Synthesis of oxindoles via Cu-mediated reactions between N-phenylacrylamides and ethyl 2-bromo-2-methylpropionate

Article abstract of DOI:10.1016/j.tetlet.2017.12.053

A novel way of synthesizing alkylated oxindoles via Cu-mediated atom transfer radical addition reaction between N-phenylacrylamides and ethyl 2-bromo-2-methylpropionate has been described. It was found that the use of N,N,N′,N′-1,1,2,2,-tetramethylethylenediamine as ligand was important for achieving good yields. Additionally, the use of DMSO as solvent and running the reaction at 130 °C were also crucial. In some cases, the product can be further brominated when the reaction temperature was raised to 150 °C.

Full text of DOI:10.1016/j.tetlet.2017.12.053

Accepted Manuscript
Synthesis of Oxindoles via Cu-Mediated Reactions between N-Phenylacryla-
mides and Ethyl 2-Bromo-2-methylpropionate
Da Liu, Shaobo Zhuang, Xiang Chen, Liu Yu, Yongqi Yu, Liang Hu, Ze Tan
PII:
S0040-4039(17)31559-9
https://doi.org/10.1016/j.tetlet.2017.12.053
TETL 49555
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 October 2017
7 December 2017
16 December 2017
Please cite this article as: Liu, D., Zhuang, S., Chen, X., Yu, L., Yu, Y., Hu, L., Tan, Z., Synthesis of Oxindoles via
Cu-Mediated Reactions between N-Phenylacrylamides and Ethyl 2-Bromo-2-methylpropionate, Tetrahedron
Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.12.053
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Synthesis of Oxindoles via Cu-Mediated
Reactions between N-Phenylacrylamides and
Ethyl 2-Bromo-2-methylpropionate
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Da Liu, Shaobo Zhuang, Xiang Chen, Lin Yu, Yongqi Yu, Liang Hu and Ze Tan*

1
Tetrahedron Letters
Synthesis of Oxindoles via Cu-Mediated Reactions between N-Phenylacrylamides
and Ethyl 2-Bromo-2-methylpropionate
Da Liua , Shaobo Zhuanga , Xiang Chena , Liu Yua , Yongqi Yua , Liang Hua and Ze Tana 
a State Key Laboratory of Chemo/Biosensing and Chemometrics College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R.
China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel way of synthesizing alkylated oxindoles via Cu-mediated atom transfer radical addition
reaction between N-phenylacrylamides and ethyl 2-bromo-2-methylpropionate has been
described. It was found that the use of N, N, N’, N’-1,1,2,2,-tetramethylethylenediamine as
ligand was important for achieving good yields. Additionally, the use of DMSO as solvent and
running the reaction at 130 oC were also crucial. In some cases, the product can be further
Available online
o
brominated when the reaction temperature was raised to 150 C.
Keywords:
Cu-mediated
2009 Elsevier Ltd. All rights reserved.
Oxindole
Atom-transfer radical addition
Cyclization
N-phenylacrylamide
Introduction
reported the oxidative benzylation-cyclization of N-
arylacrylamides to form alkyl-substituted oxindoles through
tandem radical addition/cyclization reaction.7 Van der Eycken
group described an efficient synthesis of oxindoles via
microwave-assisted Cu-catalyzed oxidative addition of non-
activated ketones with acrylamides.8 Very recently, metal-free
radical acetylation,9a,9b sulfonylation,9c arylsulfenylation,9d
azidolation,9e hydroxylalkylation9f and trifluoromethylation9g,9h of
N-arylacrylamides were also reported to deliver various
functionalized oxindoles. We also reported an efficient synthesis
of trifluoromethyl containing oxindoles from N-arylacrylamides
and Langlois reagent with Ag-catalysis.10a A similar strategy was
adopted by Xu and Wang for the synthesis of difluoro-
subsitituted oxindoles.10b
Oxindoles are important heterocyclic scaffolds found in a
wide range of bioactive natural products and pharmaceutical
molecules.1 As such, the synthesis of oxindoles has always
attracted considerable attention from synthetic chemists and
extensive research effort has been devoted to the development of
new methods for a convenient access to oxindoles. Among the
reported
synthetic
strategies,
Pd-catalyzed
oxidative
difunctionalization of alkenes in ortho-nonfunctionalized N-
arylacrylamides via C-H bond cleavage is one of the most
investigated synthetic routes.2 Even though these methods do
provide convenient access to various oxindoles starting from a
relative simple starting material, however, the use of an
expensive noble metal has severely limited the practicality of
these methods. Consequently chemists are seeking alternative
methods relying on the functionalization-cyclization of N-
arylacrylamides using cheap and environmentally benign
catalysts.3-7 For example, Yang group recently disclosed a silver-
catalyzed direct phosphorylation-cyclization and azidolation-
cyclization of N-arylacrylamides to deliver the corresponding
phosphorylated and azidolated oxindoles.4 Li and co-workers
have reported a Fe-catalyzed oxidative alkylation-cyclization of
N-arylacrylamides to provide various alkylated oxindoles.5 Duan
et al. developed a silver-catalyzed decarboxylative acylation of
N-arylacrylamides with -oxocarboxylic acids to yield various
acylated oxindoles.6 Later on, Li and Duan independently
Recently Cu-catalyzed or mediated atom-transfer radical
addition have emerged as a powerful method for the addition of
alkyl C-X bonds across C-C double bonds and triple bonds.11-12
For example, Nishikata recently demonstrated that with Cu-
catalyst, 2-bromo-2-methylpropionate and styrene derivatives can
undergo addition and elimination process to generate a Heck-
coupling type product (Eq. 1).11e,11f Lei, on the other hand, has
showed that similar reaction can be effected between styrenes
and benzyl bromides under Cu-catalysis.11g In contrast, the
reaction of alkynes with -bromo-carbonyl compounds under
Cu-catalysis gives the addition product, as demonstrated by Hu
and Zhu independently (Eq. 2).13,14 Inspired by these results, we
wonder whether Cu-catalyzed or mediated atom-transfer radical
addition strategy can be applied to the synthesis of oxindoles.
———
 Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron Letters
Herein we report that oxindoles can indeed be efficiently
ligand had a significant influence on the reaction outcome. While
the triamine ligand L2 and diamine ligand L3 both gave much
better yields, the use of Et3N or bipyridine as ligand resulted in
either complete failure or much lower yield (Table 1, entries 6-9).
In the end, L3 was found to be the most suitable choice, giving
3a in 70% yield (Table 1, entry 7). Subsequent study showed that
the reaction proceeded most efficiently in DMSO, whereas using
DMF, 1,2-dichloroethane or MeCN as the solvent reduced the
yield (Table 1, entries 10-13). Notably, the formation of 3a was
not observed when the nitrogen atmosphere was substituted with
oxygen atmosphere (Table 1, Entry 14). In addition, the yield
decreased from 72% to 48% when reaction temperature was
synthesized from 2-bromo-2-methylpropionate and N-
arylacrylamides with the assistance of CuBr (Eq. 3).
o
o
reduced from 130 C to 120 C (Table 1, Entry 15). Further
decreasing the temperature slowed down the reaction
considerably. Additionally, when the reaction was raised to 140
oC, we observed the formation of a side product 4a. Interestingly,
when we raised the temperature to 150 oC, the reaction of 1a with
2 gave 4a as the major product. On the basis of these results, we
decided to set reacting 1a with 3 equiv of 2 in the presence of 1
o
equiv of CuBr and 0.5 equiv of L3 in DMSO at 130 C for 18 h
Scheme 1. Cu-catalyzed or mediated atom-transfer radical addition
Results and Discussion
as our standard conditions.
Table 2. Scope of N-phenylmethacrylamidesa
Table 1. Reaction condition optimizationa
aReaction conditions: under a nitrogen atmosphere, 1a (0.3 mmol), ethyl 2-
bromo-2-methylpropanoate(0.9 mmol), [Cu] (0.3 mmol), Ligand(0.15mmol),
c
solvent (2 mL) at 130 oC for 18 h. bIsolated yield. Reaction run under O2.
d120 oC. eReaction run for12 h.
Our initial studies focused on the reaction of N-methyl-N-
phenylmethacrylamide
(1a)
and
ethyl
2-bromo-2-
methylpropionate (2) since 2 has been shown to be an excellent
substrate in Cu-catalyzed atom-transfer radical addition. Indeed,
when 1a was treated with 3 equiv of 2 in the presence of 1 equiv
of CuBr and 50 mol % of 1,10-phenanthroline (L1) in toluene at
130 °C for 18 h, the desired addition and cyclization product 3a
was isolated in 54% yield (Table 1, Entry 1). It should be pointed
out Li also reported the synthesis of 3a from 1a and 2 with Pd-
catalysis.2g Unfortunately, running the reaction with a catalytic
amount of CuBr led to incomplete conversion. When CuBr was
replaced with either CuI or CuCl, no improvement on the product
yield was observed (Table 1, Entry 2 and 3). In contrast, the use
of CuCl2 and CuBr2 were found to be completely ineffective
(Table 1, Entry 4 and 5). Moreover, studies showed that the
aReaction conditions: under a nitrogen atmosphere, 1 (0.3 mmol), 2 (0.9
o
mmol), CuBr (0.3 mmol), L3 (0.15 mmol), DMSO (2 mL) at 130 C for 18 h.
bIsolated yield.
With the optimized condition in hand, we next set out to
examine the scope of this reaction and the results were
summarized in Table 2. Under the standard conditions, a variety
of diversely substituted oxindoles were efficiently synthesized
from the corresponding N-phenylacrylamides in 43-76% yield.
Both electron-rich and electron-poor substituents were well
tolerated on the phenyl ring of the N-phenylmethacrylamides. For
example, anilides bearing electron-donating groups such as Me,

3
Et and MeO group at the para-position of the amide reacted
smoothly to generate the expected oxindole 3c, 3d and 3e in
75%, 68% and 76% yield, respectively. We were delighted to see
substrates bearing halogen substituents including F, Cl, Br, and I
worked satisfactorily to afford the desired products in yields
ranging from 43-68% (Table 2, entry 3f-3j). It is worthwhile to
point out these examples with iodo, bromo and chloro
substituents are important (3h, 3i) because these halogens could
be used for further transformation under transition metal
catalysis. We also found that substrate bearing a strong electron-
withdrawing group such as nitro group is not compatible with the
domino sequence, showing electron density on the phenyl ring is
important for the cyclization to proceed. Furthermore, it was
found that ortho-substituted substrates could participate in the
transformation as well, but the yields are slightly lower,
indicating the transformation was slight sensitive towards steric
hindrance. Unfortunately, if the R2 group on the nitrogen atom of
the amide bond was hydrogen or Ac, the desired reaction did not
take place. Test revealed that only N-alkyl substituted substrates
are viable substrates for this reaction.
of radical scavenger TEMPO, no reaction took place (Eq. 6).
This result suggested that the reaction is likely to involve a
radical process. When 3a was treated with 1 equiv of CuBr2 (It is
well known that CuBr2 is formed when CuBr is treated with ethyl
2-bromo-2-methylpropionate) in the presence of 0.5 equiv of L3
in DMSO at 150 oC for 12 h, 4a was obtained in 47% yield even
though complete conversion of 3a was not reached (Eq. 7). This
result confirmed that the formation of 4a was indeed formed
from 3a and CuBr2 (see Scheme 3 for mechanistic discussion).
Table 3. Scope of brominated Oxindolesa
Scheme 2 Control reactions
Based on these results and literature precedents,3-14 a tentative
reaction was proposed and depicted in Scheme 3. The reaction is
initiated by the reaction of ethyl 2-bromo-2-methylpropionate
with CuBr to give a radical intermediate A and Cu(I)Br is
oxidized to CuBr2. Next intermediate A will add to the double
bond of 1a to give the adduct B. After undergoing intramolecular
cyclization, B will be transformed into intermediate C which
subsequently is oxidized by the Cu(II) salt and rearomatized to
give the final product 3a.
aReaction conditions: under a nitrogen atmosphere, 1 (0.3 mmol), 2 (0.9
o
mmol), CuBr(0.3 mmol), L3 (0.15 mmol), DMSO (2 mL) at 150 C for 18 h.
bIsolated yield.
Since 4a became the major product when the temperature was
o
raised to 150 C, we next tried to see what happens with other
substrates under higher temperature. Even though most substrates
gave very messy results, we were able to isolate the brominated
product 4b-4e in reasonable yields. It should be noted that in
these reactions 3 bonds are formed in a single operation. Next we
attempted to extend our reaction with ethyl 2-bromo-2-
methylpropionate analogues such as ethyl 2-bromo-2-
difluoroacetate and ethyl 2-bromopropionate. Even though the
cyclizations did take place as expected, the reactions either gave
a mixture of 3q and 4q or the brominated product 4r was
generated as the major product in rather low yield (Eq. 4 and 5).
Scheme 3 A possible mechanism
Conclusions
In summary, a novel way of synthesizing alkylated oxindoles
was developed via Cu-mediated atom transfer radical addition
reaction between N-phenylacrylamides and ethyl 2-bromo-2-
methylpropionate. It was found that the use of N,N,N’,N’-
1,1,2,2,-tetramethylethylenediamine as ligand was important for
achieving good yields. In addition, the use of DMSO as solvent
o
and running the reaction at 130 C were also crucial. In some
cases, the product can be further brominated when the reaction
temperature was raised to 150 oC. Tests indicated that the
reaction may go through a radical process. Currently efforts are
underway to elucidate the reaction mechanism and the results
will be reported in due course.
In order to gain some information on the reaction mechanism,
several control reactions were performed. When the reaction of
1a with 2 was carried out in presence of a stoichiometric amount
Supplementary Material

4
Tetrahedron Letters
8. Zhao, Y.; Sharma, N.; Sharma, U. K.; Li, Z.; Song, G.; Van der Eycken, E.
Supplementary material that may be helpful in the review
V. Chem. Eur. J. 2016, 22, 5878-5882.
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5



A novel way of synthesizing alkylated oxindoles has
been described.
The use of tetramethylethylenediamine as ligand was
important for good yields.
The product can be further brominated as the
temperature was raised to 150 oC.

6
Tetrahedron Letters
A novel way of synthesizing alkylated oxindoles via Cu-
mediated atom transfer radical addition reaction has been
described.

7
Table 1. Reaction condition optimizationa
Entry
1
[Cu]
CuBr
CuCl
CuI
ligand
L1
L1
L1
L1
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
toluene
toluene
Yield(%)b
54
2
toluene
50
3
toluene
47
4
CuBr2
CuCl2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
toluene
NR
NR
65
5
toluene
6
toluene
7
toluene
70
8
toluene
NR
20
9
toluene
10
11
12
13
14c
15d
16e
DMF
55
DMSO
72
MeCN
51
1,2-dichloroethane
DMSO
43
NR
48
DMSO
Entry
product
Yield Entry
(%)b
product
Yield
(%)b
DMSO
66
a Reaction conditions: under a nitrogen atmosphere, 1a (0.3 mmol),
ethyl 2-bromo-2-methylpropanoate(0.9 mmol), [Cu] (0.3 mmol),
Ligand(0.15mmol), solvent (2 mL) at 130 oC for 18 h. b Isolated
yield. c Reaction run under O2. d 120 oC. e Reaction run for12 h
3a
72
75
76
65
60
50
45
48
3b
3d
3f
68
67
68
65
55
52
43
51
3c
3e
3g
3i
3h
3j
3k
3m
3o
3l
3n
3p
Table 2. Scope of N-phenylmethacrylamidesa
a Reaction conditions: under a nitrogen atmosphere, 1 (0.3 mmol), 2 (0.9 mmol),
CuBr (0.3 mmol), L3 (0.15 mmol), DMSO (2 mL) at 130 oC for 18 h. b Isolated
yield.

8
Tetrahedron Letters
Table 3. Scope of brominated N-phenylmethacrylamidea
Entry
product
Yield (%)b
4b
56
4c
56
51
4d
4e
41
a Reaction conditions: under a nitrogen atmosphere, 1 (0.3
mmol), 2 (0.9 mmol), CuBr(0.3 mmol), L3 (0.15 mmol), DMSO
(2 mL) at 150 oC for 18 h. b Isolated yield.