Cyclization and oxidation of o-bromophenylacetamides for the synthesis of oxindoles and isoindigoes

Article abstract of DOI:10.1016/j.tet.2017.12.005

N-substituted oxindoles were obtained through a facile KOH/DMSO promoted intramolecular cyclization of o-bromophenylacetamides in good yields. Furthermore, isoindigo derivatives were readily synthesized through sequential intramolecular cyclization, oxida

Full text of DOI:10.1016/j.tet.2017.12.005

Tetrahedron 74 (2018) 354e359
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Cyclization and oxidation of o-bromophenylacetamides for the
synthesis of oxindoles and isoindigoes
Liang Liu, Lei Song, Yujun Guo, Dewen Min, Tianchao Shi, Wu Zhang*
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of Chemistry and Materials
Science, Anhui Normal University, Wuhu 241000, People's Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
N-substituted oxindoles were obtained through a facile KOH/DMSO promoted intramolecular cyclization
of o-bromophenylacetamides in good yields. Furthermore, isoindigo derivatives were readily synthesized
through sequential intramolecular cyclization, oxidation and condensation of o-bromophenylacetamide
in the presence of copper (II) acetate monohydrate, iodobenzene diacetate and KOH/DMSO. This method
provides a convenient synthesis of a range of oxindoles and symmetrical biologically important (E)-
bisindole-2-ones using o-bromophenylacetamide as sole starting material. The reaction mechanism is
elucidated in light of the control experiment results.
Received 26 September 2017
Received in revised form
14 November 2017
Accepted 4 December 2017
Available online 6 December 2017
Keywords:
Condensation
Cyclization
Isoindigo
© 2017 Elsevier Ltd. All rights reserved.
Oxidation
Oxindole
1. Introduction
isoindigo via the reaction of substituted isatins with tris(diethyla-
mino)phosphine.3b Recently, Huang reported palladium (II)
Isoindigoes are active ingredients in some traditional Chinese
medicines and constitute the scaffold of some recently identified
molecules with antileukemia activities.1 Meisoindigo (1-
acetate-catalyzed dual CeH functionalization for the synthesis of
(E)-bisindole-2-ones from diarylbut-2- ynediamides.3d
Oxindole skeleton is the key structural motif in isoindigoes and
numerous natural products,4 and also the important starting ma-
terial for the synthesis of isoindigoes. Common method for the
synthesis of oxindole involves the derivatization of relevant het-
erocycles, such as reduction of isatins or oxidation of indoles.5
Another classical approach to the oxindole is the Friedel-Crafts
methylisoindigo) and Natura™ (1-b-D-triacetylxylopyranosyl iso-
indigo) are isoindigo derivatives of which meisoindigo is a thera-
peutic agent used for the treatment of chronic myelocytic leukemia
(CML) in China, and Natura™ exhibit anti-cancer activity (Fig. 1).
Besides, isoindigoes such as DAD have important applications in
organic electronics as one of the latest reported amide-based ac-
cyclization of
a
-haloacetanilides and related variations.6
ceptors, and their perfect planar
p
-conjugated structure, together
Transition-metal catalyzed synthesis of oxindoles via intra-
molecular arylation or alkylation of anilide derivatives have also
been developed.7 In addition, metal catalyzed CeH activation has
emerged as a highly atom-economic strategy to oxindoles,8 as
exemplified by the direct Pd-catalyzed intramolecular oxidative
coupling method developed by Kündig for the synthesis of 3,3-
disubstitued oxindoles.8a Moreover, Bolm et al. have reported the
synthesis of oxindoles by t-BuOK-promoted intramolecular aryla-
tions of fluoro- and chloro-substituted anilides under transition
metal-free conditions.9
with a strong electron-withdrawing effect, make them ideal
monomers for the synthesis of donor/acceptor low bandgap con-
jugated polymer for varied electronic applications in organic pho-
tovoltaics (OPVs) and organic field effect transistors (OFETs).2
Therefore, the development of effective methods for their synthe-
sis is a research topic of great interest.3 Facile synthesis of func-
tionalized aryl-containing isoindigo derivatives via dimerization of
substituted indolin-2-one carbenens have been reported.3a Bog-
danov group have reported the synthesis of long-chain N-alkyl
As part of our continued efforts in developing efficient protocols
for the synthesis of useful heterocycle,10 herein we report an effi-
cient base-promoted intramolecular cyclization of o-hal-
ophenylacetamide for the facile synthesis of oxindoles in good
* Corresponding author.
E-mail address: zhangwu@mail.ahnu.edu.cn (W. Zhang).
https://doi.org/10.1016/j.tet.2017.12.005
0040-4020/© 2017 Elsevier Ltd. All rights reserved.

L. Liu et al. / Tetrahedron 74 (2018) 354e359
355
improved to 84% when the reaction was conducted at 120 ꢀC (entry
4). However, no significant improvement in the yield was observed
by increasing the temperature further. Solvent also played an
important role in the reaction. Various common solvents such as
DMF, diglyme, dioxane, and toluene are inferior to DMSO (Table 1,
entries 6e9). Then, a variety of bases were examined. While strong
bases such as KOH, KOtBu and NaOH exhibited high reactivity to the
reaction in DMSO (Table 1, entries 9e14), weak ones like Na2CO3,
K2CO3, and K3PO4 were ineffective. When the amount of KOH was
decreased to 1 equiv, the yield decreased to 60%. The reaction
became sluggish under air and a lower yield was obtained. Thus,
the reaction was best performed in the presence of KOH in DMSO at
120 ꢀC under argon.
With the optimized conditions in hand, the scope of the sub-
strates was screened. Twelve oxindole derivatives were obtained,
and the best yield is up to 93% (Scheme 1). We found that the
electronic nature of the substituent group R1 of substrates had an
obvious effect on the yields, and electron-withdrawing substituents
Fig. 1. Representative examples of isoindigoes.
yields. Furthermore, isoindigo derivatives could be obtained by
sequential cyclization, oxidation and condensation of o-hal-
ophenylacetamide in the presence of copper acetate monohydrate
and iodobenzene diacetate as oxidizer in KOH/DMSO system.
2. Results and discussion
In our initial attempt to prepare 1-benzylindolin-2-one (2a)
from N-benzyl-2-(2-bromophenyl)acetamide (1a) by intra-
molecular N-arylation in the superbasic medium consisting of KOH
and DMSO at 50 ꢀC, 35% 2a was obtained (Table 1, entry 1). The
effects of base, solvent, temperature and time were further inves-
tigated and the results were summarized in Table 1. Reaction
temperature had a significant effect on this reaction. The yield was
Table 1
Optimization of the reaction conditions.a
Entry
Base
Solvent (mL)
T (ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
Na2CO3
KOtBu
NaOH
KOH
KOH
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
Diglyme (2)
DMF (2)
Dioxane (2)
DMSO (4)
DMSO (4)
DMSO (4)
DMSO (4)
DMSO (4)
DMSO (4)
DMSO (4)
50
80
35
65
70
84
84
43
nr
100
120
130
100
100
100
120
120
120
120
120
120
120
nr
9
88
65
nr
88
87
60
Trace
10c
11
12
13
14d
15e
a
Reaction conditions: 1a (0.50 mmol), base (2.0 equiv), stirred under argon for
10 h.
b
c
Isolated yield.
Reaction time: 5 h.
KOH (1.0 equiv).
KOH (4.0 equiv).
d
e
Scheme 1. Scope of the synthesis of oxindoles.a

356
L. Liu et al. / Tetrahedron 74 (2018) 354e359
on the aromatic ring are clearly favored (2h, 2i, 2j and 2k).
Comparing the cyclization results of 2-bromoderivatives 1b
(R1¼H), 1j (R1¼Cl), and 1l (R1¼OCH3) revealed that the latter pro-
cess was the most difficult one leading to product 2l in only 40%
yield. With respect to the N-substituent R,2 we observed there to be
a significant effect of amide substitution on the cyclization. We
were pleased to find that both alkyl and benzyl groups were
tolerated. However, attempted reaction of the N-aryl substituted
substrates 2-(2-bromophenyl)eN-(p-tolyl)acetamide revealed
limitation of the method, no cyclization occurred, and only trace of
oxidation product of the starting material characterized as -hy-
droxyl amide by NMR was observed, which might be due to the
existence of p- conjugation in the N-aryl substituted amide. The
a
a
p
findings demonstrated that the cyclization is highly dependent on
the nitrogen substituents.
Only a trace amount of product 2a was formed in 4 equiv KOH
(Table 1, entry 15). The reaction became sluggish under air and a
lower yield of 2a was obtained. This inspired us to expand the re-
action conditions in order to obtain more interesting results. Our
literature perusal on this aspect revealed that an efficient copper-
catalyzed synthesis of N-substituted isatins had been developed
in good yields from arylacetamides in the presence of TBAB using
3.0 equiv of K2CO3 as the base under air.11
To test the oxidative cyclization reaction of o-bromophenyla-
cetamides in KOH/DMSO system, a series of experiments were
conducted. To our surprise, with iodobenzene diacetate [PhI(OAc)2]
as the oxidant, copper (II) salt exhibit remarkable catalytic activity
toward the selective oxidation of oxindoles and isoindigo 3a could
be obtained. Cu(OAc)2$H2O proved to be the best promoter among
various copper sources that were examined. No desired product
was observed in the absence of copper salt or iodobenzene diac-
etate. Reactions in the presence of other bases, such as K2CO3, and
K3PO4, did not proceed well. This protocol provides a facile way to a
library of isoindigo derivatives with the advantages of easily
available starting materials and operational simplicity (Scheme 2).
To gain some insights into the mechanism of this trans-
formation, several control experiments were performed under the
standard conditions (Scheme 3). In view of the importance of trace
metals present in commercially available metal salts can catalyze
various reactions,12 especially some known palladium-catalyzed
related cyclizations, additional experiments were performed to
further examine this issue. No difference in the yield was noted in
experiments when KOH from different sources was used. The yield
of 2a remained essentially unchanged when high-purity KOH
(>99.995%) was applied in the reactions with new glassware and
magneton, indicating that metal residues in the base were not
critical. Also, when N-benzyl-2-(3-bromophenyl)acetamide (1m), a
regioisomer of 1a, was subjected to the KOH/DMSO system, no
cyclization product was detected, but only the starting material was
recovered. This result renders less probable the involvement of
aryne intermediates in the cyclization process. Notably, the addi-
tion of a typical radical scavenger tetramethylpiperidine N-oxide
(TEMPO) to the reaction system completely inhibited the reaction.
On the basis of the above findings, a plausible radical-nucleophilic
aromatic substitution (SRN1) mechanism is involved in the cycli-
zation reaction. The reaction may initiate with the deprotonation of
NeH by KOH leading to intermediate I, which might be trans-
formed into aryl radical intermediate II.13 The aryl radical reacts
with nitrogen nucleophile to a new radical anion III which goes on
to form the intramolecular substituted product 2 by transferring its
electron to intermediate I. The resulted oxindole 2 then undergoes
oxidation to isatins by iodobenzene diacetate and Cu(OAc)2. Finally,
isoindigo 3 was obtained by the base-promoted isatin/oxindole
condensation reaction (see Scheme 4).
Scheme 2. Synthesis of isoindigoes.
Scheme 3. Control Experiments.
3. Conclusion
In conclusion, we have successfully developed an efficient
method for the synthesis of oxindole, and isoindigo derivatives
sequential intramolecular cyclization, oxidation and condensation
of o-bromophenylacetamide. Further studies towards the synthetic
applications of base promoted intramolecular cyclization and

L. Liu et al. / Tetrahedron 74 (2018) 354e359
357
corresponding products 3a-3i.
4.4. Characterization data of product
All the products were characterized by 1H NMR, 13C NMR, GCMS,
and HRMS (for new products). The copies of NMR charts were re-
ported in supplementary data.
4.4.1. 1-Benzylindolin-2-one (2a)15
White solid (98 mg, 88% yield); m. p. 67e69 ꢀC (Lit. 66e67 ꢀC);
1H NMR (300 MHz, CDCl3)
d
7.29e7.10 (m, 7H), 6.98 (t, J ¼ 7.2, 1H),
6.69 (d, J ¼ 7.8, 1H), 4.87 (s, 2H), 3.56 (s, 2H); 13C NMR (75 MHz,
CDCl3)
d 175.2, 144.3, 136.0, 128.8, 127.8, 127.7, 127.4, 124.5, 124.5,
122.4, 109.1, 43.7, 35.8.
4.4.2. 1-(4-methoxybenzyl)indolin-2-one (2b)15
Scheme 4. Plausible Mechanism.
White solid (113 mg, 89% yield); m. p. 107e109 ꢀC (Lit.
105e107 ꢀC); 1H NMR (300 MHz, DMSO-d6)
6.99 (t, J ¼ 7.5 Hz,1H), 6.83 (d, J ¼ 8.4 Hz, 2H), 6.74 (d, J ¼ 7.5 Hz,1H),
d
¼ 7.27e7.14 (m, 4H),
oxidation of carboxylic acid derivatives are in progress.
4.84 (s, 2H), 3.75 (s, 3H), 3.59 (s, 2H). 13C NMR (75 MHz, CDCl3)
d
¼ 175.1, 159.0, 144.3, 128.8, 127.9, 124.5, 122.3, 114.1, 109.1, 55.3,
4. Experiment section
43.2, 35.8.
4.1. General
4.4.3. 1-Isopropylindolin-2-one (2c)16
Colorless oil (75 mg, 86% yield); 1H NMR (300 MHz, CDCl3)
All reactions were carried out under argon atmosphere using
pre-dried
d
7.26e7.21 (m, 2H), 7.03e6.98 (m, 2H), 4.74e4.70 (m, 1H), 3.49 (s,
glassware.
Cyclization
substrates
o-hal-
2H), 1.48 (d, J ¼ 7.2 Hz, 6H); 13C NMR (300 MHz, CDCl3)
d 174.7,
ophenylacetamides 1 were prepared from o-halophenylacetic acid
and amine in analogy to previously described methodologies.14 All
starting materials and reagents were commercially available and
used directly without further purification. KOH (99.995%) was
purchased from Sigma Aldrich. All known products gave satisfac-
tory analytical data by NMR spectra, which corresponding to the
reported literature values. Unknown compounds were confirmed
by HRMS additionally. All melting points were taken on an X-4
Digital Melting Point Apparatus without correction. NMR spectra
were recorded on Bruker Avance 300 or 500 instruments in the
solvent indicated with tetramethylsilane (TMS) as an internal
143.8, 127.5, 125.0, 124.5, 121.7, 109.8, 43.5, 36.0, 19.3. HRMS (ESI)
calcd for C11H14NO ([MþH]þ) 176.1072, found 176.1075.
4.4.4. 1-(tert-butyl)indolin-2-one (2d)
Yellowish oil (83 mg, 88% yield); 1H NMR (300 MHz, CDCl3)
d
7.26e7.18 (m, 3H), 6.98 (t, J¼7.0, 1H), 3.46 (s, 2H), 1.72 (s, 9H); 13
C
NMR (75 MHz, CDCl3)
d 175.8, 145.5, 127.1, 125.6, 124.3, 121.4, 113.1,
57.6, 37.4, 29.1. HRMS (ESI) calcd for C12H16NO ([MþH]þ) 190.1232,
found 190.1236.
4.4.5. 1-Butylindolin-2-one (2e)15
standard; chemical shifts (d) are given in ppm, the coupling con-
Colorless oil (79 mg, 84% yield); 1H NMR (300 MHz, CDCl3)
stants J are given in Hz. High-resolution mass spectral (HRMS) were
obtained on Agilent 6200 LC/MS TOF using APCI or ESI in positive
mode.
d
7.28e7.22 (m, 2H), 7.01 (t, J ¼ 7.5 Hz, 1H), 6.83 (d, J ¼ 7.8 Hz, 1H),
3.70 (t, J ¼ 7.2 Hz, 2H), 3.50 (s, 2H), 1.70e1.60 (m, 2H), 1.46e1.33 (m,
2H), 0.95 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 175.0, 144.7,
127.8, 124.7, 124.4, 122.1, 108.3, 39.8, 35.8, 29.5, 20.2, 13.8.
4.2. General procedure for the synthesis of oxindoles
4.4.6. 1-Dodecylindolin-2-one (2f)
Yellow solid (140 mg, 93% yield); m. p. 32e34 ꢀC; 1H NMR
A
mixture of N-alkyl-2-(2-halogenphenyl)acetamide
1
(0.5 mmol), KOH (1.0 mmol) was stirred in DMSO (4.0 mL) at 120 ꢀC
in an oil bath in Ar for 10 h. Upon completion, the resulting mixture
was cooled to room temperature and then extracted with EtOAc
(2 ꢁ 15 mL). The combined organic phase was washed with brine
and dried over anhydrous MgSO4. After that the organic phase was
filtered, and the filtrate was evaporated in vacuum to give the crude
product which was purified by column chromatography on silica
gel using appropriate eluent to afford the desired product 2a-2l.
(300 MHz, DMSO-d6)
d
7.28e7.22 (m, 2H), 7.02 (t, J ¼ 7.5 Hz, 1H),
6.82 (d, J ¼ 7.8 Hz, 1H), 3.69 (t, J ¼ 7.4 Hz, 2H), 3.50 (s, 2H), 1.68e1.64
(m, 2H), 1.33e1.25 (m, 18H), 0.88 (t, J ¼ 6.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3)
d 174.9, 144.7, 127.8, 124.7, 124.4, 122.1, 108.3, 40.1,
35.8, 31.9, 29.6, 29.6, 29.5, 29.4, 29.3, 27.5, 27.0, 22.7, 14.2. HRMS
(ESI) calcd for C20H32NO ([MþH]þ) 302.2484, found 302.2484.
4.4.7. 1-Cyclohexylindolin-2-one (2g)
White solid (90 mg, 84% yield); m. p. 94e96 ꢀC; 1H NMR
4.3. General procedure for the synthesis of isoindigoes
(300 MHz, CDCl3) d 7.26e7.24 (m, 2H), 7.07e6.98 (m, 2H), 4.26e4.18
(m, 1H), 3.50 (s, 2H), 2.22e2.09 (m, 2H), 1.92e1.88 (m, 2H),
A
mixture of N-alkyl-2-(2-halogenphenyl)acetamide
1
1.78e1.74 (m, 3H), 1.49e1.23 (m, 3H); 13C NMR (75 MHz, CDCl3)
(0.25 mmol), Cu(OAc)2$H2O (0.1 mmol, 40 mol %), iodobenzene
diacetate (0.5 mmol) and KOH (1.0 mmol) was stirred in DMSO
(4.0 mL) at 130 ꢀC in an oil bath under Ar for 10 h. The resulting
mixture was cooled to room temperature and then extracted with
EtOAc (2 ꢁ 10 mL). The organic phases were combined and dried
with anhydrous Na2SO4 and evaporated under vacuum. The crude
product was purified by column chromatography to give the
d 174.9, 144.2, 127.4, 125.0, 124.5, 121.6, 110.1, 51.9, 36.0, 29.0, 26.0,
25.4. HRMS (ESI) calcd for C14H18NO ([MþH]þ) 216.1388, found
216.1387.
4.4.8. 1-Benzyl-5-chloroindolin-2-one (2h)17
White solid (113 mg, 88% yield); m. p. 96e99 ꢀC (Lit.
103e104 ꢀC); 1H NMR (300 MHz, CDCl3)
d7.31e7.23 (m, 6H), 7.13 (d,

358
L. Liu et al. / Tetrahedron 74 (2018) 354e359
J ¼ 8.1 Hz, 1H), 6.61 (d, J ¼ 8.1 Hz, 1H), 4.89 (s, 2H), 3.61 (s, 2H); 13
C
4.4.16. (E)-1,10-diisopropyl-[3,30-biindolinylidene]-2,20-dione (3d)18
Red solid (54 mg, 62% yield); m. p. 183e185 ꢀC; 1H NMR
NMR (75 MHz, CDCl3)
109.9, 43.8, 35.7.
d 174.5, 142.8, 135.4, 128.9, 127.8, 127.3, 124.9,
(500 MHz, CDCl3)
d
9.11 (d, J ¼ 7.5 Hz, 1H), 7.34e7.31 (m, 1H),
7.04e7.01 (m, 1H), 6.94 (d, J ¼ 8 Hz, 1H), 4.72e4.66 (m, 1H), 1.53 (d,
J ¼ 7 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d 168.0, 144.5, 134.1, 132.5,
4.4.9. 1-Butyl-5-chloroindolin-2-one (2i)
Yellow oil (88 mg, 79% yield); 1H NMR (300 MHz, CDCl3)
130.3, 122.3, 122.1, 109.5, 44.3, 19.8. HRMS (APCI) calcd for
C
22H23N2O2 ([MþH]þ) 347.1759, found: 347.1754.
d
7.27e7.10 (m, 2H), 6.74 (d, J ¼ 8.1 Hz, 1H), 3.68 (t, J ¼ 7.2 Hz, 2H),
3.51 (s, 2H), 1.68e1.59 (m, 2H), 1.44e1.32 (m, 2H), 0.95 (t, J ¼ 7.2 Hz,
4.4.17. (E)-1,10-di-sec-butyl-[3,30-biindolinylidene]-2,20-dione (3e)
Red solid (51 mg, 54% yield); m. p. 155e156 ꢀC; 1H NMR
3H). 13C NMR (75 MHz, CDCl3)
d 174.3, 143.3, 127.7, 127.4, 126.3,
124.9, 109.1, 39.9, 35.6, 29.4, 20.2, 13.7; HRMS (ESI) calcd for
12H15NOCl ([MþH]þ) 224.0842, found 224.0837.
(500 MHz, CDCl3)
d
9.12 (d, J ¼ 8 Hz, 1H), 7.32e7.29 (m, 1H),
C
7.04e7.01 (m, 1H), 6.93 (d, J ¼ 8 Hz, 1H), 2.12e2.06 (m, 1H),
1.87e1.79 (m, 2H), 1.52e1.50 (m, 3H), 0.91 (t, J ¼ 7.5 Hz, 3H); 13C
4.4.10. 5-Chloro-1-(4-methoxybenzyl)indolin-2-one (2j)
NMR (125 MHz, CDCl3)
d 168.3, 144.7, 134.0, 132.5, 130.2, 122.3,
White solid (111 mg, 86% yield); m. p. 138e140 ꢀC; 1H NMR
122.1, 109.6, 50.4, 26.9, 18.1, 11.8. HRMS (APCI) calcd for C24H27N2O2
(300 MHz, CDCl3)
d
¼ 7.21e7.12 (m, 4H), 6.84 (d, J ¼ 7.2 Hz, 2H), 6.64
([MþH]þ) 375.2072, found: 375.2067.
(d, J ¼ 7.8 Hz, 1H), 4.82 (s, 2H), 3.76 (s, 3H), 3.58 (s, 2H). 13C NMR
(75 MHz, CDCl3)
d
¼ 174.5, 159.1, 142.8, 128.7, 127.7, 127.5, 126.1,
4.4.18. (E)-1,10-dibutyl-[3,30-biindolinylidene]-2,20-dione (3f)18
Red solid (72 mg, 77% yield); m. p. 145e146 ꢀC; 1H NMR
124.8, 114.2, 109.9, 55.3, 43.3, 35.7. HRMS (ESI) calcd for
C
16H15NO2Cl ([MþH]þ) 288.0791, found 288.0789.
(500 MHz, CDCl3)
d
9.21 (d, J ¼ 8 Hz, 1H), 7.39e7.33 (m, 1H),
7.09e7.06 (m, 1H), 6.82 (d, J ¼ 8 Hz, 1H), 3.81 (t, J ¼ 7.5 Hz, 2H),
4.4.11. 5-Chloro-1-dodecylindolin-2-one (2k)
1.75e1.69 (m, 2H), 1.49e1.41 (m, 2H), 0.99 (t, J ¼ 7.5 Hz, 3H); 13C
Yellow solid (138 mg, 82% yield); m. p. 56e58 ꢀC; 1H NMR
NMR (125 MHz, CDCl3)
d 168.3, 145.1, 134.0, 132.7, 130.3, 122.5,
(300 MHz, CDCl3)
(t, J ¼ 7.2 Hz, 2H), 3.50 (s, 2H),1.31e1.25 (m, 20H), 0.87 (d, J ¼ 6.6 Hz,
3H). 13C NMR (75 MHz, CDCl3)
174.3, 143.3, 127.7, 126.3, 124.9,
d
7.27e7.22 (m, 2H), 6.74 (d, J ¼ 7.8 Hz, 1H), 3.67
122.1,108.3, 40.2, 30.0, 20.7,14.2. HRMS (APCI) calcd for C24H27N2O2
([MþH]þ) 375.2072, found: 375.2072.
d
109.1, 40.2, 35.7, 31.9, 29.6, 29.5, 29.5, 29.3, 29.3, 27.3, 26.9, 22.7,
14.1; HRMS (ESI) calcd for C20H31NOCl ([MþH]þ) 336.2094, found
336.2089.
4.4.19. (E)-1,10-dipentyl-[3,30-biindolinylidene]-2,20-dione (3g)
Red solid (71 mg, 71% yield); m. p. 97e98 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
9.18 (d, J ¼ 8 Hz, 1H), 7.37e7.33 (m, 1H), 7.06e7.03 (m, 1H),
6.79 (d, J ¼ 7.5 Hz, 1H), 3.77 (t, J ¼ 7.5 Hz, 2H), 1.74e1.68 (m, 2H),
1.38e1.36 (m, 4H), 0.90 (t, J ¼ 7 Hz, 3H); 13C NMR (125 MHz, CDCl3)
4.4.12. 1-(4-methoxybenzyl)-6-methoxyindolin-2-one (2l)
Colorless oil (57 mg, 40% yield); 1H NMR (300 MHz, CDCl3)
d 7.25
d
168.3, 145.1, 134.0, 132.7, 130.3, 122.5, 122.1, 108.3, 40.5, 29.5, 27.6,
22.8, 14.4. HRMS (APCI) calcd for C26H31N2O2 ([MþH]þ) 403.2385,
(d, J ¼ 8.1 Hz, 2H), 7.12 (d, J ¼ 8.1 Hz, 1H), 6.84 (d, J ¼ 8.7 Hz, 2H),
6.52e6.48 (m, 1H), 6.35 (d, J ¼ 2.1 Hz, 1H), 4.82 (s, 2H), 3.77 (s, 3H),
found: 403.2380.
3.74 (s, 3H), 3.54 (s, 2H). 13C NMR (75 MHz, CDCl3)
d 175.9, 159.8,
159.0, 145.5, 128.8, 127.9, 124.8, 116.3, 114.1, 105.9, 97.4, 55.4, 55.3,
43.2, 35.2. HRMS (ESI) calcd for C17H18NO3 ([MþH]þ) 284.1287,
found 284.1281.
4.4.20. (E)-1,10-didecyl-[3,30-biindolinylidene]-2,20-dione (3h)3b
Red solid (84 mg, 62% yield); mp: 90e91 ꢀC (Lit. 107e108 ꢀC); 1H
NMR (500 MHz, CDCl3)
d
9.18 (d, J ¼ 8 Hz, 1H), 7.37e7.34 (m, 1H),
7.06e7.03 (m, 1H), 6.79 (d, J ¼ 7.5 Hz, 1H), 3.77 (t, J ¼ 7.5 Hz, 2H),
4.4.13. (E)-1,10-dibenzyl-[3,30-biindolinylidene]-2,20-dione (3a)3c
Red solid (77 mg, 70% yield); m. p. 248e249 ꢀC (Lit.
1.73e1.67 (m, 2H), 1.40e1.28 (m, 14H), 0.87 (t, J ¼ 7 Hz, 3H); 13C
NMR (125 MHz, CDCl3)
d 168.2, 145.1, 133.9, 132.6, 130.2, 122.5,
242e244 ꢀC); 1H NMR (500 MHz, CDCl3)
d
: 9.23 (d, J ¼ 15 Hz, 1H),
7.34e7.26 (m, 6H), 7.05 (t, J ¼ 12.5 Hz, 1H), 6.72 (d, J ¼ 12.5 Hz, 1H),
5.02 (s, 2H); 13C NMR (125 MHz, CDCl3)
168.4, 144.9, 136.1, 133.9,
122.0, 108.2, 40.4, 32.2, 30.0, 29.8, 29.7, 29.6, 27.8, 27.4, 23.0, 14.4.
HRMS (APCI) calcd for C36H51N2O2 ([MþH]þ) 543.3950, found:
543.3945.
d
132.9, 130.4, 129.3, 128.0, 127.6, 122.9, 122.0, 109.0, 44.1.
4.4.21. (E)-1,10-didodecyl-[3,30-biindolinylidene]-2,20-dione (3i)3b
Red solid (101 mg, 67% yield); m. p. 87e88 ꢀC (Lit. 111 ꢀC); 1H
4.4.14. (E)-1,10-bis(4-methoxybenzyl)-[3,30-biindolinylidene]-2,20-
dione(3b)
NMR (500 MHz, CDCl3)
d
9.18 (d, J ¼ 8 Hz, 1H), 7.37e7.34 (m, 1H),
Red solid (80 mg, 64% yield); m. p. 274e275 ꢀC; 1H NMR
7.06e7.03 (m, 1H), 6.79 (d, J ¼ 8 Hz, 1H), 3.77 (t, J ¼ 7.5 Hz, 2H),
(500 MHz, CDCl3)
J ¼ 8 Hz, 1H), 6.85 (d, J ¼ 8.5 Hz, 2H), 6.74 (d, J ¼ 8 Hz, 1H), 4.95 (s,
2H), 3.77 (s, 3H); 13C NMR (125 MHz, CDCl3)
168.4, 159.5, 144.9,
d
9.21 (d, J ¼ 8 Hz, 1H), 7.30e7.27 (m, 3H), 7.04 (t,
1.73e1.67 (m, 2H), 1.42e1.25 (m, 18H), 0.87 (t, J ¼ 7.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3)
d 168.3, 145.1, 134.0, 132.7, 130.3, 122.5,
d
122.1, 108.3, 40.5, 32.3, 30.1, 30.0, 30.0, 29.9, 29.7, 27.9, 27.6, 27.5,
23.1, 14.5. HRMS (APCI) calcd for C40H59N2O2 ([MþH]þ) 599.4576,
found: 599.4571.
134.0, 132.8, 130.3, 129.0, 128.2, 122.8, 122.1, 114.6, 109.0, 55.7, 43.6.
HRMS (APCI) calcd for C32H27N2O4 ([MþH]þ) 503.1971, found:
503.1970.
Acknowledgments
4.4.15. (E)-1,10-dicyclohexyl-[3,30-biindolinylidene]-2,20-dione(3c)
Red solid (71 mg, 67% yield); m. p. 81e82 ꢀC; 1H NMR (500 MHz,
We gratefully acknowledge the financial support from the Na-
tional Natural Science Foundation of China (21272006).
CDCl3)
d
9.02 (d, J ¼ 7.5 Hz, 1H), 7.26e7.23 (m, 1H), 6.96e6.91 (m,
2H), 2.19e2.12 (m, 1H), 1.85 (d, J ¼ 12.5 Hz, 2H), 1.74e1.67 (m, 2H),
1.40e1.32 (m, 2H), 1.26e1.21 (m, 2H), 0.82e0.80 (m, 2H); 13C NMR
Appendix A. Supplementary data
(125 MHz, CDCl3)
d 168.0, 144.8, 134.0, 132.3, 130.2, 122.2, 122.0,
109.5, 30.0, 29.4, 26.5, 25.7. HRMS (APCI) calcd for C28H31N2O2
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2017.12.005.
([MþH]þ) 427.2385, found: 427.2380.

L. Liu et al. / Tetrahedron 74 (2018) 354e359
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