Nickel(II)-catalyzed addition reaction of arylboronic acids to isatins

Article abstract of DOI:10.1016/j.tet.2018.03.039

A Ni-catalyzed addition of arylboronic acids to isatins was first developed. The reaction, driven by Ni(acac)₂ and dppp as the phosphine ligand, gave 3-aryl-3-hydroxy-2-oxindoles in up to 97% yield. Scopes of benzyl-protected isatins and arylboronic acids were examined. Substituted phenylboronic acids along with fused-ring and heterocyclic boronic acids reacted with isatins smoothly. Preliminary asymmetric catalysis was investigated as well, showing moderate enantioselectivity. The mechanism was also described.

Full text of DOI:10.1016/j.tet.2018.03.039

Accepted Manuscript
Nickel(II)-catalyzed addition reaction of arylboronic acids to isatins
Yu-Yang Zhang, Huixuan Chen, Xiaoding Jiang, Hao Liang, Xufeng He, Yaqi Zhang,
Xiangmeng Chen, Wenhuan He, Yongsu Li, Liqin Qiu
PII:
S0040-4020(18)30304-1
10.1016/j.tet.2018.03.039
TET 29379
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 January 2018
Revised Date: 18 March 2018
Accepted Date: 20 March 2018
Please cite this article as: Zhang Y-Y, Chen H, Jiang X, Liang H, He X, Zhang Y, Chen X, He W, Li
Y, Qiu L, Nickel(II)-catalyzed addition reaction of arylboronic acids to isatins, Tetrahedron (2018), doi:
10.1016/j.tet.2018.03.039.
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Nickel(II)-Catalyzed Addition Reaction of
Arylboronic Acids to Isatins
Leave this area blank for abstract info.
Yu-Yang Zhanga, Huixuan Chena, Xiaoding Jianga, Hao Lianga, Xufeng Hea, Yaqi Zhanga, Xiangmeng Chena,
Wenhuan Hea, Yongsu Lia, Liqin Qiua,*
School of Chemistry, The Key Laboratory of Low-Carbon Chemistry & Energy Conservation of Guangdong
Province, South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center, Sun
Yat-sen University, No. 135 Xingangxi Road, Guangzhou 510275, People’s Republic of China.

1
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Tetrahedron
journal homepage: www.elsevier.com
Nickel(II)-Catalyzed Addition Reaction of Arylboronic Acids to Isatins
Yu-Yang Zhanga, Huixuan Chena, Xiaoding Jianga, Hao Lianga, Xufeng Hea, Yaqi Zhanga, Xiangmeng
Chena, Wenhuan Hea, Yongsu Lia, Liqin Qiua,
a
School of Chemistry, The Key Laboratory of Low-Carbon Chemistry & Energy Conservation of Guangdong Province, South China Sea Bio-Resource
Exploitation and Utilization Collaborative Innovation Center, Sun Yat-sen University, No. 135 Xingangxi Road, Guangzhou 510275, People’s Republic of China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A Ni-catalyzed addition of arylboronic acids to isatins was first developed. The reaction, driven
by Ni(acac)2 and dppp as the phosphine ligand, gave 3-aryl-3-hydroxy-2-oxindoles in up to 97%
yield. Scopes of benzyl-protected isatins and arylboronic acids were examined. Substituted
phenylboronic acids along with fused-ring and heterocyclic boronic acids reacted with isatins
smoothly. Preliminary asymmetric catalysis was investigated as well, showing moderate
enantioselectivity. The mechanism was also described.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
nickel catalysis
addition reaction
isatins
boronic acids
———
Corresponding author. E-mail: qiuliqin@mail.sysu.edu.cn

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
B performed high affinity for the arginine-vasopressin receptors
and/or the ocytocin receptors (Figure 1).9 These analogues can be
effectively synthesized through addition of precursor isatins with
some organometallic reagents such as organosilicon10 and
triorganoaluminium11. Reactions of organoboron reagents have
been developed as well. Since 2006, pioneered by Minnaard12a
and Hayashi12b, rhodium12, palladium13, copper14, ruthenium15
and iridium16 have been applied as the catalytic metals, whereas
most of them are expensive and sensitive to atmosphere.
Compared with the reactions catalyzed by noble metals, the
nickel-catalyzed reaction remains challenge due to less stability
of C-Ni bonds in the intermediate, which leads to high activation
energy and facile decomposition of the intermediate.17
Encouraged by the fact that nickel catalysts have not yet been
applied in this field, we studied and herein report the synthesis of
3-aryl-3-hydroxy-2-oxindoles from isatins and arylboronic acids
catalyzed by air-stable nickel(II) salts along with various
phosphine ligands.
In these decades, a variety of transition metal-catalyzed C-C
1
bond building methods have been extensively studied , in which
nickel catalysis, for its inexpensiveness and versatility, is
considered as one of the most promising fields.2 Numerous
precursors were used in various reactions such as substitution
reactions3
and
addition
reactions4
and
outstanding
accomplishments have been achieved. Organoboronic acid not
only is a class of air and moisture tolerant reagents, but also have
less reactivity, better chemoselectivity and suppression of side
reactions. Up to date, some nickel-catalyzed reactions with
organoboron reagents have been well developed.5-8
3-Aryl-3-hydroxy-2-oxindoles are studied as a common motif
2. Results and Discussion
Considering that Ni(0) precursors are expensive and very
sensitive to air and moisture, we first utilized more practical
Ni(II) salt Ni(acac)2 as the metal source. To investigate how
ligands influence the metal-catalyzed reactions, N-benzyl isatin
1a and phenylboronic acid 2a were chosen as the substrates in a
primary conditions screening with different ligands to detect the
reactivity
Figure 1. Application examples of 3-aryl-3-hydroxy-2-oxindoles
motif.
in several drugs and natural products. For instance, A (SM-
130686) was found as a potent growth hormone secretagogue and
Table 1. General Conditions Screeninga
entry
R
Ni source
ligand
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14c
15d
16e
17
18
Bn
Bn
Bn
Bn
Bn
H
Boc
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
PPh3
PCy3
dppb
dppf
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DME
38
34
33
19
84
< 5
< 5
47
42
63
41
41
39
48
73
54
64
52
Ni(ClO4)2·6H2O
Ni(OAc)2·4H2O
Ni(dppe)Cl2
Ni(PPh3)Cl2
Ni(cod)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
1,4-dioxane
19
20
Bn
Bn
Ni(acac)2
Ni(acac)2
dppp
dppp
MeCN
toluenef
32
77
a The reactions were performed using N-substituted isatin (0.2 mmol), phenlyboronic acid (0.4 mmol), Ni precursor (0.03 mmol) and ligand (0.04 mmol) at 80 oC
b
c
o
d
o
e
o
f
for 22 h under N2. Isolated yields. The reaction was performed at 60 C. The reaction was performed at 70 C. The reaction was performed at 90 C.
Toluene/H2O = 20/1 (v/v)

3
3ak). Satisfactorily, fused-ring and electron-rich heterocyclic
Table 3. Scope of N-benzylisatins.a,b
ACCEPTED MANUSCRIPT
a
The reactions were performed using N-benzylisatins (0.2 mmol),
phenlyboronic acid (0.4 mmol), Ni(acac)2 (0.03 mmol) and dppp (0.04 mmol)
at 80 oC in toluene for 22 h under N2. b Isolated yield.
arylboronic acids also gave the products in reasonable yields
respectively (3al-3an, 88%-92%). This is scarce in most cases
with other metals, though 3-thiophenyl arylboronic acid
performed moderately (3ao, 67%).
Studies on the scope of benzyl-protected isatins showed that
electronic effect played an important role in the reaction (Table
3). 5-Haloisatin afforded lower yields as atomic weight rises
(3ba-3da, 47%-59%) due to increasing steric hindrance and
electron withdrawing effect in substrates isatins. Fluoro-
substituent in other position affected the yields similarly (3ea,
62%). In contrast, 5-methyl and 5-methoxylisatin bearing
electron donating groups facilitated the reaction (3fa and 3ga,
77% and 88%).
The preliminary investigation of the addition reaction in
asymmetric way was also performed. After examining an array of
chiral ligands instead of dppp, the best enantioselectivity (50% ee
and 29% yield) for the product was obtained using Me-Duphos
L1 as the ligand (Scheme 1). The experiments further indicate
that the six-membered ring chelate similar to the Ni-dppp
skeleton is crucial to the high reactivity, while ligands with
longer or shorter chains remain relatively inert to the reaction.
Chiral ligands with appropriate stereoscopic effect are expected
to acquire good yield and enantioselectivity.
Table 2. Scope of arylboronic acids.a,b
a
The reactions were performed using N-benzylisatin (0.2 mmol), arylboronic
o
acids (0.4 mmol), Ni(acac)2 (0.03 mmol) and dppp (0.04 mmol) at 80 C in
toluene for 22 h under N2. b Isolated yield.
(table 1, entries 1-5). Among the selected phosphines, ligand
dppp displayed prominent advantage. This is possibly attributed
to the appropriate coordination of the ligand with nickel. N-
substituents on the isatin exerted a great influence on the
transformation (table 1, entries 5-8). Among of them, benzyl
group showed its superiority. Nickel source was investigated as
well (table 1, entries 9-13). Meanwhile, counterion was found to
influence the yield. As the result, Ni(acac)2 gave the best yield. In
comparsion, employment of zero-valent nickel Ni(cod)2 just
acquired a disappoionting result (table 1, entry 13). Temperature
The mechanism of the catalytic cycle was considered
preliminarily (Figure 2).8c,18 Ni(0) species is first generated
plausibly by reduction of Ni(II) precursor with arylboronic acids.
Coordinating with phosphine ligand, the complex interacts with
isatins leading to the η2-coordinate intermediate 4, which can be
interconverted into its resonance 5. After transmetalation of the
intermediate with arylboronic acid, Ni(II) compound 6 is formed.
Scheme 1. Preliminary investigation of asymmetric reaction.
o
screening indicated that the reaction worked best at 80 C (table
1, entries 14-16). Solvent effect was also nonnegligible on this
reaction (table 1, entries 5, 17-20), and toluene is the best choice.
Noticeably, addition of water as a common additive also resulted
in a slight decrease in the yield (table 1, entry 20).
O
HO
Ph
Ni(acac)2 (15 mol%)
L1
P
P
(15 mol%)
Ph B(OH)2
O
+
O
toluene, 80 o
C
N
Bn
N
2a
Bn
2.0 equiv.
1a
3aa
With the optimal conditions in hand, we set about expanding
the scope of substrates. Firstly, different arylboronic acids were
employed (Table 2). As the para substituents, functional groups
with different electron effects reasonably influenced the reaction
L1
29% yield
50% ee
Ni(II)
O
Ni(0)L
yields
(3ab-3af,
72%-97%),
and
remarkably
p-
O
N
chlorophenylboronic acid gave an excellent yield (3ad, 97%).
This result is consistent with Hu’s report8e. Meta substituents
with electron withdrawing effect could somewhat decrease the
yields and those having electron donating effect was beneficial to
the reaction in some degree (3ag-3ai, 69%-83%). In contrast,
ortho substituents of arylboronic acids showed significant steric
hindrance and dropped the product yields fiercely (3aj, 72%, and
Bn
1a
O
O
Ni(II)L
O
Ni(0)L
O
N
N
Bn
Bn
5
4
PhB(OH)2
2a
(HO)2BO Ni(II)L
O
Ph
Ni(0)L
N
Bn
6
HO Ph
N
(HO)2BO Ph
N
O
O
Bn
Bn
3aa
7

4
Tetrahedron
1H), 5.06 (d, J = 15.7 Hz, 1H), 4.84 (d, J = 15.7 Hz, 1H), 3.61 (s,
ACCEPTED MANUSCRIPT
1H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 177.78, 142.63,
138.16, 137.24, 135.47, 131.75, 129.69, 129.37, 128.87, 127.76,
127.29, 125.26, 124.95, 123.53, 109.72, 77.90 44.04, 21.13.
4.2.3. 1-benzyl-3-hydroxy-3-(4-
methoxyphenyl)indolin-2-one (3ac)
1 5
White solid, 55.3 mg, 80% yield. 1H NMR (400 MHz, CDCl3)
δ 7.40 – 7.27 (m, 8H), 7.24 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 7.5
Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 7.8 Hz, 1H), 5.04
(d, J = 15.7 Hz, 1H), 4.81 (d, J = 15.7 Hz, 1H), 3.88 (s, 1H), 3.81
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 177.83, 159.61, 142.55,
135.48, 132.26, 131.77, 129.65, 128.87, 127.74, 127.28, 126.87,
124.97, 123.51, 114.04, 109.73, 77.66, 55.30, 44.00.
Figure 2. Plausible mechanism of the nickel-catalyzed addition
reaction.
Via a subsequent reductive elimination, compound 7 is given,
which affords product 3aa upon workup. Furthermore, the
regenerated Ni(0) species goes on the catalytic cycle ceaselessly.
4.2.4. 1-benzyl-3-(4-chlorophenyl)-3-
hydroxyindolin-2-one (3ad)1 6
3. Conclusions
White solid, 67.9 mg, 97% yield. 1H NMR (400 MHz, CDCl3)
δ 7.38 – 7.30 (m, 9H), 7.26 (t, J = 7.2 Hz, 2H), 7.07 (t, J = 7.5 Hz,
1H), 6.82 (d, J = 8.0 Hz, 1H), 5.04 (d, J = 15.6 Hz, 1H), 4.82 (d,
J = 15.6 Hz, 1H), 3.87 (s, 1H). 13C NMR (101 MHz, CDCl3) δ
177.29, 142.53, 138.70, 135.27, 134.31, 131.29, 130.02, 128.94,
128.82, 127.90, 127.31, 126.90, 124.94, 123.75, 109.91, 77.62,
44.11.
In conclusion, the nickel(II)-catalyzed addition of arylboronic
acids to isatins was developed successfully, giving 3-aryl-3-
hydroxy-2-oxindoles in up to 97% yield. To our knowledge, this
is the first example using nickel catalysts in this kind of
reactions. Counterion was effective and H2O was unnecessary in
the catalytic system. Substrate investigations demonstrate that
steric hindrance of arylboronic acids has significant influence on
the yield, whereas electron-rich isatins are beneficial to get
higher yields. Reaction mechanism was also considered and
described as a Ni-catalytic cycle. Further exploration of the
nickel-catalyzed reactions is ongoing in our laboratory.
4.2.5. 1-benzyl-3-hydroxy-3-(4-
phenoxyphenyl)indolin-2-one (3ae)1 6
White solid, 70.1 mg, 86% yield. 1H NMR (400 MHz, CDCl3)
δ 7.43 – 7.22 (m, 11H), 7.14 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.3
Hz, 1H), 7.03 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.81
(d, J = 7.8 Hz, 1H), 5.05 (d, J = 15.7 Hz, 1H), 4.84 (d, J = 15.7
Hz, 1H), 3.70 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 177.67,
157.52, 156.75, 142.57, 135.38, 134.75, 131.58, 129.83, 129.80,
128.91, 127.82, 127.29, 127.08, 125.01, 123.61, 123.58, 119.24,
118.64, 109.83, 77.71, 44.07.
4. Experimental section
4.1. General information
Anhydrous toluene was distilled from sodium and
benzophenone before use and other solvents were dried through
standard method. Reagents were obtained from commercial
sources and used directly without further purification unless
otherwise specified. Column chromatography was performed
with silica gel (200-300 mesh). NMR spectra were recorded on a
Brucker Avance III 400 MHz instrument with chemical shifts
reported relative to Tetramethylsilane (TMS).
4.2.6. 1-benzyl-3-(3,4-difluorophenyl)-3-
hydroxyindolin-2-one (3af)1 6
White solid, 56.9 mg, 81% yield. 1H NMR (400 MHz, CDCl3)
δ 7.38 – 7.24 (m, 8H), 7.14 – 7.03 (m, 3H), 6.83 (d, J = 7.8 Hz,
1H), 5.01 (d, J = 15.6 Hz, 1H), 4.81 (d, J = 15.6 Hz, 1H), 4.59 –
4.36 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 177.21, 151.59,
151.53, 151.46, 151.40, 149.12, 149.05, 148.99, 148.92, 142.39,
137.30, 135.16, 131.18, 130.13, 128.96, 127.95, 127.30, 124.92,
123.89, 121.72, 121.69, 121.66, 121.62, 117.45, 117.28, 115.25,
115.06, 110.01, 77.32, 44.13.
4.2. General procedure
N-benzylisatins (0.2 mmol) and arylboronic acids (0.4 mmol)
were placed in a seal tube, in which Ni(acac)2 (0.03 mmol) and
dppp (0.04 mmol) were subsequently added under N2
atmosphere. Using toluene (2 mL) as solvent, the reaction
4.2.7. 1-benzyl-3-(3-chlorophenyl)-3-
hydroxyindolin-2-one (3ag)1 6
o
proceeded for 22 h at 80 C with stirring. After concentrating
White solid, 48.3 mg, 69% yield. 1H NMR (400 MHz, CDCl3)
δ 7.43 (s, 1H), 7.39 – 7.23 (m, 10H), 7.07 (t, J = 7.5 Hz, 1H),
6.83 (d, J = 8.0 Hz, 1H), 5.04 (d, J = 15.6 Hz, 1H), 4.83 (d, J =
15.6 Hz, 1H), 4.17 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 177.30,
142.45, 142.30, 135.25, 134.62, 131.34, 130.03, 129.94, 128.96,
128.49, 127.91, 127.35, 125.68, 124.95, 123.83, 123.56, 109.95,
77.69, 44.13.
solvent under reduced pressure, the mixture was purified by
column chromatography on silica gel with petroleum ether and
ethyl acetate. Eluent was removed to give the product.
4.2.1. 1-benzyl-3-hydroxy-3-phenylindolin-2-one
(3aa)1 6
White solid, 53.0 mg, 84% yield. 1H NMR (400 MHz, CDCl3)
δ 7.44 (d, J = 8.0 Hz, 2H), 7.40 – 7.29 (m, 9H), 7.25 (td, J = 7.8,
1.1 Hz, 1H), 7.07 (dd, J = 11.1, 4.0 Hz, 1H), 6.81 (d, J = 7.8 Hz,
1H), 5.07 (d, J = 15.7 Hz, 1H), 4.85 (d, J = 15.7 Hz, 1H), 3.67 (s,
1H). 13C NMR (101 MHz, CDCl3) δ 177.59, 142.67, 140.15,
135.41, 131.57, 129.82, 128.90, 128.69, 128.37, 127.81, 127.30,
125.30, 125.01, 123.58, 109.78, 77.99, 44.08.
4.2.8. 1-benzyl-3-(3,5-dimethoxyphenyl)-3-
hydroxyindolin-2-one (3ah)
White solid, 62.3 mg, 83% yield. 1H NMR (400 MHz, CDCl3)
δ 7.39 – 7.29 (m, 6H), 7.25 (td, J = 11.2, 4.4 Hz, 1H), 7.06 (t, J
= 7.5 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.58 (d, J = 2.2 Hz, 2H),
6.41 (t, J = 2.1 Hz, 1H), 5.09 (d, J = 15.6 Hz, 1H), 4.82 (d, J =
15.6 Hz, 1H), 3.75 (s, 6H), 3.48 – 3.33 (m, 1H). 13C NMR (101
MHz, CDCl3) δ 177.34, 161.00, 142.58, 135.51, 131.49, 129.84,
128.88, 127.81, 127.36, 124.86, 123.59, 109.70, 103.32, 100.36,
77.98, 55.33, 44.06.
4.2.2. 1-benzyl-3-hydroxy-3-(p-tolyl)indolin-2-one
1 6
(3ab)
White solid, 47.4 mg, 72% yield. 1H NMR (400 MHz, CDCl3)
δ 7.40 – 7.29 (m, 8H), 7.24 (td, J = 7.8, 1.1 Hz, 1H), 7.18 (d, J =
8.0 Hz, 2H), 7.06 (dd, J = 11.0, 4.0 Hz, 1H), 6.80 (d, J = 7.8 Hz,

5
1
4.2.9. methyl 3-(1-benzyl-3-hydroxy-2-oxoindolin-
White solid, 39.3 mg, 59% yield. H NMR (400 MHz,
ACCEPTED MANUSCRIPT
3-yl)benzoate (3ai)1 6
CDCl3) δ 7.45 – 7.29 (m, 10H), 7.04 (dd, J = 7.6, 2.5 Hz, 1H),
6.93 (td, J = 8.8, 2.6 Hz, 1H), 6.71 (dd, J = 8.6, 4.0 Hz, 1H), 5.05
(d, J = 15.7 Hz, 1H), 4.83 (d, J = 15.7 Hz, 1H), 3.94 (s, 1H). 13C
NMR (101 MHz, CDCl3) δ 177.63, 160.86, 158.45, 139.72,
138.38, 135.08, 133.40, 133.32, 128.97, 128.79, 128.74, 128.56,
127.93, 127.26, 125.20, 116.15, 115.92, 113.25, 113.00, 110.54,
110.46, 78.18, 44.23.
White solid, 55.3 mg, 74% yield. 1H NMR (400 MHz, CDCl3)
δ 8.12 (s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H),
7.43 (t, J = 7.8 Hz, 1H), 7.38 – 7.30 (m, 5H), 7.25 (t, J = 7.7 Hz,
2H), 7.06 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 5.07 (d, J
= 15.6 Hz, 1H), 4.85 (d, J = 15.6 Hz, 1H), 3.90 (s, 4H). 13C NMR
(101 MHz, CDCl3) δ 177.32, 166.68, 142.59, 140.79, 135.29,
131.35, 130.61, 130.04, 129.85, 129.55, 128.94, 128.81, 127.86,
127.33, 126.48, 124.93, 123.76, 109.97, 77.79, 52.20, 44.14.
4.2.16. 1-benzyl-5-chloro-3-hydroxy-3-
phenylindolin-2-one (3ca)1 6
White solid, 32.9 mg, 47% yield. 1H NMR (400 MHz, CDCl3)
7.43 – 7.26 (m, 11H), 7.20 (dd, J = 8.4, 2.1 Hz, 1H), 6.71 (d, J
4.2.10. 1-benzyl-3-(2-fluorophenyl)-3-
hydroxyindolin-2-one (3aj)1 5
δ
White solid, 48.0 mg, 72% yield. 1H NMR (400 MHz, CDCl3)
δ 7.95 (td, J = 7.8, 1.6 Hz, 1H), 7.44 – 7.30 (m, 6H), 7.28 – 7.20
(m, 2H), 7.16 (d, J = 7.3 Hz, 1H), 7.04 – 6.94 (m, 2H), 6.77 (d, J
= 7.8 Hz, 1H), 5.11 (d, J = 15.8 Hz, 1H), 4.89 (d, J = 15.8 Hz,
1H), 3.94 – 3.76 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 176.92,
160.31, 157.86, 143.04, 135.34, 130.18, 130.09, 130.00, 128.83,
127.71, 127.52, 127.49, 127.34, 127.33, 124.58, 124.37, 124.34,
123.36, 115.79, 115.58, 109.82, 75.33, 44.25.
= 8.4 Hz, 1H), 5.04 (d, J = 15.7 Hz, 1H), 4.83 (d, J = 15.7 Hz,
1H), 3.96 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 177.38, 141.05,
139.59, 134.95, 133.34, 129.65, 129.04, 128.99, 128.82, 128.60,
127.97, 127.25, 125.54, 125.20, 110.82, 78.01, 44.19.
4.2.17. 1-benzyl-5-bromo-3-hydroxy-3-
phenylindolin-2-one (3da)1 5
White solid, 37.1 mg, 47% yield. 1H NMR (400 MHz, CDCl3)
δ 7.44 – 7.29 (m, 12H), 6.67 (d, J = 8.3 Hz, 1H), 5.03 (d, J = 15.7
Hz, 1H), 4.83 (d, J = 15.7 Hz, 1H), 3.89 (s, 1H). 13C NMR (101
MHz, CDCl3) δ 177.28, 141.55, 139.57, 134.91, 133.68, 132.56,
128.99, 128.83, 128.61, 128.27, 127.98, 127.25, 125.19, 116.32,
111.30, 77.95, 44.17.
4.2.11. 1-benzyl-3-hydroxy-3-(naphthalen-1-
yl)indolin-2-one (3al)1 9
White solid, 67.2 mg, 92% yield. 1H NMR (400 MHz, CDCl3)
δ 8.05 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.67 – 7.47
(m, 4H), 7.39 (dt, J = 14.1, 7.6 Hz, 4H), 7.27 (td, J = 7.8, 1.0 Hz,
1H), 7.18 (t, J = 7.0 Hz, 2H), 6.96 (dd, J = 12.8, 7.6 Hz, 2H),
5.23 (d, J = 15.4 Hz, 1H), 4.90 (d, J = 15.4 Hz, 1H), 3.85 – 3.74
(m, 1H). 13C NMR (101 MHz, CDCl3) δ 177.47, 142.62, 135.45,
134.97, 134.27, 131.68, 130.03, 129.64, 129.05, 128.95, 128.03,
127.98, 126.26, 125.55, 125.07, 124.97, 124.77, 124.33, 123.59,
109.98, 78.41, 44.37.
4.2.18. 1-benzyl-6-fluoro-3-hydroxy-3-
phenylindolin-2-one (3ea)
White solid, 41.3 mg, 62% yield. 1H NMR (400 MHz, CDCl3)
δ 7.43 – 7.29 (m, 10H), 7.24 (dd, J = 8.2, 5.4 Hz, 1H), 6.77 –
6.70 (m, 1H), 6.54 (dd, J = 8.8, 2.1 Hz, 1H), 5.03 (d, J = 15.7 Hz,
1H), 4.80 (d, J = 15.7 Hz, 1H), 3.84 (s, 1H). 13C NMR (101 MHz,
CDCl3) δ 177.93, 164.95, 162.49, 144.32, 144.21, 139.92, 134.90,
129.03, 128.74, 128.47, 128.02, 127.28, 126.41, 126.31, 125.35,
125.26, 109.89, 109.67, 98.78, 98.50, 77.61, 44.22.
4.2.12. 1-benzyl-3-(furan-2-yl)-3-hydroxyindolin-2-
one (3am)
White solid, 53.7 mg, 88% yield. 1H NMR (400 MHz, CDCl3)
δ 7.61 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 0.6 Hz, 1H), 7.38 – 7.22
(m, 6H), 7.12 (t, J = 7.5 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.43 –
6.33 (m, 2H), 5.04 (d, J = 15.8 Hz, 1H), 4.85 (d, J = 15.8 Hz, 1H),
4.09 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 175.33, 151.44,
143.92, 142.57, 135.15, 130.15, 128.86, 128.37, 127.73, 127.09,
125.48, 123.42, 110.42, 109.77, 108.87, 73.64, 43.95.
4.2.19. 1-benzyl-3-hydroxy-5-methyl-3-
phenylindolin-2-one (3fa)1 5
1
White solid, 50.7 mg, 77% yield. H NMR (400 MHz, CDCl3)
δ 7.44 (dd, J = 7.9, 1.2 Hz, 2H), 7.40 – 7.29 (m, 8H), 7.12 (s, 1H),
7.04 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.04 (d, J =
15.6 Hz, 1H), 4.83 (d, J = 15.6 Hz, 1H), 3.82 (s, 1H), 2.27 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 177.71, 140.41, 140.17,
135.55, 133.28, 131.76, 130.00, 128.85, 128.64, 128.24,
127.73, 127.30, 125.69, 125.30, 109.54, 78.16, 44.08, 21.00.
4.2.13. 1-benzyl-3-hydroxy-3-(thiophen-2-
yl)indolin-2-one (3an)
White solid, 58.5 mg, 91% yield. 1H NMR (400 MHz, CDCl3)
δ 7.55 (d, J = 7.4 Hz, 1H), 7.37 – 7.24 (m, 7H), 7.12 (t, J = 7.3
Hz, 1H), 7.05 (dd, J = 3.6, 1.0 Hz, 1H), 6.98 (dd, J = 4.9, 3.7 Hz,
1H), 6.77 (d, J = 7.8 Hz, 1H), 5.05 (d, J = 15.7 Hz, 1H), 4.84 (d,
J = 15.8 Hz, 1H), 3.77 (s, 1H). 13C NMR (101 MHz, CDCl3) δ
176.27, 143.53, 142.23, 135.19, 130.53, 130.13, 128.93, 128.89,
128.85, 127.79, 127.22, 127.18, 127.13, 126.90, 126.75, 125.82,
125.03, 123.50, 109.90, 75.58, 44.07.
4.2.20. 1-benzyl-3-hydroxy-5-methoxy-3-
phenylindolin-2-one (3ga)
1
White solid, 60.8 mg, 88% yield. H NMR (400 MHz, CDCl3)
δ 7.46 – 7.41 (m, 2H), 7.40 – 7.29 (m, 8H), 6.91 (d, J = 2.4 Hz,
1H), 6.76 (dd, J = 8.6, 2.5 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 5.04
(d, J = 15.7 Hz, 1H), 4.82 (d, J = 15.7 Hz, 1H), 3.93 – 3.76 (m,
1H), 3.72 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 177.62, 156.64,
140.24, 135.84, 135.50, 132.95, 128.89, 128.69, 128.33, 127.79,
127.32, 125.31, 114.65, 111.71, 110.40, 78.42, 55.77, 44.17.
4.2.14. 1-benzyl-3-hydroxy-3-(thiophen-3-
yl)indolin-2-one (3ao)
White solid, 43.1 mg, 67% yield. 1H NMR (400 MHz, CDCl3)
δ 7.44 (d, J = 7.4 Hz, 1H), 7.37 – 7.22 (m, 8H), 7.17 (dd, J = 4.8,
1.1 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H),
5.04 (d, J = 15.7 Hz, 1H), 4.84 (d, J = 15.7 Hz, 1H), 3.83 (s, 1H).
13C NMR (101 MHz, CDCl3) δ 177.03, 142.34, 140.98, 135.34,
130.81, 129.86, 128.89, 127.78, 127.21, 126.87, 125.62, 124.87,
123.49, 122.96, 109.80, 75.98, 44.00.
Acknowledgement
This work was supported by the Guangzhou Science and
Technology Program (201510010080).
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phenylindolin-2-one (3ba)1 6

6
Tetrahedron
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