Synthesis of oxindole-3-acetates through iron-catalyzed oxidative arylalkoxycarbonylation of activated alkenes

Article abstract of DOI:10.1016/j.tet.2014.03.062

An iron-catalyzed alkoxycarbonylation/cyclization reaction of N-arylacrylamides with carbazates has been developed. This new alkene difunctionalization reaction provides an efficient and straightforward method to obtain various ester-containing oxindoles.

Full text of DOI:10.1016/j.tet.2014.03.062

Tetrahedron 70 (2014) 3466e3470
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of oxindole-3-acetates through iron-catalyzed oxidative
arylalkoxycarbonylation of activated alkenes
*
*
Gao Wang, Shan Wang, Jian Wang, Shan-Yong Chen , Xiao-Qi Yu
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An iron-catalyzed alkoxycarbonylation/cyclization reaction of N-arylacrylamides with carbazates has
been developed. This new alkene difunctionalization reaction provides an efficient and straightforward
method to obtain various ester-containing oxindoles.
Received 21 January 2014
Received in revised form 10 March 2014
Accepted 19 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Available online 29 March 2014
Keywords:
Carbazates
Alkene difunctionalization
Alkoxycarbonylation/cyclization
The direct difunctionalization of alkenes has become an at-
tractive strategy for the assembly of functionalized organic com-
pounds. A number of difunctionalization reactions for alkenes have
been developed, such as arylalkylation,1 carboamination,2 diami-
nation3 and dioxygenation.4 However, examples of alkox-
ycarbonylative alkene difunctionalization reactions are rare.
Carboxylic esters are valuable commodity chemicals and useful
synthetic building blocks.5 The addition of alkoxycarbonyl radicals
to multiple bonds is an efficient way to prepare esters. However, the
generation of an alkoxycarbonyl radical often requires the use of
toxic reagents and special equipment.6 Using carbazates as the
precursors of alkoxycarbonyl radicals, Taniguchi et al. found that
alkoxycarbonyl groups could be easily introduced into a-methyl-
styrenes under mild conditions (Scheme 1, equation a).7 These
readily available and environmentally friendly materials make
alkoxycarbonyl radicals a useful tool for alkoxycarbonylation re-
Scheme 1. The introduction of an alkoxycarbonyl group into alkenes.
actions.8 Very recent progress on the difunctionalization of N-ary-
lacrylamides1,9 prompted us to envision the addition of an
alkoxycarbonyl radical to N-phenylacrylamide to generate a new
radical that would be trapped by the benzene ring, thus providing
* Corresponding authors. Tel./fax: þ86 28 85415886; e-mail addresses: chensy@
scu.edu.cn (S.-Y. Chen), xqyu@scu.edu.cn (X.-Q. Yu).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.062

G. Wang et al. / Tetrahedron 70 (2014) 3466e3470
3467
oxindole-3-acetates (Scheme 1, equation b).10 Oxindole-3-acetates
have shown important biological activities and are versatile start-
ing materials for the synthesis of a broad range of polycyclic com-
pounds. For example, the substitution of oxindole-3-acetates can
easily produce the acetylcholinesterase inhibitor, (ꢀ)-physovenine
(Scheme 2).11
sensitive to air or a small amount of water and that ethyl acetate
was the best solvent.
With the optimal reaction conditions in hand, we examined the
reaction of 1a with various carbazates (Table 2). The reactions of
methyl, ethyl and propyl carbazates with 1a gave the corresponding
products 3aec in good yields (entries 1e3). Phenyl carbazates were
Scheme 2. The utilization of oxindole-3-acetate derivatives.
We initiated our study on the reaction of N-methyl-N-phenyl-
methacrylamide (1a) with methyl carbazate (2a) in ethyl acetate at
80 ꢁC to optimise the conditions (Table 1). In the presence of FeCl3
and TBHP (tert-butyl hydroperoxide 70 wt % in water), the desired
product, methyl 1,3-dimethyl-oxindole-3-acetate (3a), was isolated
in low yield (entry 3). Subsequently, we were delighted to discover
that the addition of 2a over 30 min could significantly increase the
yield (entry 4 vs entry 3). After screening other catalysts, we found
that n-Bu4NI or Co(OAc)2$4H2O were less effective, whereas
FeCl2$4H2O was as effective as FeCl3. Due to the ease of its handling,
FeCl2$4H2O was chosen as the catalyst (entries 5e7). Only a trace
amount of the product was detected in the absence of a catalyst
(entry 2). K2S2O8 is an alternative oxidant; other oxidants are not
suitable for this transformation (entries 8e12). We discovered that
ligands could remarkably influence the yields of this trans-
formation. Among the tested ligands, 4-cyanopyridine was the best
choice, providing the product in 80% yield (entry 20 vs entries
13e19).12 The influence of air, water and solvents was also in-
vestigated. The results demonstrated that this reaction was not
also good substrates (entry 4). It should be noted that trace amounts
of alkylarylation products 4 were often observed. In particular,
when tert-butyl carbazate was subjected to this reaction, no product
3 was observed. Instead, 10% of alkylarylation product 4a was iso-
lated (entry 5). This result shows that the tert-butyloxycarbonyl
radical readily undergoes decarboxylation to produce alkyl
radicals.13
Next, the scope of N-arylacrylamides was investigated, as shown
in Table 3. First, the effects of substituents on the benzene ring were
studied. N-Arylacrylamides bearing an electron-withdrawing or
electron-donating group at the para-position of the benzene ring
always afforded the desired products in good to excellent yields
(3ee3m). Notably, halides, esters, nitro and cyano groups were
tolerated and furnished the corresponding products. N-Arylacry-
lamides bearing meta-substituents showed good reactivity but
poor regioselectivity (3n). An ortho-substituent had a negative in-
fluence on this transformation. For example, ortho-fluoro-N-phe-
nylacrylamide and ortho-phenyl-N-phenylacrylamide provided
products 3o and 3p in 40% and 43% yield, respectively. The effects of
Table 1
Optimisation of reaction conditionsa
Entry
Catalyst
Oxidant
Ligand
Yield (%)
1
2
3
4
5
6
7
8
FeCl3
d
d
d
0
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
O2
H2O2
PhI(OAc)2
K2S2O8
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
d
Trace
10b
45
32
17
45
0
0
Trace
Trace
35
56
40
Trace
65
Trace
68
40
80
FeCl3
FeCl3
n-Bu4NI
d
d
d
Co(OAc)2$4H2O
FeCl2$4H2O
FeCl2$4H2O
FeCl2$4H2O
FeCl2$4H2O
FeCl2$4H2O
FeCl2$4H2O
FeCl2$4H2O
FeCl2$4H2O
FeCl2$4H2O
FeCl2$4H2O
Fe(pc)
d
d
d
9
d
10
11
12
13
14
15
16
17
18
19
20
d
d
d
18-Crown-6
Cyclen
TMEDA
Pyridine
d
FeCl2$4H2O
FeCl2$4H2O
FeCl2$4H2O
Phen
2,20-Bipyridine
4-Cyanopyridine
a
Reaction conditions: 1a (0.2 mmol), catalyst (10 mol %), ligand (20 mol %), oxidant (1.0 mmol) in ethyl acetate (2 mL). After stirring well at 80 ꢁC, 2a (0.8 mmol) was added
in portions over 20 min, and the reaction was exposed to air for 4 h at the same temperature.
b
2a was fed in one batch before the reaction. Cyclen¼1,4,7,10-tetraazacyclododecane, TMEDA¼tetramethylethyl-enediamine, phen¼1,10-phenanthroline.

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G. Wang et al. / Tetrahedron 70 (2014) 3466e3470
Table 2
Scope of carbazates estera
Entry
R
Product/yield (%)
3
4
1
2
3
4
5
6
Me
Et
n-Pr
Ph
t-Bu
Bn
(3a)80
(3b)76
(3c)66
(3d)62
0
Trace
Trace
Trace
0
(4a)10
Trace
0
a
Reaction conditions: 1a (0.2 mmol), FeCl2$4H2O (10 mol %), 4-cyanopyridine (20 mol %), TBHP (1.0 mmol) in ethyl acetate (2 mL). After stirring well at 80 ꢁC, 2 (0.8 mmol)
was added in portions, and the reaction was exposed to air for 4 h at the same temperature.
Table 3
The scope of N-arylacrylamidesa
3a 80%
3h 72%
3l 58%
3e 66%
3i 73%
3f 82%
3j 61%
3g 78%
3k 66%
3m 54%
3n + 3n’ 65% (3:2)
3r 55%
3v 0%
3o 40%
3p 43%
3t 0%
3q 53%
3u 60%
3y 90%
3s 48%
3w 0%
3x 77%
a Reaction conditions: 1 (0.2 mmol), FeCl2 ·4H2O (10 mol %), 4-cyanopyridine (20 mol %), TBHP
(1.0 mmol) in ethyl acetate (2 mL). After stirring well at 80 °C, 2a (0.8 mmol) was added in portions,
and the reaction was exposed to the air for 4 h at the same temperature.

G. Wang et al. / Tetrahedron 70 (2014) 3466e3470
3469
substituents on nitrogen were then investigated. Alkylated N-
phenylacrylamides gave the corresponding product in moderate to
good yields (3qe3s). However, N-phenylacrylamides with a free
NeH did not undergo this transformation (3t). Finally, substrates
with various alkenes were examined. N-Arylacrylamides without
a substituent at the alkene did not produce the desired product
(3v). Substrates with an acetoxymethyl or Phth-protected amino-
methyl group generated the corresponding products in excellent
yields (3x and 3y); this tolerance would be useful for the con-
struction of complicated compounds with multiple functional
groups. In contrast, a substrate with a free hydroxymethyl did not
give the product (3w), which may be a result of its instability under
oxidative conditions.
To elucidate the mechanism, this reaction was conducted in
the presence of a radical inhibitor (Scheme 3, a). In the pres-
ence of 5 equiv of TEMPO, this reaction did not afford oxin-
doles, but gave trapped product 5, suggesting that an
alkoxycarbonyl radical was generated in this reaction. An in-
termolecular kinetic isotope experiment was also performed
(Scheme 3, b). No kinetic isotope effect (kH/kD¼1.0) was ob-
served, demonstrating that the cleavage of the aromatic CeH
bond was not the rate-limiting step. Simultaneously, controlled
experiments support that Fe (III) directly oxidizes and disinte-
grates carbazates to give alkoxycarbonyl radicals. Meanwhile,
TBHP can oxidize Fe (II) to Fe (III) and make cycle smoothly
proceed (Scheme 3, c and d).
In terms of these experimental results and the previous reports,
a plausible mechanism for this reaction is shown in Scheme 4.
Carbazate 2 is oxidised to diazene A, which further undergoes
oxidisation to give radical intermediate B. The release of molecular
nitrogen from B gives alkoxycarbonyl radical C, which adds to the
carbonecarbon double bond of N-arylacrylamide to produce radi-
cal intermediate D. Alkoxycarbonyl radical C may undergo de-
carboxylation to produce an alkyl radical. The intramolecular
cyclization of intermediate D with its aryl ring generates radical
intermediate E. Finally, the radical E gives an electron to TBHP and
then loses a proton to product 3 via a proton-coupled electron
transfer (PCET) process.
In summary, we have developed a new arylalkoxycarbonylation
of alkenes in which an alkoxycarbonyl radical attacks carbon-
ecarbon bonds in N-arylacrylamide, which is followed by intra-
molecular cyclization of the generated intermediates with the aryl
rings. This reaction affords various oxindole-3-acetates in good
yields from simple substrates. Asymmetric arylalkoxycarbonylation
Scheme 3. Control experiments.
Scheme 4. Plausible reaction mechanism.

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G. Wang et al. / Tetrahedron 70 (2014) 3466e3470
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This work was supported financially by the National Program on
Key Basic Research Project of China (973 Program, 2013CB328900)
and the National Natural Science Foundation of China (Grant No.
21202107, 21321061, J1310008 and J1103315); we also thank the
Analytical & Testing Center at Sichuan University for performing
NMR analyses.
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