The carbomethylation of arylacrylamides leading to 3-ethyl-3-substituted indolin-2-one by cascade radical addition/cyclization

Article abstract of DOI:10.1039/c4cc01053a

An FeCl₂-promoted carbomethylation of arylacrylamides by di-tert-butyl peroxide (DTBP) is achieved, leading to 3-ethyl-3-substituted indolin-2-one in high yield. The reaction tolerates a series of functional groups, such as cyano, nitro, ethyloxy carbonyl, bromo, chloro, and trifluoromethyl groups. The radical methylation and arylation of the alkenyl group are involved in this reaction. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01053a

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The carbomethylation of arylacrylamides leading
to 3-ethyl-3-substituted indolin-2-one by cascade
radical addition/cyclization†
Cite this: Chem. Commun., 2014,
50, 3865
Received 22nd January 2014,
Accepted 12th February 2014
Qiang Dai,a Jintao Yu,a Yan Jiang,a Songjin Guo,a Haitao Yanga and Jiang Cheng*ab
DOI: 10.1039/c4cc01053a
www.rsc.org/chemcomm
An FeCl2-promoted carbomethylation of arylacrylamides by di-tert-
butyl peroxide (DTBP) is achieved, leading to 3-ethyl-3-substituted
indolin-2-one in high yield. The reaction tolerates a series of functional
groups, such as cyano, nitro, ethyloxy carbonyl, bromo, chloro, and
trifluoromethyl groups. The radical methylation and arylation of the
alkenyl group are involved in this reaction.
Methylation is a fundamental transformation in organic chemistry
because of the ubiquitousness of methyl groups in organic com-
pounds and its importance in biologically active molecules.1
Undoubtedly, the introduction of methyl along with other function-
Scheme 1 The radical methylation reaction.
alizations in one step would be beneficial for the diversity and functionalization using visible-light photoredox catalysis toward
complexity of the final product. The oxidative difunctionalization of 3,3-dialkyl substituted indolin-2-one.16 Liu demonstrated the copper-
alkenes is a powerful strategy which enables the bond formation at catalyzed alkylarylation of arylacrylamides by simple alkanes.17 Herein,
the vicinal positions.2 Like the well-developed metal-catalyzed we report our study onthe radical carbomethylation of arylacrylamides,
oxidative aminooxygenation,3 diamination,4 and dioxygenation involving the addition of the methyl radical and cyclization.
of alkenes,5 the oxidative dicarbonation of alkenes has attracted
increasing attention from chemists.6
Initially, the reaction of phenylacrylamide with DTBP was chosen
as the model reaction in CH3CN at 135 1C. The desired product was
Meanwhile, the radical coupling was well developed in the isolated in 25% yield, along with 49% of the product via the addition
methylation of the C–H bond,7 amides8 and carboxylic acid of the cyanoethyl radical followed by cyclization (Table 1, entry 1).
(Scheme 1).9 These elegant examples spurred us to test the To our delight, the sequential methylation/cyclization product was
feasibility of difunctionalization of alkenes involving radical formed in 38% yield in DMSO (Table 1, entry 2). By replacing DMSO
methylation. To achieve such a transformation, the choice of a with benzene or chlorobenzene, the desired product was isolated in
suitable substrate is essential. Recently, much attention has been 55% and 50% yields, respectively (Table 1, entries 3 and 4). The
paid to the difunctionalization of arylacrylamides as activated reaction did not work in toluene. The yield was further increased to
alkenes,10 leading to indolin-2-one as a useful scaffold in a wide 72% in the presence of 20 mol% FeCl2, indicating that FeCl2 acts as
range of natural products and biologically active drugs.11 With a promoter rather than a catalyst in this procedure (Table 1, entry 6).
respect to the dicarbonation of arylacrylamides, arylalkylation,12 However, the employment of CuCl (20 mol%) had little effect on the
trifluoromethylarylation,13 diarylation14 and arylcyanation15 were reaction (Table 1, entry 7). The reaction temperature is crucial for
well developed. Zhu developed the cascade decarboxylation/C–H this transformation, as the reaction efficiency did not increase at
150 1C but sharply decreased at 120 1C (Table 1, entries 8 and 9).
a School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology, and Jiangsu Province Key Laboratory of Fine
Petrochemical Engineering, Changzhou University, Changzhou, 213164,
P. R. China. E-mail: jiangcheng@cczu.edu.cn
With the optimized conditions in hand, the scope of substrates
was investigated as shown in Fig. 1. Firstly, the effect of substituted
groups on the aryl ring was probed. The reaction was not sensitive to
the electronic nature of the phenylacrylamide as both electron-
withdrawing and donating substituted substrates worked well
to deliver the desired product in good to excellent yields. The
reaction tolerated a series of functional groups, such as cyano,
b State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing,
210093, P. R. China
† Electronic supplementary information (ESI) available: Detailed synthetic pro-
cedures and characterization of new compounds. See DOI: 10.1039/c4cc01053a
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Table 1 Selected results for optimal reaction conditionsa
reaction efficiency was found between 3q and 3r. Importantly, the
applicable scope was not limited to 3-ethyl-3-methyl indolinone, as
the 3-acetoxymethyl, methoxymethyl and chloromethyl analogues
(3s, 3t and 3u) were efficiently prepared in 76%, 62% and 72%
yields, respectively.
Entry
Metal
Solvent
T/1C
Yieldb (%)
1c
2
3
—
—
—
—
MeCN
DMSO
135
135
135
135
135
135
135
120
150
25
38
55
50
Trace
72
62
54
73
Benzene
Chlorobenzene
Toluene
Benzene
Benzene
Benzene
Benzene
4
5d
6
—
(1)
FeCl2
CuCl
FeCl2
FeCl2
7
8
9
Next, the developed procedure was applied to the synthesis of 3w,
which is a progesterone receptor antagonist.18 Using the standard
procedure, 3w was isolated in 73% yield (eqn (1)).
a
Reaction conditions: phenylacrylamide (0.2 mmol), metal (20 mol%),
b
DTBP (2.5 equiv.), solvent (1.5 mL) in a sealed tube, N2. Isolated yield.
More experiments were conducted to get some insight into this
reaction (Scheme 2). Firstly, adding 2.5 equivalents of 2,2,6,6-
tetramethyl-1-piperidinyloxyl (TEMPO) inhibited the reaction and the
radical coupling product between the methyl radical and TEMPO was
confirmed by GC-MS (eqn (2)). Moreover, a trace amount of toluene,
which was derived from the radical methylation of benzene, was also
detected by GC-MS. These results strongly indicated that a methyl
radical was involved in this reaction. Secondly, the inter- and intra-
molecular isotopic kinetic experiments were conducted, and the kH/kD
was found to be nearly 1.0 and 1.0, respectively (eqn (3) and (4)),
indicating that the cleavage of the arene C–H bond is not the rate-
determining step.19 Moreover, these results implied that either an
electrophilic aromatic substitution or a free-radical substitution was
involved in the cyclization step.20 However, the substituent effect on the
reaction rate was observed in the competitive experiment, where the
electron-withdrawing substituent was beneficial for the reaction. This
result is not consistent with the electrophilic aromatic substitution and
supports the radical aromatic pathway (eqn (5)).
c
d
3-Cyanoethyl-3-methyl indolinone was isolated in 49% yield. 3-Benzyl-
3-methyl indolinone. DTBP = di-tert-butyl peroxide.
Based on the aforementioned experimental results, a proposed
mechanism is outlined in Scheme 3. Initially, the homolytic
cleavage of DTBP produces a tert-butoxy radical, which is converted
to a methyl radical by the loss of one equivalent of acetone. In the
Fig. 1 FeCl2-promoted carbomethylation of an arylacryamide. All reactions
were carried out with arylacrylamide 1 (0.2 mmol), DTBP (0.5 mmol,
2.5 equiv.), FeCl2 (20 mol%), in benzene (1.5 mL) at 135 1C under N2 for
12 h. Isolated yield. Mixture of 6- and 4-Me products, the ratio is determined
1
by H NMR spectroscopy. The 6-Br isomer was isolated in 21% yield.
nitro, ethoxycarbonyl, bromo, chloro, and trifluoromethyl groups.
Notably, bromo and chloro groups survived well under the reaction
conditions, which were suitable for further potential functionaliza-
tion (3j–3l). The steric hindrance had little effect on this transfor-
mation, as evidenced by the comparable yields between 3f and 3g.
Importantly, the hetero-aryl analogue was also a good reaction
partner in this transformation. For example, 3p was isolated in 73%
yield. For the meta-substituted substrates, cyclization at the more
hindered site is preferred to form the 4-substituted indolinones as
the major products (3h and 3j). Secondly, the effect of the protect-
ing group on the nitrogen atom was studied. No difference in the Scheme 2 Preliminary mechanism study.
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In conclusion, we developed an FeCl2-promoted carbomethyla-
tion of arylacrylamides, which provided a facile pathway leading to
ethyl-3-substituted indolin-2-one. The procedure tolerates cyano,
nitro, ethyloxy carbonyl, bromo, chloro and trifluoromethyl groups.
A sequential methyl radical addition and cyclization is involved
in this reaction.
We thank the National Natural Science Foundation of China
(no. 21272028 and 21202013), the ‘‘Innovation & Entrepreneurship
Talents’’ Introduction Plan of Jiangsu Province, the Natural Science
Foundation of Zhejiang Province (no. R4110294), the Jiangsu Key
Laboratory of Advanced Catalytic Materials & Technology and
the State Key Laboratory of Coordination Chemistry at Nanjing
University for financial support.
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