Visible-light-induced and iron-catalyzed methylation of N -arylacrylamides with dimethyl sulphoxide: A convenient access to 3-ethyl-3-methyl oxindoles

Article abstract of DOI:10.1039/c7ob00779e

A visible-light-induced and iron-catalyzed methylation of arylacrylamides by dimethyl sulphoxide (DMSO) is achieved, leading to 3-ethyl-3-methyl indolin-2-ones in high yields. This reaction tolerates a series of functional groups, such as methoxy, trifluoromethyl, cyano, nitro, acetyl and ethyloxy carbonyl groups. The visible-light promoted radical methylation and arylation of the alkenyl group are involved in this reaction.

Full text of DOI:10.1039/c7ob00779e

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Visible-light-induced and iron-catalyzed methylation of N-
arylacrylamides with dimethyl sulphoxide：A convenient access
to 3-ethyl-3-methyl oxindoles
Received 00th January 20xx,
Accepted 00th January 20xx
Zuguang Xie,a Pinhua Li,*a Yu Hu,a Ning Xu,a and Lei Wang*a,b
DOI: 10.1039/x0xx00000x
A visible-light-induced and iron-catalyzed methylation of arylacrylamides by dimethyl sulphoxide (DMSO) is achieved,
leading to 3-ethyl-3-methyl indolin-2-ones in high yields. This reaction tolerates a series of functional groups, such as
methoxy, trifluoromethyl, cyano, nitro, acetyl and ethyloxy carbonyl groups. The visible-light promoted radical methylation
and arylation of the alkenyl group are involved in this reaction.
www.rsc.org/
Intraduction
In last year, we reported the sulfonylative arylation and
Methylation is
a fundamental transformation in organic
decarboxylative acylarylation of N-arylacrylamides by visible-
light photoredox catalysis.10 Based on our interest in
difunctionalization of N-arylacrylamides, we herein document
a novel iron-catalyzed, visible-light-promoted methylation of
N-arylacrylamides with dimethyl sulphoxide for the
construction of 3-ethyl-3-methyl oxindoles (Scheme 1).11
chemistry, since the methyl group is one of the most prevalent
functionalities in biologically active molecules, and a lot of
small molecule drugs contain at least one methyl group.1 In
the past few years, much attention has been devoted by
chemists to the development of new methylating reagents,
which have successfully been applied in the organic
transformations.2 Since Weiner and co-workers3 discovered
that quinolone and isoquinoline can be readily methylated
with the dimsyl anion generated from DMSO, which has been
widely used as a methyl source in organic reactions.4
Scheme 1 visible-light promoted oxidative methylation–carbocyclization of
Recently, much attention has been paid to the N-arylacrylamides.
difunctionalization of arylacrylamides by oxidative C–H
functionalization/carbocyclization, leading to indolin-2-one as
Results and discussion
a useful scaffold in
a wide range of natural products,
pharmaceuticals and biologically active compounds.5 Generally,
there are two powerful strategies for this transformation, the
one is transition-metal-catalyzed cyclization of N-
arylacrylamides with different nucleophiles,6 the other is
radical-initiated cyclizations with different radical precursors.7
Very recently, visible-light promoted radical oxidative 1,2-
alkylarylation of N-arylacrylamides have also been successfully
developed.8 Although notable progress has been achieved in
the construction of 3-ethyl-3-methyl oxindoles, the reaction
conditions are usually unsatisfactory (additives, strong base or
acid, high catalyst loading).9 Therefore, the development of a
convenient access to the family of oxindoles is of great interest.
For the optimization of the reaction conditions, N-methyl-N-
phenylmethacrylamide
chosen as the model substrates. Initially, the reaction was
performed in the presence of 20 mol% FeSO4 7H2O as catalyst,
(1a) and dimethyl sulfoxide were
•
2 equiv. of H2O2 as an oxidant in neat conditions at room
temperature for 4h, and the desired product (3a) was obtained
in 17% isolated yield (Table 1, entry 1). In the absence of
FeSO4
(Table 1, entries 2-3). Surprisingly, when the reaction was
carried out at either room temperature or 70 in the dark,
•7H2O or H2O2, none of the desired product was formed
℃
only trace amount of desired product was formed (Table 1,
entries 4-5). However, an improved yield (49%) of 3a was
obtained when the reaction was irradiated by sunlight for 4 h
(Table 1, entry 6). As shown in Table 1, the application of white
LED, blue LED and green LED provided comparative yields of 3a
(Table 1, entries 7-9). Further exploration of a variety of iron
a.Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P.
R. China, Tel: +86-561-3802-069; Fax: +86-561-3090-518 E-mail:
pphuali@126.com; leiwang@chnu.edu.cn.
b.State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China.
Electronic Supplementary Information (ESI) available. See DOI: 10.1039/
x0xx00000x
salts indicated that FeSO4•7H2O was superior to the others,
such as FeCl2, FeBr2 and Fe(OAc)2, while the reaction was failed
when FeCl3 was used as catalyst (Table 1, entries 10-13).
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Moreover, variation of the oxidant also affected the reaction products in moderate to good yields. Gratifyingly, electron-
efficiency, TBHP, DTBP and molecular oxygen failed to give any donating groups on the N-aryl moiety, such as methyl, ethyl,
product (Table 1, entries 14-16). And also, the solvent tert-butyl, methoxy and ethoxy group, resulted in a moderate
screening revealed that the neat reaction condition was the yields of the corresponding products (2a-f), whereas halogen
best choice (Table 1, entry 7 vs entries 17-20). The loading of atoms as well as strong electron-withdrawing substituents,
FeSO4•7H2O catalyst and the amount of H2O2, as well as the such as CN, NO2, CF3, CF3O, acetyl and ester group, resulted in
reaction time were optimized, which are outlined in Table 1
(entries 21-26).
Table 2 The scope of the methylation of N-arylacrylamides
with dimethyl sulfoxide.a,b
Table 1 Optimization of the reaction conditions.a
tBu
Me
Et
O
O
O
O
O
O
O
O
Entry
1
Fe Source
Oxidant
H2O2
Solvent
neat
Light source
--
Yieldb (%)
17
N
N
N
N
FeSO4
--
•7H2O
3b, 65%
3c, 65%
3d, 71%
3a, 72%
2
H2O2
--
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
--
n.r.
MeO
EtO
F
Cl
3
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeCl2
FeBr2
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
--
n.r.
O
O
N
N
N
N
4
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
TBHP
DTBP
O2
Dark
Dark
trace
tracec
49
3f, 61%
3g, 78%
3h, 70%
3e, 62%
5
Br
I
NC
O2N
6
Sunlight
O
O
N
N
N
N
7
53
3W white LED
3W blue LED
3W green LED
3W white LED
3W white LED
3W white LED
3W white LED
3j, 76%
3k, 70%
3l, 82%
8
50
3i, 75%
O
9
51
F3C
F3CO
EtO2C
Me
O
O
O
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
49
N
N
N
N
51
3n, 79%
3o, 68%
3p, 74%
3m, 68%
Me
Fe(OAc)2
FeCl3
47
O
n.r.
neat
neat
N
N
N
N
Me
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
FeSO4
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
•7H2O
n.r.
Et
OMe
Br
3W white LED
3W white LED
3s, 54%
3t, 75%
3q, 52%
3r, 55%
n.r.
neat
neat
Br
Cl
3W white LED
3W white LED
3W white LED
n.r.
+
O
O
O
O
O
31d
N
N
N
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
DCE
N
Br
Cl
CH3CN
Traced
27d
3u, 69%
3v, 63%
3w, 20%
3w', 63%
Toluene 3W white LED
Traced
72e
+
O
O
O
DMF
neat
neat
neat
neat
neat
neat
3W white LED
3W white LED
3W white LED
3W white LED
3W white LED
3W white LED
3W white LED
N
N
N
N
N
3x, 41%
3x', 29%
3y, 66%
3z, 63%
70f
51e,g
71e,h
53e,h,i
72e,h,j
O
O
O
O
N
N
N
N
Ph
Et
Bn
CH2CH2CN
3ab
, 74%
3aa, 70%
3ac, 76%
3ad, 85%
O
O
O
O
a Reaction conditions: 1a (0.20 mmol), 2 (1.0 mL), Fe salt (20 mol%), oxidant
(2.0 equiv), r.t., air, 4 h. b Isolated yield. c At 70 ℃ in dark. d Solvent (0.5 mL)
and DMSO (0.5 mL) were added. e H2O2 (3.0 equiv) was added. f H2O2 (4.0
N
Ts
N
N
H
N
Ms
O
3ag, 0%
3ah, 0%
3ae, 0%
3af, 0%
a Reaction conditions:
1
(0.20 mmol),
2
(1.0 mL), FeSO4
•
7H2O (15 mol
equiv) was added. g FeSO4 7H2O (10 mol%) was added. h FeSO4
• •7H2O (15
%), H2O2 (3.0 equiv), r.t., air, 3 W white LED irradiated for 2 h. b Isolated
mol%) was added. i Reaction for 1 h. j Reaction for 2 h. n.r. = no reaction.
H2O2 is 30% solution in water. Blue LED (450-455 nm) and green LED (525-
530 nm).
yield.
higher yields of the desired products (2g-p). In addition, the
reaction occurred smoothly with ortho-substituted and
polysubstituted N-arylacrylamides, and the desired products
were obtained in good yields (3q-u). Additional experiments
showed that the N-methyl-N-(naphthalen-1-yl)methacrylamide
was also effective substrates in this reaction (3v). As expected,
substrates bearing meta-substituent afforded mixtures of two
To explore the substrate scope of the reaction, various
substituted acrylamides were investigated under the
optimized reaction conditions. In general,
a variety of
functional groups on the phenyl ring of arylacrylamides were
compatible under this procedure, affording the desired
2 | J. Name., 2012, 00, 1-3
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O
S
regioselective products (3w/3w’ in a ratio of 1:3 and 3x/3x’ in
Fe2+
H2O2
Me
Me
a ratio of 4:3). Furthermore, substrates with pyridine ring can
also be survived in this protocol 3y), and when 1-
2a
N
O
Detected by
(
HO
HRMS
Me
methacryloyl-1,2,3,4-tetrahydroquinoline was used as
substrate, the desired product was also obtained in good yield
Trapped by
TMPEO
O
OH
Me
S Me
(
3z). To our delight, different N-protection groups such as ethyl,
OH
N
O
benzyl and phenyl were tolerated, leading to the
corresponding products in good yields (3aa-ad). However, the
amide at which the N-methyl substituent was replaced by
hydrogen atom, acetyl, methylsulfonyl and p-toluene sulfonyl
group resulted in no conversion (3ae-ah). Unfortunately, n-
propyl sulfoxide, n-butyl sulfoxide and methyl phenyl sulfoxide
failed for the oxidative methylation–carbocyclization reaction
under the current catalyst system.
A
Me
H2O2
Me
H+
HOO
B
1a
O
O
S
C
N
3a
Detected by
HRMS
Me
OH
H
HOOH
Me
O
N
O
Ph
N
N
O
N
O
Trapped by
TMPEO
E
D
Scheme 4 Proposed mechanism.
The reaction could also be performed on a gram scale. As
shown in Scheme 2, treatment of 1.76 g (10 mmol) of N-
arylacrylamide 1a with DMSO (20 mL) under the optimized
reaction conditions afforded the corresponding product 3a
(1.24 g) in 65% isolated yield, clearly demonstrating the
preparative practicality of this protocol.
reduction of Fe3+ formed and more hydroxyl radicals produced
during Fenton process.12 Initially, the reaction might begin
with the FeII-catalyzed decomposition of H2O2 to generate
hydroxyl radical, along with the generation of FeIII species.12b,e
Subsequently, FeII is regenerated for next run and produces a
hydroperoxyl radical by photo-Fenton process, electron
transfer reaction between FeIII species and H2O2 under visible
light irradiation.12b-d Next, the formed hydroxyl radical reacts
with DMSO, and the formed intermediate
methyl radical by the loss of one equivalent of methanesulfinic
acid . Subsequently, the addition of the methyl radical to the
arylacrylamide forms a new radical species . Then, the
cyclization takes place to form the radical intermediate
Finally, the single electron oxidation reaction between
intermediate and the hydroperoxyl radical along with
A converts to a
Scheme 2 Gram-scale reaction.
C
D
E
.
E
deprotonation (aromatization process) delivers the indolinone.
Conclusions
In summary, we have achieved an economical and convenient
protocol for the preparation of various 3-ethyl-3-methyl
oxindoles by visible-light promoted and iron-catalyzed
difunctionalization of N-arylacrylamides through a free radical-
triggered cascade process. The method showed considerable
synthetic advantages in terms of product diversity, simplicity
of the reaction procedure and mild reaction conditions.
Further studies on visible-light-promoted methylation
reactions via the free radical approach and associated
mechanisms are currently being investigation in our laboratory.
Scheme 3 The control experiments.
To illustrate the possible mechanism of this transformation, a
series of control experiments were conducted and the results
were summarized in Scheme 3. When d6-DMSO was used, the
corresponding d3-3a was obtained as a colorless liquid in 76%
yield, which indicated that DMSO is the methylating reagent.
When
a
radical
scavenger,
2,2,6,6-tetramethyl-1-
piperidinyloxyl (TEMPO) was added into the reaction, no
desired product 3a was detected. Meanwhile, an adduct of
methyl radical with TEMPO was detected by HRMS. Moreover,
when TEMPO was added after the reaction conducting 20
Experimental
Typical procedure for the N-arylacrylamide with dimethyl
sulphoxide
minutes, an adduct of radical
D with TEMPO was also detected
by HRMS. These results indicated that a radical progress was
involved in this transformation. Based on the aforementioned
experimental results and literature, a plausible mechanism is
outlined in Scheme 4. Although the exact role of light is still
unclear, the previous reports indicate that the increased
efficiency of photo-Fenton is attributable to the photo-
N-Arylacrylamide (1a, 0.20 mmol), dimethyl sulfoxide (DMSO,
2, 1.0 mL), FeSO4•7H2O (0.03 mmol) and H2O2 (0.60 mmol) was
added to an oven-dried reaction vessel equipped with
magnetic stirring bar. Then the reaction vessel was irradiated
using
3 W white LED under air atmosphere at room
temperature for 2 h. After the reaction was completed, the
reaction solution was extracted with EtOAc (2×5.0 mL). The
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organic layers were combined, dried over anhydrous Na2SO4, 110.51 (d, J = 24.3 Hz), 108.05 (d, J = 8.1 Hz), 49.25, 31.22, 25.96,
and concentrated under reduced pressure to yield crude 23.03, 8.57. HRMS (ESI) [M+H]+ Calcd. for C12H15NOF: 208.1132,
product, which was purified by flash chromatography (silica gel, Found: 208.1136.
petroleum ether/ethyl acetate = 10:1) to give the desired
1
product 3a in 72% yield as a colorless oil.
5-Chloro-3-ethyl-1,3-dimethylindolin-2-one (3h).9b Colorless oil; H
NMR (400 MHz, CDCl3): δ 7.24 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 6.77
3-Ethyl-1,3-dimethylindolin-2-one (3a).9b Colorless oil; 1H NMR (d, J = 8.0 Hz, 1H), 3.20 (s, 3H), 1.96-1.89 (m, 1H), 1.78-1.71 (m, 1H),
(400 MHz, CDCl3): δ 7.28-7.24 (m, 1H), 7.17-7.16 (m, 1H), 7.08-7.05 1.34 (s, 3H), 0.59 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
(m, 1H), 6.84 (d, J = 7.6 Hz, 1H), 3.21 (s, 3H), 1.98-1.89 (m, 1H), 1.82- 179.99, 141.94, 135.56, 127.67, 127.41, 122.94, 108.62, 49.10,
1.73 (m, 1H), 1.35 (s, 3H), 0.59 (t, J = 7.6 Hz, 3H); 13C NMR (100 31.26, 26.01, 23.07, 8.65.
MHz, CDCl3): δ 180.56, 143.31, 133.75, 127.47, 122.34, 122.26,
107.68, 48.77, 31.30, 25.89, 23.15, 8.68.
5-Bromo-3-ethyl-1,3-dimethylindolin-2-one (3i).9b Colorless oil; 1H
NMR (400 MHz, CDCl3): δ 7.39 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 6.73
3-Ethyl-1,3,5-trimethylindolin-2-one (3b).9b Colorless oil; 1H NMR (d, J = 8.4 Hz, 1H), 3.20 (s, 3H), 1.98-1.89 (m, 1H), 1.80-1.71 (m, 1H),
(400 MHz, CDCl3): δ 7.06 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.73 (d, J = 1.34 (s, 3H), 0.59 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
7.6 Hz, 1H), 3.19 (s, 3H), 2.35 (s, 3H), 1.96-1.87 (m, 1H), 1.79-1.70 179.96, 142.43, 135.97, 130.37, 125.72, 115.07, 109.20, 49.14,
(m, 1H), 1.34 (s, 3H), 0.59 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, 31.31, 26.06, 23.14, 8.72.
CDCl3): δ 180.54, 141.01, 133.87, 131.72, 127.70, 123.24, 107.39,
48.84, 31.34, 25.91, 23.22, 21.00, 8.73.
3-Ethyl-5-iodo-1,3-dimethylindolin-2-one (3j). Colorless oil; 1H
NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 6.64
3,5-Diethyl-1,3-dimethylindolin-2-one (3c). Colorless oil; 1H NMR (d, J = 8.0 Hz, 1H), 3.19 (s, 3H), 1.96-1.87 (m, 1H), 1.79-1.70 (m, 1H),
(400 MHz, CDCl3): δ 7.09 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.75 (d, J = 1.33 (s, 3H), 0.59 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
8.0 Hz, 1H), 3.20 (s, 3H), 2.65 (q, J1 = 15.2 Hz, J2 = 7.6 Hz, 2H), 1.96- 179.52, 142.99, 136.22, 136.19, 131.11, 109.71, 84.84, 48.76, 31.16,
1.88 (m, 1H), 1.80-1.72 (m, 1H), 1.35 (s, 3H), 1.24 (t, J = 7.6 Hz, 3H), 25.89, 23.00, 8.62. HRMS (ESI) [M+H]+ Calcd. for C12H15NOI:
0.59 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 180.67, 141.25, 316.0193, Found: 316.0198.
138.48, 133.95, 126.57, 122.14, 107.48, 48.93, 31.41, 28.57, 25.98,
23.25, 15.95, 8.79. HRMS (ESI) [M+H]+ Calcd. for C14H20NO: 3-Ethyl-1,3-dimethyl-2-oxoindoline-5-carbonitrile (3k).9d White
1
218.1539, Found: 218.1538.
solid; H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.0 Hz, 1H), 7.45 (s,
1H), 6.97 (d, J = 8.0 Hz, 1H), 3.27 (s, 3H), 2.01-1.92 (m, 1H), 1.86-
5-(tert-Butyl)-3-ethyl-1,3-dimethylindolin-2-one (3d). Colorless oil; 1.77 (m, 1H), 1.39 (s, 3H), 0.61 (t, J = 7.2 Hz, 3H); 13C NMR (100
1H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), MHz, CDCl3): δ 180.01, 147.15, 134.72, 132.90, 125.61, 119.05,
6.77 (d, J = 8.0 Hz, 1H), 3.20 (s, 3H), 1.97-1.88 (m, 1H), 1.82-1.73 (m, 108.12, 105.20, 48.51, 31.07, 26.04, 22.76, 8.46.
1H), 1.36 (s, 3H), 1.33 (s, 9H), 0.60 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 180.59, 145.37, 140.86, 133.37, 123.88, 119.39, 3-Ethyl-1,3-dimethyl-5-nitroindolin-2-one (3l).9d Yellow solid; 1H
106.96, 48.85, 34.31, 31.45, 31.29, 25.80, 23.09, 8.68. HRMS (ESI) NMR (400 MHz, CDCl3): δ 8.27 (d, J = 8.8 Hz, 1H), 8.07 (s, 1H), 6.96
[M+H]+ Calcd. for C16H24NO: 246.1852, Found: 246.1850.
(d, J = 8.8 Hz, 1H), 3.30 (s, 3H), 2.04-1.95 (m, 1H), 1.90-1.81 (m, 1H),
1.42 (s, 3H), 0.63 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
3-Ethyl-5-methoxy-1,3-dimethylindolin-2-one (3e).9b Colorless oil; 180.57, 149.12, 143.39, 134.70, 125.06, 118.31, 107.30, 48.92,
1H NMR (400 MHz, CDCl3): δ 6.80-6.73 (m, 3H), 3.81 (s, 3H), 3.19 (s, 31.28, 26.38, 22.94, 8.63.
3H), 1.97-1.88 (m, 1H), 1.79-1.70 (m, 1H), 1.34 (s, 3H), 0.59 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 180.24, 155.95, 136.96, 3-Ethyl-1,3-dimethyl-5-(trifluoromethyl)indolin-2-one
(3m).9d
135.28, 111.40, 110.22, 107.89, 55.67, 49.27, 31.38, 26.00, 23.27, White solid; 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.0 Hz, 1H),
8.72.
7.41 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 3.26 (s, 3H), 2.02-1.93 (m, 1H),
1.86-1.77 (m, 1H), 1.39 (s, 3H), 0.60 (t, J = 7.2 Hz, 3H); 13C NMR (100
5-Ethoxy-3-ethyl-1,3-dimethylindolin-2-one (3f). Colorless oil; 1H MHz, CDCl3): δ 180.46, 146.42, 134.48, 125.41 (q, J1 = 8.0 Hz, J2 = 4.0
NMR (400 MHz, CDCl3): δ 6.79-6.72 (m, 3H), 4.01 (q, J1 = 14.0 Hz, J2 = Hz), 124.57 (q, J1 = 64.5 Hz, J2 = 32.2 Hz), 124.45 (q, J1 = 539.6 Hz, J2
7.2 Hz, 2H), 3.19 (s, 3H), 1.97-1.88 (m, 1H), 1.78-1.69 (m, 1H), 1.42 = 269.8 Hz), 119.38 (q, J1 = 7.1 Hz, J2 = 3.5 Hz), 107.46, 48.85, 31.27,
(t, J = 7.2 Hz, 3H), 1.34 (s, 3H), 0.59 (t, J = 7.2 Hz, 3H); 13C NMR (100 26.05, 22.97, 8.58.
MHz, CDCl3): δ 180.28, 155.24, 136.90, 135.24, 112.11, 110.89,
107.90, 63.98, 49.29, 31.40, 26.03, 23.31, 14.83, 8.76. HRMS (ESI) 3-Ethyl-1,3-dimethyl-5-(trifluoromethoxy)indolin-2-one
[M+H]+ Calcd. for C14H20NO2: 234.1489, Found: 234.1482. Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.15 (d, J = 8.4 Hz, 1H),
7.06 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 3.23 (s, 3H), 1.99-1.91 (m, 1H),
(3n).
3-Ethyl-5-fluoro-1,3-dimethylindolin-2-one (3g). Colorless oil; 1H 1.82-1.73 (m, 1H), 1.36 (s, 3H), 0.61 (t, J = 7.6 Hz, 3H); 13C NMR (100
NMR (400 MHz, CDCl3): δ 6.99-6.92 (m, 2H), 6.80-6.77 (m, 1H), 3.21 MHz, CDCl3): δ 180.28, 144.76, 142.10, 135.49, 120.58, 120.55 (q, J1
(s, 3H), 1.99-1.90 (m, 1H), 1.80-1.71 (m, 1H), 1.35 (s, 3H), 0.60 (t, J = = 509.3 Hz, J2 = 254.7 Hz), 116.47, 108.04, 49.22, 31.33, 26.05,
7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 180.09, 159.20 (d, J = 22.99, 8.58. HRMS (ESI) [M+H]+ Calcd. for C13H15NO2F3: 274.1049,
238.7 Hz), 139.23, 135.50 (d, J = 7.6 Hz), 113.53 (d, J = 23.3 Hz), Found: 274.1047.
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5-Acetyl-3-ethyl-1,3-dimethylindolin-2-one (3o). White solid; 1H 2.41-2.32 (m, 1H), 1.89-1.80 (m, 1H), 1.69 (s, 3H), 0.61 (t, J = 7.6 Hz,
NMR (400 MHz, CDCl3): δ 7.95 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 6.90 3H); 13C NMR (100 MHz, CDCl3): δ 173.47, 138.11, 136.92, 133.18,
(d, J = 8.0 Hz, 1H), 3.27 (s, 3H), 2.61 (s, 3H), 2.01-1.92 (m, 1H), 1.88- 126.95, 126.22, 125.77, 122.61, 122.33, 119.99, 108.10, 48.10,
1.79 (m, 1H), 1.39 (s, 3H), 0.59 (t, J = 7.6 Hz, 3H); 13C NMR (100 37.98, 29.96, 29.48, 9.66.
MHz, CDCl3): δ 196.84, 180.91, 147.81, 134.13, 132.02, 129.81,
122.26, 107.13, 48.73, 31.31, 26.27, 26.20, 23.14, 8.71. HRMS (ESI) 6-Bromo-3-ethyl-1,3-dimethylindolin-2-one (3w).9d Colorless oil; 1H
[M+H]+ Calcd. for C14H18NO2: 232.1332, Found: 232.1325.
NMR (400 MHz, CDCl3): δ 7.19 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 8.0 Hz,
1H), 6.99 (s, 1H), 3.19 (s, 3H), 1.96-1.87 (m, 1H), 1.79-1.70 (m, 1H),
3-Ethyl-1,3-dimethyl-2-oxoindoline-5-ethyl carboxylate (3p).9d 1.33 (s, 3H), 0.59 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
Light yellow oil; 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 8.4 Hz, 1H), 180.36, 144.79, 132.76, 125.04, 123.74, 120.99, 111.26, 48.69,
7.85 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.38 (q, J1 = 14.0 Hz, J2 = 7.2 Hz, 31.23, 26.07, 23.08, 8.70.
2H), 3.26 (s, 3H), 2.01-1.92 (m, 1H), 1.87-1.78 (m, 1H), 1.43-1.38 (m,
6H), 0.59 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 180.80, 4-Bromo-3-ethyl-1,3-dimethylindolin-2-one (3w’).9d Colorless oil;
166.38, 147.46, 133.71, 130.30, 124.62, 123.58, 107.17, 60.69, 1H NMR (400 MHz, CDCl3): δ 7.18-7.11 (m, 2H), 6.79 (d, J = 7.2 Hz,
48.68, 31.27, 26.09, 23.09, 14.26, 8.65.
1H), 3.21 (s, 3H), 2.40-2.31 (m, 1H), 1.95-1.87 (m, 1H), 1.49 (s, 3H),
0.50 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 179.94, 145.48,
3,7-Diethyl-1,3-dimethylindolin-2-one (3q). Colorless oil; 1H NMR 131.07, 129.06, 126.57, 118.70, 106.76, 51.56, 28.23, 26.12, 21.03,
(400 MHz, CDCl3): δ 7.05-7.02 (m, 1H), 6.99-6.98 (m, 2H), 3.49 (s, 9.01.
3H), 2.92 (q, J1 = 15.2 Hz, J2 = 7.6 Hz, 2H), 1.96-1.87 (m, 1H), 1.77-
1.68 (m, 1H), 1.33 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H), 0.56 (t, J = 7.2 Hz, 1-Ethyl-1,3-dimethyl-1H-benzo[e]indol-2-(3H)-one (3x). Colorless
3H); 13C NMR (100 MHz, CDCl3): δ 181.58, 140.47, 134.84, 129.63, oil; 1H NMR (400 MHz, CDCl3): δ 7.91-7.82 (m, 3H), 7.51-7.47 (m,
126.12, 122.42, 120.23, 48.01, 31.86, 29.11, 24.80, 23.67, 16.79, 1H), 7.37-7.33 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 3.32 (s, 3H), 2.31-
8.69. HRMS (ESI) [M+H]+ Calcd. for C14H20NO: 218.1539, Found: 2.15 (m, 2H), 1.61 (s, 3H), 0.46 (t, J = 7.2 Hz, 3H); 13C NMR (100
218.1540.
MHz, CDCl3): δ 181.72, 140.88, 130.45, 129.63, 129.44, 128.95,
126.88, 124.83, 123.32, 121.85, 109.36, 50.98, 31.12, 26.23, 23.64,
3-Ethyl-7-methoxy-1,3-dimethylindolin-2-one (3r). Colorless oil; H 9.18. HRMS (ESI) [M+H]+ Calcd. for C16H18NO: 240.1383, Found:
1
NMR (400 MHz, CDCl3): δ 7.02-6.98 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 240.1384.
6.78 (d, J = 7.2 Hz, 1H), 3.86 (s, 3H), 3.49 (s, 3H), 1.96-1.87 (m, 1H),
1.77-1.68 (m, 1H), 1.32 (s, 3H), 0.57 (t, J = 7.6 Hz, 3H); 13C NMR (100 3-Ethyl-1,3-dimethyl-1H-benzo[f]indol-2-(3H)-one (3x’). Colorless
MHz, CDCl3): δ 180.85, 145.15, 135.59, 131.16, 122.83, 115.20, oil; 1H NMR (400 MHz, CDCl3): δ 7.80-7.77 (m, 2H), 7.57 (s, 1H),
111.43, 55.81, 48.93, 31.57, 29.23, 23.55, 8.77. HRMS (ESI) [M+H]+ 7.46-7.43 (m, 1H), 7.39-7.35 (m, 1H), 7.09 (s, 1H), 3.30 (s, 3H), 2.06-
Calcd. for C13H18NO2: 220.1332, Found: 220.1330.
1.97 (m, 1H), 1.90-1.81 (m, 1H), 1.44 (s, 3H), 0.62 (t, J = 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 180.24, 142.09, 134.91, 133.59,
7-Bromo-3-ethyl-1,3-dimethylindolin-2-one (3s). Colorless oil; 1H 130.39, 127.89, 126.97, 126.18, 124.03, 121.64, 103.25, 48.38,
NMR (400 MHz, CDCl3): δ 7.36 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.2 Hz, 31.91, 26.23, 23.78, 8.84. HRMS (ESI) [M+H]+ Calcd. for C16H18NO:
1H), 6.92-6.88 (m, 1H), 3.60 (s, 3H), 1.99-1.90 (m, 1H), 1.78-1.69 (m, 240.1383, Found: 240.1380.
1H), 1.34 (s, 3H), 0.58 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ 181.01, 140.79, 137.14, 133.26, 123.56, 121.49, 102.27, 48.69, 3-Ethyl-1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one
31.80, 29.58, 23.68, 8.74. HRMS (ESI) [M+H]+ Calcd. for C12H15NOBr: (3y).9b Colorless oil; 1H NMR (400 MHz, CDCl3): δ 8.19-8.17 (m,
268.0332, Found: 368.0334.
1H), 7.42-7.40 (m, 1H), 6.99-6.95 (m, 1H), 3.30 (s, 3H), 2.00-
1.91 (m, 1 H), 1.84-1.75 (m, 1H), 1.38 (s, 3H), 0.64 (t, J = 7.6 Hz,
3-Ethyl-1,3,4,6-tetramethylindolin-2-one (3t).9d Colorless oil; 1H 3H); 13C NMR (100 MHz, CDCl3): δ 180.23, 156.93, 146.47,
NMR (400 MHz, CDCl3): δ 6.65 (s, 1H), 6.52 (s, 1H), 3.18 (s, 3H), 2.34 129.76, 128.15, 117.91, 48.51, 30.91, 25.09, 22.58, 8.71.
(s, 3H), 2.31 (s, 3H), 1.99-1.96 (m, 2H), 1.40 (s, 3H), 0.49 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 180.77, 143.74, 137.24, 1-Ethyl-1-methyl-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-
1
133.61, 127.19, 125.32, 106.43, 49.71, 29.28, 25.89, 22.08, 21.34, 2(4H)-one (3z) Colorless oil; H NMR (400 MHz, CDCl3): δ 7.01-
17.77, 9.03.
6.99 (m, 2H), 6.96-6.92 (m, 1H), 3.73-3.70 (m, 2H), 2,79 (t, J =
6.0 Hz, 1H), 2.03-1.97 (m, 2H), 1.94-1.85 (m, 1H), 1.82-1.73 (m,
4,6-Dichloro-3-ethyl-1,3-dimethylindolin-2-one (3u).9d White solid; 1H), 1.35 (s, 3H), 0.66-0.62 (m, 3H); 13C NMR (100 MHz, CDCl3):
1H NMR (400 MHz, CDCl3): δ 7.01 (s, 1H), 6.77 (s, 1H), 3.20 (s, 3H), δ 179.47, 139.09, 132.36, 126.28, 121.69, 120.31, 119.72,
2.28-2.19 (m, 1 H), 2.00-1.91 (m, 1H), 1.47 (s, 3H), 0.51 (t, J = 7.6 Hz, 50.14, 38.55, 31.09, 24.56, 22.80, 21.24, 8.79. HRMS (ESI)
3H); 13C NMR (100 MHz, CDCl3): δ 179.84, 146.00, 134.05, 130.82, [M+H]+ Calcd. for C14H18NO: 216.1383, Found: 216.1390.
127.92, 122.85, 107.17, 50.67, 28.45, 26.29, 21.08, 9.04.
1,3-Diethyl-3-methylindolin-2-one (3aa).9b Colorless oil; 1H NMR
3-Ethyl-1,3-dimethyl-1H-benzo[g]indol-2(3H)-one (3v).9d Colorless (400 MHz, CDCl3): δ 7.27-7.23 (m, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.07-
oil; 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.0 Hz, 1H), 7.55- 7.03 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 3.88-3.79 (m, 1H), 3.75-3.66
7.49(m, 2H), 7.43-7.39 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 3.53 (s, 3H), (m, 1H), 1.99-1.90 (m, 1H), 1.81-1.72 (m, 1H), 1.34 (s, 3H), 1.25 (t, J
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= 7.2 Hz, 3H), 0.58 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
180.13, 142.43, 134.03, 127.43, 122.54, 122.05, 107.84, 48.64,
34.32, 31.43, 23.23, 12.64, 8.64.
Soc., 2006, 128, 12634; (b) Y. Zhang, J. Feng and C.-J. Li, J. Am.
Chem. Soc., 2008, 130, 2900; (c) S. R. Neufeldt, C. K. Seigerman
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Zhang, C. Chen and W. Chen, Org. Lett., 2013, 15, 3326; (e) Y.
Zhu, H. Yan, L. Lu, D. Liu, G. Rong and J. Mao, J. Org. Chem., 2013,
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J. Donohoe, Angew. Chem., Int. Ed., 2014, 53, 761; (g) Y. Li, D.
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3198.
1-Benzyl-3-ethyl-3-methylindolin-2-one (3ab).9b Colorless oil; 1H
NMR (400 MHz, CDCl3): δ 7.28-7.27 (m, 4H), 7.24-7.20 (m, 1H), 7.17-
7.15 (m, 1H), 7.14-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.71 (d, J = 8.0
Hz, 1H), 4.98 (d, J = 15.6 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 2.05-1.96
(m, 1H), 1.87-1.78 (m, 1H), 1.40 (s, 3H), 0.64 (t, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 180.65, 142.41, 136.05, 133.71, 128.57,
127.40, 127.35, 127.11, 122.44, 122.30, 108.79, 48.79, 43.46, 31.33, 3 G. A. Russell and S. A. Weiner, J. Org. Chem., 1966, 31, 248.
23.63, 8.93.
4 For selected review: X.-F. Wu and K. Natte, Adv. Synth. Catal.,
2016, 358, 336; For selected examples: (a) K. Kawai, Y.-S. Li, M.-F.
Song and H. Kasai, Bioorg. Med. Chem. Lett., 2010, 20, 260; (b) B.
Yao, R.-J. Song, Y. Liu, Y.-X. Xie, J.-H. Li, M.-K. Wang, R.-Y. Tang, X.-
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B. N. Atkinson and J. M. J. Williams, ChemCatChem., 2014, 6,
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3-(3-Ethyl-3-methyl-2-oxoindolin-1-yl)propanenitrile (3ac). White
solid; 1H NMR (400 MHz, CDCl3): δ 7.30-7.26 (m, 1H), 7.20 (d, J = 7.2
Hz, 1H), 7.12-7.08 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.10-3.95 (m, 2H),
2.78-2.74 (m, 3H), 1.99-1.91 (m, 1H), 1.84-1.75 (m, 1H), 1.37 (s, 3H),
0.61 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 180.48, 141.16,
133.49, 127.59, 122.79, 117.04, 107.60, 48.55, 35.47, 31.26, 23.23,
16.11, 8.61. HRMS (ESI) [M+H]+ Calcd. for C14H17N2O: 229.1335, 5 For selected reviews: (a) B. M. Trost and M. K. Brennan, Synthesis,
Found: 229.1339.
2009, 3003; (b) R.-J. Song, Y. Liu, Y.-X. Xie and J.-H. Li, Synthesis,
2015, 1195; (c) C.-C. Li and S.-D. Yang, Org. Biomol. Chem., 2016,
14, 4365.
3-Ethyl-3-methyl-1-phenylindolin-2-one (3ad).9b Colorless oil;
1H NMR (400 MHz, CDCl3): δ 7.52-7.48 (m, 2H), 7.41-7.38 (m, 6 For selected examples: (a) S. Jaegli, J. Dufour, H.-L. Wei, T. Piou,
3H), 7.23-7.21 (m, 1H), 7.19-7.16 (m, 1H), 7.11-7.07 (m, 1H),
6.82 (d, J = 8.0 Hz, 1H), 2.09-2.00 (m, 1H), 1.90-1.81 (m, 1H),
1.47 (s, 3H), 0.71 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ 180.03, 143.36, 134.71, 133.64, 129.44, 127.77, 127.45,
126.50, 122.81, 122.73, 109.08, 48.91, 31.99, 23.53, 8.80.
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J. Am. Chem. Soc., 2015, 137, 16028; (e) H. Wang, L.-N. Guo and
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7 For selected examples: (a) M.-B. Zhou, R.-J. Song, X.-H. Ouyang, Y.
Liu, W.-T. Wei, G.-B. Deng and J.-H. Li, Chem. Sci., 2013, 4, 2690;
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Chem., Int. Ed., 2013, 52, 3972; (c) K. Matcha, R. Narayan and A.
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554; (k) J. Li, Z. Wang, N. Wu, G. Gao and J. You, Chem. Commun.,
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Chem., 2014, 12, 6349; (m) J.-Y. Wang, Y.-M. Su, F. Yin, Y. Bao, X.
Zhang, Y.-M. Xu and X.-S. Wang, Chem. Commun., 2014, 50, 4108;
(n) J.-H. Fan, W.-T. Wei, M.-B. Zhou, R.-J. Song and J.-H. Li,
Angew. Chem., Int. Ed., 2014, 53, 6650；(o) C. Pan, H. Zhang and
C. Zhu, Org. Biomol. Chem., 2015, 13, 361; (p) L. Zhang, D. Liu,
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Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (No. 21572078, 21372095), Nature
Science Foundation of Anhui Province (No. 170808J02) and the
Key Project of Science and Technology of Anhui Educational
Bureau (No. KJ2015ZD34) for financial support of this work.
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M. Fraga, Chem. Rev., 2011, 111, 5215; (b) H. Schönherr and T.
Cernak, Angew. Chem., Int. Ed., 2013, 52, 12256. For selected
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6 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
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11 During the preparation of our manuscript, Li and co-workers
reported a similar work, see: Z. Li, X. Cui, L. Niu, Y. Ren, M. Bian,
X. Yang, B. Yang, Q. Yan and J. Zhao, Adv. Synth. Catal., 2017, 359,
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