Copper-catalyzed Meerwein carboarylation of alkenes with anilines to form 3-benzyl-3-alkyloxindole

Article abstract of DOI:10.1007/s11426-014-5158-z

A simple and direct route for double C-C bond formation by copper-catalyzed Meerwein carboarylation process has been developed. In the presence of CuI (5 mol%), tert-butyl nitrite and anilines, a wide variety of N-arylacrylamides underwent tandem Meerwein arylation/C-H cyclization to produce pharmaceutically important 3-benzyl-3-alkyloxindole in moderate to good yield.

Full text of DOI:10.1007/s11426-014-5158-z

SCIENCE CHINA
Chemistry
November 2014 Vol.57 No.11: 1–5
doi: 10.1007/s11426-014-5158-z
• ARTICLES •
doi: 10.1007/s11426-014-5158-z
Copper-catalyzed Meerwein carboarylation of alkenes with
anilines to form 3-benzyl-3-alkyloxindole
TANG Shi1,2*, ZHOU Dong1, DENG YouLin1, LI ZhiHao1, YANG You1,
HE JianGuang1 & WANG YingChun1,3
1College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China
2College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, China
3Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China),
Guangxi Normal University, Guilin 541004, China
Received April 1, 2014; accepted May 6, 2014
A simple and direct route for double C–C bond formation by copper-catalyzed Meerwein carboarylation process has been de-
veloped. In the presence of CuI (5 mol%), tert-butyl nitrite and anilines, a wide variety of N-arylacrylamides underwent tan-
dem Meerwein arylation/C–H cyclization to produce pharmaceutically important 3-benzyl-3-alkyloxindole in moderate to
good yield.
radical reaction, C–H cyclization, Meerwein arylation, oxindole, copper-catalyzed
possible in the Meerwein arylation of alkenes (Figure 1).
1 Introduction
However, such a protocol has, to the best of our knowledge,
rarely met success except for a newly reported reaction us-
ing expensive [Ru(bpy)3]Cl2 catalyst under light irradiation
[9]. Use of inexpensive and abundant metal complexes such
as copper and iron instead of Ru for this coupling reaction is
still in great demand. In addition, given the simplicity of
preparation and handling as well as easy availability of
starting material, the anilines; the transformations using aryl
diazonium salts by in situ diazotization of anilines with al-
kyl nitrite are undoubtedly of huge concern [7, 10]. In this
paper, we want to demonstrate a direct pathway for copper-
catalyzed carboarylation of alkenes with anilines by a tan-
dem Meerwein arylation/C–H cyclization process to con-
struct 3,3-disubstituted oxindoles. More importantly, the
3,3-disubstituted oxindoles are common structural motifs in
pharmaceutical agents and natural products (Figure 2), and
their synthesis have attained increasing attention [11]. It is
to be noted that significant progress has currently been
achieved in the construction of these scaffolds through rad-
ical difunctionalization of N-arylacrylamides [12]. However,
The clean and uncomplicated construction of multiple C–X
(X = carbon and heteroatom) bonds in a cascade process is a
continuing topic of interest for organic chemists [1]. In this
regard, the Meerwein arylation of alkenes with aryl diazo-
nium salts has gained increasing attention in recent years [2].
In these transformations, the alkyl radicals derived from
oxidative addition of aryl radicals onto alkenes would trap
various nucleophilic ions or groups to provide C–X (X = N
[3], O [4], S [5], CN [6], CF3 [7], etc.) bond and C–C bond
in a single step. On the other hand, direct C–C formation by
coupling a aryl radical generated from aryl diazonium salts
with an aromatic C(sp2)–H bond has been achieved recently
which has gained increasing importance [8]. Therefore, we
envisaged that a twofold C–C bond formed by the coupling
of alkyl radical generated from addition of aryl radical onto
alkene with an intermolecular aromatic C(sp2)–H bond is
*Corresponding author (email: stang@jsu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2014
chem.scichina.com link.springer.com

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Zhou D, et al. Sci China Chem November (2014) Vol.57 No.11
3–4 equiv.), CuI (5 mol%) in CH3CN (2 mL) was added
tBuONO (3–4 equiv.) dropwise at 55 °C, and then the re-
sulting solution was stirred 5 h. The solvent was evaporated
under reduced pressure and the resulted mixture was filtered
through a Florisil pad, diluted with Et2O, and washed with
water and brine successively. The organic layer was dried
over anhydrous MgSO4 and concentrated in vacuo. The res-
idue was purified by flash chromatography on silica gel to
obtain the desired 3,3-disubstituted oxindoles.
The characterizations of compounds 3a–3v were shown
in the Supporting Information online.
Figure 1 Meerwein arylation of alkenes.
3 Results and discussion
In the course of our research project aiming at the
production of 3,3-disubstituted oxindoles by carboaryla-
tion of alkenes with anilines, the reaction between N-
methyl-N-phenylacrylamide 1a and 4-nitroaniline 2a was
employed as the model reaction whose conditions were
alsooptimized (Table 1). In the initial experiment it was
observed that, even in absence of any catalyst the above
mentioned reaction yielded as much as 26% of the desired
cyclization product 3a (Table 1, entry 1). On the basis of the
preceding result, a number of metallic salts (e.g. Cu, Fe, Mn,
Co, Ag）were subsequently used as the initiator for en-
hancing the yield (entries 2–12) [2b]. Among them, the
copper iodine was found to be the most effective, producing
3a with a yield of 75%. It was seen that decrease of CuI
loading retarded the reaction to some extend (entry 14).
Sequential screening of solvents revealed CH3CN to be the
best suited. The effect of temperature was investigated, and
a lower temperature retarded the reaction to some extend
(entry 20). i-AmONO instead of tBuONO gave an inferior
yield (entry 18).
Figure 2 Several bioactive compounds containing the 3,3-disubstituted
oxindole skeleton.
the reaction conditions are usually unfavourable owing to
the use of expensive metal catalyst, elevated temperature
and excess oxidant. Therefore, the development of practi-
cally feasible copper-catalyzed carboarylation of N-aryla-
crylamides with anilines to furnish 3-benzyl-3-alkyloxin-
doles under mild conditions is still of great interest, provid-
ing an alternative pathway to construct the family of 3,3-
disubstituted oxindoles.
2 Experimental
2.1 Materials and methods
After optimization of the reaction conditions, the scope
of N-arylacrylamides in the carboarylation reaction using
4-nitroaniline 2a as aryl diazonium source was investigat-
ed (Table 2). Initial screening revealed that N-substituents
of acrylamides have obvious effect on the reaction. For
example, N-arylarylamides with a methyl or ethyl group on
the N-atom were found to be well compatible with the reac-
tion conditions, whereas unprotected N-arylacrylamide (R2
= H) was less efficient in the cyclization as a consequence
of getting easily decomposed under the reaction conditions
(3c). Next, the substitution effect on the N-aryl moiety in
the reaction was examined. Remarkably, a wide array of
substituents, Me, MeO, Cl, Br, CN and F, at the 4-, 3- or
2-position of the aromatic ring displayed good reactivity
[13], and the reactive order was: poor electron-withdrawing
group and electron donating > strong-withdrawing groups,
which was in consensus with the previous reports [12c].
Interesting, the halo groups, such as Cl, Br and F group
were intact in the C–H functionalization process, thereby
All reactions were carried out under argon atmosphere in
flame-dried glassware. Syringes which were used to transfer
anhydrous solvents or reagents were purged with argon pri-
or to use. NMR spectra were recorded on solutions in deu-
terated chloroform (CDCl3) with residual chloroform (δ:
1
7.26 ppm for H NMR and δ 77.0 ppm for 13C NMR). Ab-
breviations for signal coupling are as follows: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad. Col-
umn chromatographical purifications were performed using
SiO2 (0.040–0.063 mm, 230–400 mesh ASTM) and
n-hexane/ethyl acetate combination was used as the eluent.
Commercially available starting materials and solvents were
purchased and used without any further purification. N-
arylacrylamides were prepared according to previously pub-
lished procedures [11e].
2.2 Synthesis of 3,3-disubstituted oxindoles
To a mixture of N-arylacrylamide (1, 0.3 mmol), aniline (2,

Zhou D, et al. Sci China Chem November (2014) Vol.57 No.11
3
Table 1 Screening of reaction conditionsa)
facilitating additional modifications at halogenated posi-
tions. However, low yield or only trace amount of product
was obtained for the ortho-substituted N-arylacrylamide.
The results might attribute to steric hindrance of ortho-
substituent. Expectedly, the pyridyl ring was observed to be
perfectly stable under the optimal conditions, providing the
desired oxindoles 3m in a yield of 58%. Sequential investi-
gations revealed that several groups, Ph, CH2OH, CH2OAc
at the 2-position of the acrylamide moiety were compatible
to the optimal conditions for producing 3m, 3n and 3o, re-
spectively, whereas mono-substituted olefin (R3 = H) was
inert for the carboarylation process.
Ratio (1a:2a:
Yield
(%) b)
Enrty
Metal (mol%)
Solvent
tBuONO)
1:3:3
1:3:3
1:3.3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1
2
none
CuCl (5)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
EtOAc
EtOH
26
56
62
75
23
19
68
57
71
36
37
32
59
4
3
CuBr (5)
4
CuI (5)
5
CuCN
The scope of anilines in the presence of N-methyl-N-
6
Cu
t
phenylacrylamide 2a, CuI and BuONO was explored (Ta-
7
FeSO4·7H2O (5)
FeCl2·7H2O
Fe(NH4)2(SO4)2·6H2O
Mn(Oac)2·4H2O (5)
CoCl3.6H2O (5)
AgNO4
ble 3). It was noteworthy to find that, the carboarylation
process was compatible with various other anilines bearing
different substituents on the aromatic ring, such as Cl, F, Br,
OEt, MeO. Interesting, 4-fluoroaniline gave a higher yield
when the reaction was conducted in the absence of initiator
CuI. Sequentially, it was found that 3-aminopyridine was
suitable aryl diazonium source, and underwent the C–H
cyclization smoothly to introduce a pyridyl mioety into de-
sired oxindole. With this, the generality of C–H cyclization
protocol was examined.
8
9
10
11
12
13
14
15
16
17 c)
18 d)
CuI (2)
CuI (5)
CuI (5)
35
46
41
<10
CuI (5)
CuI (5)
CH3CN
CH3CN
CuI (5)
To elucidate the mechanism of this tandem Meerwein ar-
ylation/C(sp2)–H cyclization process, the inter- and intra-
molecular kinetic isotope control experiments were per-
formed as shown in Scheme 1, where little kinetic isotope
effect (kH/D = 1.0) was observed, suggesting the compatibil-
ity of C–H functionalization cyclization step with either the
SEAr mechanism or the free radical mechanism [14]. Nota-
bly, the free radical mechanism was supported by the con-
trol experiment: a stoichiometric amount of TEMPO (4
equiv.), a well-known radical inhibitor, was used in the re-
action of N-methyl-N-phenylmethacrylamide (1a) with
4-nitroaniline (2a) and CuI, and the formation of the desired
disubstituted oxindole was suppressed considerably.
t
a) Reaction conditions: 1a (0.3 mmol), 2a (2–4 equiv.), BuONO (2–4
equiv.), initiator (5–10 mol%), and solvent (2 mL) at 55 °C for 5 h. tBuO-
NO = tert-butyl nitrite, i-AmONO = isoamyl nitrite; b) yield of the isolated
product; c) 30 °C; d) i-AmONO instead of tBuONO.
Table 2 Scope of N-arylacrylamines a)
Enrty
1
R1/R2/R3
H/Me/Me
Product
3a
Yield (%) b)
81 c)
2
H/Et/Me
3b
3c
71
3
H/H/Me
< 5
75
Table 3 Scope of anilines a)
4
p-Cl/Et/Me
3d
3e
5
p-F/Et/Me
71
6
p-OMe/Et/Me
p-Me/Et/Me
p-CN/Et/Me
o-Br/Et/Me
3f
45
7
3g
51
8
3h
3i
43
9
72
10
11
12
13
14
15
16
2-methyl-4-chloro/Et/Me
o-OMe/Me/Me
3-pyridyl/Me/Me
H/Me/Ph
3j
39
Enrty
R1
p-Cl
Product
3q
Yield (%) b)
3k
3l
< 5
55
1
2 c)
51
43
55
43
58
53
p-F
3r
3m
3n
3o
41
3
o-Br
3s
H/Me/CH2OH
H/Me/CH2OOAc
H/Me/H
42
4
p-OEt
o-OMe
3-pyridyl
3t
61
5
3u
3p
< 5
6
3v
t
a) Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), BuONO (0.9
mmol), CuI (5 mol%), and CH3CN (2 mL) at 55 °C for 5 h; b) yield was
given for isolated product after column chromatography; c) Run on a 3
mmol scale.
a) Reaction conditions: 1 (0.3 mmol), 2 (1.2 mmol), tBuONO (1.2 mmol),
CuI (5 mol%), and CH3CN (2 mL) at 55 °C for 5 h; b) yield was given for
isolated product after column chromatography; c) in the absence of CuI.

4
Zhou D, et al. Sci China Chem November (2014) Vol.57 No.11
3-benzyl-3-alkyloxindole through a direct and practical
process. The detailed mechanism and the application of the
novel reaction for more complex targets are currently being
explored in our laboratory.
This work was supported by the National Science Foundation of China
(21462017), China Posdoctoral Science Foundation Funded Project
(2014M560649), the Scientific Research Fund of Hunan Provincial Educa-
tion Department (13B094), the Fund of Science and Technology Innovation
and Entrepreneur for Hunan Young Talents, and the Project Sponsored by
the Scientific Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry for the financial and infrastructural
assistance.
Scheme 1 Control experiments on carboarylation of alkenes with anilines.
Consequently, a possible mechanism was proposed as
outlined in Scheme 2 for this carboarylation process of
N-arylacrylamides on the basis of the preceding results
and previously reported mechanism [2–8, 10–12]. Firstly,
in situ diazotization of aryl amines with tBuONO gener-
ated aryl diazonium salt A. In the presence of CuI, the
resulted diazonium alcoholate easily decomposed to give
aryl radical [15], which was followed by its addition onto
the carbon-carbon double bond of N-methyl-N-pheny-
lacrylamide (1a) to yield an alkyl radical B. Intramolec-
ular cyclization of intermediate B with a aryl ring formed
radical intermediate C, proceeded by abstraction of an
aryl hydrogen in radical intermediate C to yield the de-
sired 3-benzyl-3-alkyloxindoles.
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4
4 Conclusions
In summary, we have demonstrated a copper-catalyzed
carboarylation reaction of alkenes and anilines via a radical
C–H cyclization to produce pharmaceutically important
3,3-disubstituted oxindole scaffold. Notably, this protocol
proceeds through a radical process and eliminates the re-
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