyliodonium
triflate, oxindoles, electrophilic arylation
Me
catalyst
1a
DTBP (1.2 equiv)
+
solvent, T, N2, 24 h
N
O
–OTf
The synthesis of oxindoles has attracted much interest not
only because of their significant biological activities1 but
also because they are important intermediates in the syn-
thesis of heterocyclic compounds.2 Thus, the development
of new methods for their synthesis has been a major focus
of study.3 Among them, difunctionalization reaction of
alkenes through a radical process provided an appealing
approach for the synthesis of functional oxindoles. To
date, various radicals such as aryl, CF3 and NO2 have been
successfully introduced into the oxindoles skeleton.4
I+
Me
3a
2a
Entry
Catalyst
Solvent
T (°C)
Yield (%)b
1c
2
CuI
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DCE
70
70
70
70
70
70
70
70
70
70
70
70
70
60
60
60
32
60
62
72
35
56
70
Trace
82
65
55
23
34
82
81
0
CuI
3
CuCl2
CuCl
CuBr
Cu(OAc)2
Cu(OTf)2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
–
On the other hand, diaryliodonium salts have emerged as
powerful electrophilic arylation reagents in metal-cata-
lyzed or metal-free cross-coupling reactions.5 Since the
seminal work of Gaunt,6 the combined use of copper and
diaryliodonium salts to form a Cu(III)-aryl intermediate
has been extensively studied.7 Various heterocyclic com-
pounds such as oxazine8 and quinazoline9 have been suc-
cessfully built by using diaryliodonium salts as coupling
partner.
4
5
6
7
8
9
CH2Cl2
Inspired by the above works and in connection with radi-
cal-mediated cyclizations of arylacrylamides, we envi-
10
11
12
13
14
15d
16
toluene
THF
MeCN
Cu(I)
DMF
Ph-Cu(III)
Ph+
Ph2IOTf
Ar
CH2Cl2
+
Ph
Ph
cat.
CH2Cl2
Ar
Ar
N
R
O
N
R
O
N
R
O
CH2Cl2
a Reaction conditions: catalyst (0.06 mmol), 1a (0.30 mmol), 2a (0.36
mmol), under N2 in a Schlenk tube with screw caps, 24 h, oil-bath
temperature.
Scheme 1 Strategy for the synthesis of oxindoles
b Isolated yield.
SYNLETT 2014, 25, 2009–2012
Advanced online publication: 28.07.2014
c The reaction was performed without DTBP.
d The amount of CuCl used was 0.045 mmol.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378354; Art ID: st-2014-w0287-l
© Georg Thieme Verlag Stuttgart · New York

2010
X. Li et al.
LETTER
sioned that diaryliodonium salts might react with N-aryl- introduced as a base, 3a was obtanied in 60% yield (entry
acrylamides to form the oxindole (Scheme 1).
2). Screening of a few other copper salts, such as CuCl2,
CuCl, CuBr, Cu(OAc)2 and Cu(OTf)2 revealed that CuCl
was the best choice and the yield could reach 72% (Table
1, entries 2–7). The solvents were crucial for this transfor-
mation. Among the solvents screened, CH2Cl2 was opti-
mal, providing 3a in 82% yield (entry 9).
Initially, we examined the reaction of arylacrylamide 1a
with diphenyliodonium triflate (2a) in the presence of CuI
in dioxane at 70 °C under N2. To our delight the desired
product 3a was obtained in 32% yield (Table 1, entry 1).
2,6-Di-tert-butylpyridine (DTBP) has often been used as
a base in this type reaction. When DTBP (1.2 equiv) was
–OTf
I+
CuCl (0.15 equiv)
DTBP (1.2 equiv)
+
N
R1
1
O
R2
R4
CH2Cl2, 60 °C, 24 h
R3
N
R1
O
R3
R2
2
3
2a: R3 = H, R4 = H
2b: R3 = 4-Me, R4 = 2,4,6-Me3
2c: R3 = 4-Cl, R4 = 2,4,6-Me3
2d: R3 = 4-F, R4 = 2,4,6-Me3
MeO
N
O
N
O
N
O
Me
Me
Me
3a, 81%
3b, 86%
3c, 72%
F
Cl
Br
N
O
N
O
N
O
Me
Me
Me
3d, 85%
3e, 86%
3f, 72%
O2N
N
O
N
O
N
O
Me
Me
I
Me
3g, 62%
3h, 42%
3i, 46%
N
O
N
O
N
O
O
Me
Me
Me
3j
3j:3j' = 1:1, 71%
3j'
3k, 75%
Ph
N
O
N
N
O
Ph
3l, 82%
Ph
Bn
Me
3n, 59%
3m, 75%
N
O
Cl
N
O
Cl
N
O
Me
3o, 57%
Me
3p, 55%
Me
3q, 83%
Ph
N
H
O
N
O
F
N
O
Me
3r, 50%
Me
3t, 0%
3s, 0%
Scheme 2 Synthesis of oxindoles from acrylamides and iodonium salts
Synlett 2014, 25, 2009–2012
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper-Catalyzed Tandem Oxidative Cyclization of Arylacrylamides
2011
Other solvents such as toluene, THF, DMF, provided indole derivatives.10 A broad scope of N-arylacrylamides
moderate to low yields, whereas DCE gave a only trace and diphenyliodonium salt coupling partners has been de-
amount of 3a (Table 1, entries 4 and 8–13). NaHCO3 was fined. The studies of the reactions of diaryliodonium salts
an efficient base in Zhou’s report.5b In our system, some with other coupling partners are currently in progress.
inorganic bases such as Na2CO3 and NaHCO3 gave 20%
and 30% yields, respectively. When the reaction tempera-
ture was lowered to 60 °C (Table 1, entry 14) or the load-
Acknowledgment
We acknowledge financial support from the Chinese National Na-
tural Science Foundation (21173178, 21232005, 21375113), the
National Basic Research Program of China (2012CB821600), and
the Program for Changjiang Scholars and Innovative Research
Team in University.
ing of CuCl was reduced to 15 mol% (Table 1, entry 15),
the yield remained almost the same. The reaction did not
occur at all in the absence of a copper salt (Table 1, entry
16). Thus, the optimized reaction conditions for this cop-
per-catalyzed coupling reaction was: 1a (0.5 mmol), 2a
(0.6 mmol), CuCl (15 mol%), in CH2Cl2 at 60 °C under N2
for 24 hours.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
Subsequently, we evaluated the scope of substituted aryl-
acrylamides 1 with diphenyliodonium salt 2a and the re-
sults are summarized in Scheme 2. In general, a variety of
functional groups on the phenyl ring of arylacrylamides
were compatible under this procedure, affording the de-
sired products in moderate to good yields. The substituted
arylacrylamides with electron-donating groups, such as
methoxy and methyl reacted with diphenyliodonium salt
2a efficiently and gave the desired products 3b, 3c in 86%
and 72% yields, respectively. Halo-substituted acryl-
amides worked well to afford the corresponding products
in good yields (3d–3f), which could allow for further syn-
thetic transformations. The ortho-substituted arylacryl-
amides exhibited a particularly distinct steric hindrance
effect, and the corresponding oxindoles 3h, 3i were ob-
tained in low yields. As expected, when the meta-substi-
tuted arylacrylamides were used as the substrate, a
mixture of the products 3j and 3j′ were obtained in 71%
yield with poor regioselectivity (1:1). More bulky sub-
strates such as naphthalene acrylamide also efficiently re-
acted with 2a and gave the product 3k in 75% yield.
Different N-protection groups such as phenyl and benzyl
were tolerated, leading to the corresponding products in
good yields (3l, 3m). 2-Benzyl-N-methyl-N-phenylacryl-
amide also exhibited a distinct steric hindrance effect to
afford 3n in 59% yield. Unfortunately, unprotected N–H
acrylamide did not yield the product under the reaction
condition, giving small amount of N-arylation by-prod-
ucts. When N-methyl-N-phenylcinnamamide was used,
the desired six-membered ring 3t was not obtained.
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
References and Notes
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cal diaryliodonium salts. Observations suggested that
more bulky aryl groups did not transfer into the products.5j
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triflate (2b) was used, steric control resulted in substitu-
tion of the less hindered 4-methylphenyl ring as the only
product 3q in 83% yield. The less hindered phenyl ring
with electron-withdrawing 4-chloro- (2c) and 4-fluoro-
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proach for the assembly of the biologically important ox-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2009–2012

2012
X. Li et al.
LETTER
(d) Kang, S. K.; Yoon, S. K.; Kim, Y. M. Org. Lett. 2001, 3,
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(10) Typical Procedure: An oven-dried 10-mL Schlenk tube
containing CuCl (4.5 mg, 15 mol%), N-arylacrylamide 1a
(90.3 mg, 0.3 mmol), and diphenyliodonium triflate (2a;
154.8 mg, 0.36 mmol) was evacuated and purged with
nitrogen three times. DTBP (68.8 mg, 0.36 mmol) in freshly
distilled CH2Cl2 (2.0 mL) was added to the system at r.t. The
reaction mixture was heated with stirring at 60 °C for 24 h.
The reaction mixture was allowed to cool to ambient
temperature, and then transferred to a round-bottom flask.
Silica gel (3.0 g) was added, and the solvent was removed
under reduced pressure to afford a free-flowing powder. This
powder was then dry-loaded onto a silica gel column and
purified by flash chromatography using petroleum ether–
EtOAc (20:1) as the eluent to give the product 3a. Yield: 75
mg (81%). MS (ESI): m/z = 274.0 [M + Na]+. 1H NMR (400
MHz, CDCl3): δ = 7.03–7.18 (m, 6 H), 6.83–6.85 (m, 2 H),
6.62 (d, J = 7.7 Hz, 1 H), 3.12 (d, J = 13.0 Hz, 1 H), 3.01 (d,
J = 13.0 Hz, 1 H), 2.98 (s, 3 H), 1.47 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 179.9, 142.9, 136.0, 132.9, 129.7, 127.6,
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Synlett 2014, 25, 2009–2012
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