Full text of DOI:10.1055/s-0037-1610537

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
paper
A
en
Y.-Y. Liao et al.
Paper
Synthesis
Palladium-Catalyzed Selective Synthesis of 3-Hydroxy-2-oxindoles
via Cascade C–H Cycloaddition and Oxidation of α-Aminoaceto-
phenones
Yan-Yan Liao
H2O
R2
H
HO
Pd(OAc)2 (10 mol%)
AgOAc (3 equiv)
Li Xu
R2
R1
Ri-Yuan Tang*
Wen-Xu Zheng*
R1
O
N
MeCN/t-BuOH
120 °C, 12 h
N
Me
O
Me
Department of Applied Chemistry, College of Materials and
Energy, South China Agricultural University, Guangzhou
510642, P. R. of China
15 examples
37–69% yields
rytang@scau.edu.cn
wzheng@scau.edu.cn
Received: 18.05.2018
Accepted after revision: 06.07.2018
Published online: 08.08.2018
halides to α-ketoamides. However, the methodology re-
quired the pre-bromination of substrates and the use of an
expensive catalyst (Scheme 1, eq. 2). Direct C–H cyclization
of α-ketoamides into 3-hydroxyindolin-2-ones has also
been developed.8 This methodology requires the use of ex-
pensive Lewis acids such as scandium(III) triflate8a or corro-
sive trifluoroacetic acid8b,c (Scheme 1, eq. 3). Thus far, tran-
sition-metal-catalyzed C–H addition to ketones remains
scare.9 As our ongoing interest is in the chemical transfor-
mation of α-aminoacetophenone derivatives,10,11 we envi-
sioned that tandem C–H cycloaddition/oxidation of α-ami-
noacetophenones enables access to 3-hydroxyindolin-2-
ones. The reaction selectivity is crucial for this transforma-
tion because α-aminoacetophenones could be converted
into an indole10 or an α-ketoamide,11 and even undergo an
oxidative cleavage of the C–N bond. Thus selective C–H cy-
cloaddition to the ketone of α-aminoacetophenone remains
challenging. A solution to this problem is to develop a tran-
sition-metal-catalyzed selective tandem C–H activation
system.12 Herein, we report a palladium-catalyzed selective
synthesis of 3-hydroxyindolin-2-ones via tandem C–H cy-
cloaddition and oxidation of α-aminoacetophenones
(Scheme 1, eq. 4).
Our investigation began with the cyclization of α-ami-
noacetophenone 1a under different reaction conditions (Ta-
ble 1). Initially, Pd(OAc)2 (10 mol%) and AgOAc (2 equiv)
were applied as the catalyst and oxidant for the reaction
development. The solvent effect, including toluene, diox-
ane, NMP, DCE, DMAc, DMSO, MeNO2, t-BuOH, and MeCN,
was evaluated at 100 °C for 12 hours (entries 1–9). MeCN is
a preferable solvent for the reaction, affording product 2a in
44% yield (entry 9). Other silver salts, such as AgOTf, Ag2O,
and AgBF4, are not suitable for this transformation (entries
10–12). When the reaction was carried out in the presence
of Pd(OAc)2 and Cu(OAc)2, α-ketoamide (N-methyl-2-oxo-
DOI: 10.1055/s-0037-1610537; Art ID: ss-2018-h0346-op
Abstract A novel method for the synthesis of 3-hydroxy-2-oxindole
(3-hydroxyindolin-2-one) derivatives by palladium-catalyzed tandem
C–H cycloaddition and oxidation of α-aminoacetophenone has been
developed. In the presence of Pd(OAc)2 and AgOAc, a variety of 3-hy-
droxy-2-oxindoles were synthesized in moderate yields. Control experi-
ments show that the selective cycloaddition occurs prior to the oxida-
tion is crucial for this successful chemical transformation.
Key words palladium, indole, cyclization, oxidation, C–H functional-
ization
The indolin-2-ones are an important class of drug skele-
ton that have a wide range of excellent biological activity,
being found in many natural products as well as pharma-
ceuticals.1 3-Hydroxyindolin-2-ones derived from indolin-
2-ones are privileged scaffolds for drug development,2
which have been used as kinase inhibitors and protease in-
hibitors.3 Owing to their versatility in medicinal applica-
tion, significant effort has been devoted to the development
of synthetic methods for 3-hydroxyindolin-2-ones. The al-
dol reaction of indoline-2,3-diones is an effective pathway
towards 3-hydroxyindolin-2-ones.4 However, indoline-2,3-
diones bearing functional groups are not easily accessible,5
the limited scope is insufficient for diversity synthesis of 3-
hydroxyindolin-2-ones. Endeavors for the pursuit of more
efficient synthetic methods have been made in recent
years.6–8 For example, in 2016, Liu and co-workers6a dis-
closed an interesting tandem autoxidation/aldol reaction of
2-oxindoles with ketones leading to the formation of 3-hy-
droxyindolin-2-ones under mild reaction conditions
(Scheme 1, eq. 1). In 2011, Kündig and co-workers7a report-
ed a Pd-catalyzed efficient synthesis of 3-hydroxyindolin-
2-ones via an intramolecular nucleophilic addition of aryl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
Y.-Y. Liao et al.
Paper
Synthesis
tuted substrate delivered the desired product 2b in 69%
yield at 120 °C for 12 hours. The methoxy group appeared
to have good compatibility, affording product 2c in 55%
yield. Halo groups, such as chloro and fluoro, were also tol-
erated, providing the corresponding products 2d and 2e in
51% and 56% yields, respectively. Next, the effect of substit-
uents on the aniline motif was investigated (products 2f–
m). The presence of halo groups, such as bromo, fluoro, and
chloro, on the benzene ring of aniline would decrease the
Ph
O
O
O
HO
air
O
R1
O
TBAF, MS 4Å
R1
(Eqn 1)
(Eqn 2)
+
N
R2
Ph
N
DMF, r.t.
R2
Br
HO
Ar
O
Pd(dba)2
R1
t-Bu3PHBF4
Ar
R1
O
N
N
R2
O
K3PO4• H2O
n-BuOH
R2
toluene, 80 °C
HO
Table 1 Screening of Optimal Conditionsa
H
R2
Sc(OTf)2
MgSO4
O
R1
R2
R1
O
(Eqn 3)
N
HO
N
H
DME,100 °C
Ph
Me
O
[Pd]/[O]
Me
Ph
O
N
N
This work
R1
Me
O
Me
R2
HO
1a
2a
H
[Pd]/[O]
R2
(Eqn 4)
R1
O
Entry Catalyst
Oxidant (equiv) Solvent
Isolated
yield (%)
N
N
Me
Me
O
Scheme 1 Synthetic methods for 3-hydroxyindolin-2-ones
1
2
Pd(OAc)2
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOTf (2)
Ag2O (2)
toluene
dioxane
NMP
15
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OCOCF3)2
PdCl2
18
3
trace
12
N,2-diphenylacetamide) was obtained as the major byprod-
uct in 65% yield, whereas only 5% yield of desired product
2a was obtained (entry 13).11 Next, other palladium cata-
lysts were also examined. Both Pd(OCOCF3)2 and PdCl2 were
suitable for this reaction, affording product 2a in 45% and
25% yields, respectively (entries 14 and 15).
4
DCE
5
DMAc
DMSO
MeNO2
t-BuOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
27
6
trace
trace
trace
44
7
8
The mixed solvent of MeCN and t-BuOH was also stud-
ied (entries 16–18). The product yield was increased to 50%
when the reaction was carried out in MeCN/t-BuOH (5:1)
(entry 17). No target product was observed in the mixed
solvent of MeCN and HFIP (entry 19). The mixed solvent of
MeCN/EtOH was also effective, but only a 36% yield of prod-
uct 2a was obtained (entry 20). The reaction temperature
also affects the transformation. The reaction at 80 °C gave a
lower yield (entry 21). To our delight, the product yield in-
creased to 56% when the reaction was carried out at 120 °C
(entry 22). The product yield increased to 65% when 3
equivalents of AgOAc were used (entry 24), whereas the re-
action with 1.5 equivalents of AgOAc led to a lower yield
(entry 23). In the absence of Pd(OAc)2, the reaction did not
occur (entry 25). Without the addition of AgOAc, only a 5%
yield of product 2a was obtained (entry 26). These results
demonstrate that both Pd(OAc)2 and AgOAc are essential for
this chemical transformation.
With the optimized reaction conditions in hand (Table
1, entry 24), we investigated the scope of this tandem C–H
cycloaddition and oxidation reaction (Scheme 2). α-Amino-
acetophenones bearing either an electron-withdrawing or
electron-donating substituents on the benzene ring were
tolerated to afford the corresponding products 2a–o in
moderate yields. Initially, substituents on the benzene ring
adjacent to the ketone were examined. The methyl-substi-
9
10
11
12
13
14
15
16
17
18
19
20
21b
22c
23c
24c
25c
26c
trace
trace
trace
5
AgBF4 (2)
Cu(OAc)2 (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (1.5)
AgOAc (3)
AgOAc (3)
–
45
25
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
MeCN/t-BuOH (2:1)
MeCN/t-BuOH (5:1)
MeCN/t-BuOH (10:1)
MeCN/HFIP (5:1)
32
50
45
0
MeCN/EtOH (5:1)
36
MeCN/t-BuOH (5:1)
MeCN/t-BuOH (5:1)
MeCN/t-BuOH (5:1)
MeCN/t-BuOH (5:1)
MeCN/t-BuOH (5:1)
MeCN/t-BuOH (5:1)
48
56
40
65
trace
5
Pd(OAc)2
a Reaction conditions: 1a (0.2 mmol), H2O (0.4 mmol, 2 equiv), solvent (2
mL), 100 °C, 12 h; unless otherwise stated.
b At 80 °C.
c At 120 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
Y.-Y. Liao et al.
Paper
Synthesis
H2O
H
Pd(OAc)2 (10 mol%)
AgOAc (3 equiv)
R3
HO
R3
R1
N
R2
R1
O
MeCN/t-BuOH, 120 °C
O
N
R2
1
2
F
O
Cl
HO
HO
HO
HO
HO
HO
O
O
O
O
O
O
N
N
N
N
N
N
2a, 65%
2b, 69%
2c, 55%
2d, 51%
2e, 56%
2f, 50%
O
Cl
HO
HO
HO
HO
HO
HO
F
Br
O
O
O
O
O
N
O
N
N
N
N
N
Cl
2g, 52%
2k, 41%
2l, 37%
2h, 51%
2i, 50%
2j, 48%
O
O
HO
N
HO
HO
HO
Cl
O
O
O
O
N
N
H
N
2m, 40%
2p, trace
2n, 43%
2o, 39%
Scheme 2 Substrate scope. Reagents and conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol%), AgOAc (3 equiv), H2O (0.4 mmol, 2 equiv), MeCN/t-BuOH (5:1,
2 mL), 120 °C, 12 h.
reactivity to some extent, leading to lower yields (products
2j–m). These results demonstrate that the electron-with-
drawing groups on the aniline disfavor the C–H cycloaddi-
tion. Compared with the N-methyl-substituted substrate
1a, the N-ethyl substituted substrates were less effective
(products 2n and 2o). In this reaction, the N-protecting
group is essential for the successful transformation. The re-
action did not occur when there was no protecting group
on the amide (product 2p). However, neither N-benzyl- nor
N-allyl-substituted substrates were compatible with the re-
action conditions. The majority of the substrates decom-
posed under the reaction conditions, and the reactions
were messy, only a small amount of desired products were
observed on GC-MS.
to the reaction. The 18O labeled 3-hydroxyindolin-2-one 2a
was observed on GC-MS (Scheme 3, eq. 2), suggesting that
the oxygen atom came from water.
HO
Ph
Pd(OAc)2 (10 mol%)
O
AgOAc (3 equiv)
Ph
O
(Eq. 1)
N
N
MeCN/t-BuOH (5:1)
120 °C, 24 h
O
3
2a, trace
H218O (2 equiv)
Pd(OAc)2 (10 mol%)
AgOAc (3 equiv)
HO
Ph
18O
Ph
N
(Eq. 2)
N
MeCN/t-BuOH (5:1)
O
120 °C, 24 h
1a
2a, 68%
Subsequently, control experiments were conducted to
gain insight into the reaction mechanism (Scheme 3).
During the reaction development, a small amount of dike-
tone 3 was observed by GC-MS analysis, suggesting that
diketone 3 might be the reaction intermediate. Thus dike-
tone 3 was subjected to the reaction conditions. However,
no desired product 2a was observed in the reaction of dike-
tone 3, suggesting that the formation of the amide com-
pletely suppress the C–H cycloaddition to the ketone
(Scheme 3, eq. 1). In order to confirm the origin of the oxy-
gen atom in the amide, two equivalents of H218O was added
Scheme 3 Control experiments
Based on the present results, a possible reaction mecha-
nism is proposed as shown in Scheme 4. The cycloaddition
of compound 1a should occur prior to the formation of am-
ide. Initially, Pd(OAc)2 chelates with compound 1a to afford
a complex A, followed by hydrogen abstraction and a cy-
cloaddition process to produce an intermediate B. Interme-
diate B then is oxidized by AgOAc to afford an imine cation
C. The imine cation C undergoes hydrolysis to produce an
intermediate D. The newly formed hydroxyl group may
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
Y.-Y. Liao et al.
Paper
Synthesis
O
OAc
Pd(II)
Ph
O
O
O
N
Ph
Pd(OAc)2
OAc
Pd(II)
H
N
O
B
N
AcOH
1a
Ph
HO
Ph
AgOAc
A
O
N
Ag + AcOH
OAc
Pd(II)
AgOAc
2a
Ag + Pd(OAc)2
OAc
Pd(II)
Ph
OAc
Pd(II)
Ph
O
Ph
O
O
H2O
OH
O
N
N
H
N
D
E
C
Scheme 4 A possible reaction mechanism
chelate with Pd(OAc)2 to give a complex E. Finally, interme-
diate E is further oxidized by AgOAc to afford the target
product 2a.
3-Hydroxy-1-methyl-3-p-tolylindolin-2-one (2b)7a
Yellow solid; yield: 34.9 mg (69%); mp 197.4–198.5 °C (Lit. 191.4–
192.9 °C).
1H NMR (600 MHz, CDCl3): δ = 7.21–7.19 (m, 3 H), 7.06 (d, J = 8.0 Hz, 2
H), 7.01 (t, J = 7.5 Hz, 1 H), 6.82 (d, J = 7.8 Hz, 1 H), 3.24 (s, 1 H), 3.17 (s,
3 H), 2.24 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 177.6, 143.5, 138.1, 137.1, 131.6,
129.8, 129.3, 125.3, 124.9, 123.5, 108.6, 77.8, 26.5, 21.1.
In summary, a novel method for the selective synthesis
of 3-hydroxyindolin-2-ones through palladium-catalyzed
tandem C–H bond cycloaddition and oxidation of α-amino-
acetophenones has been established. Although α-aminoac-
etophenones have multiple reactive sites for different
chemical transformation,10,11 the reaction selectivity was
controlled well in the presence of Pd(OAc)2 and AgOAc.
However, the reaction scope and efficiency are not satisfac-
tory. Significant effort is needed to improve the reaction.
LRMS (EI, 70 eV): m/z (%) = 253 (63), 224 (100), 210 (42), 208 (62),
165 (13), 91 (30).
3-Hydroxy-3-(4-methoxyphenyl)-1-methylindolin-2-one (2c)13
Yellow solid; yield: 30.0 mg (55%); mp 147.3–148.1 °C (Lit. 142.5–
143.7 °C).
1H NMR (600 MHz, CDCl3): δ = 7.39–7.30 (m, 4 H), 7.11 (td, J = 7.6, 0.9
Hz, 1 H), 6.91 (d, J = 7.8 Hz, 1 H), 6.89–6.84 (m, 2 H), 3.79 (s, 3 H), 3.39
(s, 1 H), 3.25 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 177.7, 159.6, 143.5, 132.1, 131.6,
129.8, 126.9, 124.9, 123.5, 114.0, 108.7, 77.6, 55.3, 26.5.
1H and 13C NMR spectra were measured on a Bruker Avance-III 600
instrument (600 MHz for 1H, 151 MHz for 13C NMR spectroscopy) us-
ing CDCl3 as the solvent. Chemical shifts for 1H and 13C NMR were re-
ferred to internal TMS (δ = 0) as the standard. Mass spectra were
measured on an Agilent GC-MS-5975C Plus spectrometer (EI). HRMS
(ESI) analysis was measured on a Bruker micrOTOF-Q II instrument.
LRMS (EI, 70 eV): m/z (%) = 269 (55), 241 (48), 240 (100), 226 (33),
224 (56), 135 (25), 77 (27).
3-Hydroxy-1-methyl-3-phenylindolin-2-one (2a); Typical Proce-
dure13
3-(4-Chlorophenyl)-3-hydroxy-1-methylindolin-2-one (2d)7d
To a flame-dried Schlenk tube with a magnetic stirring bar charged
with 1a (0.2 mmol), Pd(OAc)2 (0.02 mmol, 10 mol%), AgOAc (0.6
mmol, 3 equiv) under an air atmosphere was added MeCN/t-BuOH
(5:1, 1 mL). The mixture was stirred at 120 °C for 12 h. When the re-
action was complete, the mixture was filtered and purified by column
chromatography (petroleum ether/EtOAc) to afford 2a as a yellow sol-
id; yield: 31.1 mg (65%); mp 136.6–138.0 °C (Lit. 137.5–138.4 °C).
Yellow solid; yield: 27.8 mg (51%); mp 171.5–172.3 °C (Lit. 174.5–
175.5 °C).
1H NMR (600 MHz, CDCl3): δ = 7.39 (td, J = 7.8, 1.3 Hz, 1 H), 7.36–7.32
(m, 2 H), 7.31–7.29 (m, 2 H), 7.27–7.25 (m, 1 H), 7.12 (td, J = 7.6, 0.9
Hz, 1 H), 6.93 (d, J = 7.8 Hz, 1 H), 3.57 (s, 1 H), 3.26 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 177.1, 143.4, 138.6, 134.3, 131.2,
130.2, 128.7, 126.9, 124.9, 123.7, 108.8, 77.6, 26.6.
1H NMR (500 MHz, CDCl3): δ = 7.34–7.16 (m, 7 H), 7.01 (t, J = 7.6 Hz, 1
H), 6.83 (d, J = 7.8 Hz, 1 H), 3.48 (s, 1 H), 3.17 (s, 3 H).
LRMS (EI, 70 eV): m/z (%) = 273 (62), 244 (100), 228 (65), 210 (17),
193 (21), 152 (17), 134 (26), 111 (24), 77 (25).
13C NMR (126 MHz, CDCl3): δ = 177.5, 143.5, 140.1, 131.6, 129.9,
128.6, 128.3, 125.3, 124.9, 123.5, 108.7, 78.0, 26.5.
3-(4-Fluorophenyl)-3-hydroxy-1-methylindolin-2-one (2e)14
LRMS (EI, 70 eV): m/z (%) = 239 (66), 211 (56), 210 (100), 195 (17),
194 (65), 134 (24), 105 (20), 77 (36).
Yellow solid; yield: 28.8 mg (56%); mp 170.3–172.4 °C.
1H NMR (600 MHz, CDCl3): δ = 7.44–7.33 (m, 3 H), 7.29 (dd, J = 7.4, 0.7
Hz, 1 H), 7.12 (s, 1 H), 7.02 (t, J = 8.7 Hz, 2 H), 6.94 (s, 1 H), 3.50 (s, 1
H), 3.26 (s, 3 H).
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E
Y.-Y. Liao et al.
Paper
Synthesis
13C NMR (151 MHz, CDCl3): δ = 177.3, 162.7 (d, J = 247.6 Hz, 1 C),
143.4, 135.9, 131.3, 130.1, 127.4 (d, J = 9.1 Hz, 1 C), 124.9, 123.7, 115.5
(d, J = 22.6 Hz, 1 C), 108.8, 77.5, 26.6.
5-Bromo-3-hydroxy-1-methyl-3-phenylindolin-2-one (2j)2c
Yellow solid; yield: 30.4 mg (48%); mp 154.4–156.2 °C.
1H NMR (600 MHz, CDCl3): δ = 7.48 (dd, J = 8.3, 2.0 Hz, 1 H), 7.40 (d, J =
1.9 Hz, 1 H), 7.39–7.30 (m, 5 H), 6.80 (d, J = 8.3 Hz, 1 H), 3.83 (s, 1 H),
3.23 (s, 3 H).
LRMS (EI, 70 eV): m/z (%) = 257 (61), 229 (60), 228 (100), 212 (83),
134 (19), 123 (20), 95 (26).
13C NMR (151 MHz, CDCl3): δ = 177.1, 142.4, 139.5, 133.5, 132.6,
128.7, 128.6, 128.2, 125.2, 116.2, 110.2, 77.9, 26.6.
3-Hydroxy-1,5-dimethyl-3-phenylindolin-2-one (2f)13
Yellow solid; yield: 25.3 mg (50%); mp 124.4–125.9 °C (Lit. 116.2–
117.1 °C).
1H NMR (600 MHz, CDCl3): δ = 7.40 (d, J = 7.8 Hz, 2 H), 7.31 (dt, J =
19.7, 9.4 Hz, 3 H), 7.15 (d, J = 7.8 Hz, 1 H), 7.11 (s, 1 H), 6.81 (d, J = 7.8
Hz, 1 H), 3.96 (s, 1 H), 3.23 (d, J = 0.7 Hz, 3 H), 2.31 (s, 3 H).
LRMS (EI, 70 eV): m/z (%) = 317 (80), 291 (70), 290 (100), 289 (68),
288 (88), 274 (25), 272 (27), 194 (22), 193 (95), 165 (23), 152 (25),
151 (16), 133 (24), 105 (64), 104 (20), 78 (16), 77 (96), 76 (24), 75
(17).
13C NMR (151 MHz, CDCl3): δ = 177.7, 141.0, 140.3, 133.2, 131.8,
5-Fluoro-3-hydroxy-1-methyl-3-phenylindolin-2-one (2k)13
130.0, 128.5, 128.1, 125.6, 125.3, 108.4, 78.2, 26.5, 21.1.
Yellow solid; yield: 21.0 mg (41%); mp 163.3–165.9 °C (Lit. 169.5–
171.0 °C).
LRMS (EI, 70 eV): m/z (%) = 253 (71), 225 (57), 224 (100), 209 (19),
1H NMR (600 MHz, CDCl3): δ = 7.36 (m, 5 H), 7.06 (m, 2 H), 6.85 (dd,
J = 8.4, 4.0 Hz, 1 H), 3.67 (s, 1 H), 3.26 (s, 3 H).
208 (74), 148 (23), 91 (22), 77 (39).
3-Hydroxy-1,5-dimethyl-3-p-tolylindolin-2-one (2g)
13C NMR (151 MHz, CDCl3): δ = 177.4, 160.0 (d, J = 243.1 Hz, 1 C),
139.6, 139.3, 133.1 (d, J = 7.5 Hz, 1 C), 128.7, 128.5, 125.2, 116.1 (d, J =
24.1 Hz, 1 C), 113.2 (d, J = 24.1 Hz, 1 C), 109.3 (d, J = 9.1 Hz, 1 C), 78.1,
26.7.
Yellow solid; yield: 27.8 mg (52%); mp 155.2–157.6 °C.
IR (KBr): 3368, 1696, 1624, 1599, 1494, 1356, 999 cm–1
1H NMR (600 MHz, CDCl3): δ = 7.20–7.19 (m, 2 H), 7.07–7.05 (m, 3 H),
7.02 (s, 1 H), 6.71 (d, J = 7.9 Hz, 1 H), 3.31 (s, 1 H), 3.15 (s, 3 H), 2.25 (s,
3 H), 2.22 (s, 3 H).
.
LRMS (EI, 70 eV): m/z (%) = 257 (68), 229 (52), 228 (100), 213 (13),
212 (68), 105 (33), 77 (40).
13C NMR (151 MHz, CDCl3): δ = 177.6, 141.1, 138.0, 137.3, 133.2,
131.6, 130.0, 129.3, 125.6, 125.2, 108.4, 78.0, 26.5, 21.1, 21.0.
6-Chloro-3-hydroxy-1-methyl-3-p-tolylindolin-2-one (2l)
White solid; yield: 21.2 mg (37%); mp 143.6–143.8 °C.
IR (KBr): 3302, 1703, 1609, 1493, 1370, 1070, 813 cm–1
LRMS (EI, 70 eV): m/z (%) = 267 (66), 239 (53), 238 (100), 224 (33),
223 (16), 222 (63), 119 (19), 91 (38).
.
1H NMR (600 MHz, CDCl3): δ = 7.25 (d, J = 8.2 Hz, 2 H), 7.20 (d, J = 7.9
Hz, 1 H), 7.13 (d, J = 8.1 Hz, 2 H), 7.06 (dd, J = 7.9, 1.7 Hz, 1 H), 6.91 (d,
J = 1.7 Hz, 1 H), 3.84 (s, 1 H), 3.22 (s, 3 H), 2.33 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H18NO2: 268.1326; found:
268.1332.
3-Hydroxy-3-(4-methoxyphenyl)-1,5-dimethylindolin-2-one (2h)
13C NMR (151 MHz, CDCl3): δ = 177.8, 144.6, 138.3, 136.7, 135.5,
130.2, 129.3, 125.9, 125.2, 123.3, 109.4, 77.5, 26.6, 21.1.
Yellow solid; yield: 28.9 mg (51%); mp 155.2–157.6 °C.
IR (KBr): 3376, 1694, 1623, 1601, 1491, 1352, 1242, 1032 cm–1
.
LRMS (EI, 70 eV): m/z (%) = 289 (22), 287 (63), 261 (16), 260 (41), 259
(50), 258 (100), 246 (16), 244 (64), 242 (53), 207 (20), 91 (24).
HRMS (ESI): m/z [M + H]+ calcd for C16H15ClNO2: 288.0786; found:
288.0789.
1H NMR (600 MHz, CDCl3): δ = 7.34 (d, J = 8.9 Hz, 2 H), 7.15 (d, J = 8.0
Hz, 1 H), 7.13 (s, 1 H), 6.90–6.83 (m, 2 H), 6.80 (d, J = 7.9 Hz, 1 H), 3.79
(s, 3 H), 3.38 (s, 1 H), 3.24 (s, 3 H), 2.32 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 177.6, 159.5, 141.0, 133.1, 132.3,
131.6, 130.0, 126.8, 125.6, 114.0, 108.4, 77.7, 55.3, 26.5, 21.1.
5-Chloro-3-hydroxy-3-(4-methoxyphenyl)-1-methylindolin-2-one
(2m)15
LRMS (EI, 70 eV): m/z (%) = 283 (64), 267 (38), 255 (60), 254 (100),
240 (27), 238 (69), 224 (28).
HRMS (ESI): m/z [M + H]+ calcd for C17H18NO3: 284.1280; found:
284.1281.
White solid; yield: 24.2 mg (40%); mp 160.0–161.2 °C.
1H NMR (600 MHz, CDCl3): δ = 7.31–7.25 (m, 2 H), 7.20 (d, J = 7.9 Hz, 1
H), 7.07 (dd, J = 7.9, 1.8 Hz, 1 H), 6.89 (d, J = 1.7 Hz, 1 H), 6.84 (d, J = 8.9
Hz, 2 H), 4.06 (s, 1 H), 3.78 (s, 3 H), 3.19 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 177.7, 159.7, 144.6, 135.5, 131.6,
130.1, 126.8, 125.9, 123.3, 114.0, 109.4, 55.3, 26.6.
3-(4-Chlorophenyl)-3-hydroxy-1,5-dimethylindolin-2-one (2i)
White solid; yield: 28.9 mg (50%); mp 188.2–189.2 °C.
LRMS (EI, 70 eV): m/z (%) = 305 (18), 303 (53), 277 (14), 276 (41), 275
(44), 274 (100), 261 (26), 260 (47), 259 (78), 258 (100), 135 (24).
IR (KBr): 3362, 1692, 1603, 1498, 1486, 1356, 1093, 829 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.31–7.26 (m, 4 H), 7.15 (d, J = 7.9 Hz, 1
H), 7.05 (s, 1 H), 6.80 (d, J = 7.9 Hz, 1 H), 3.91 (s, 1 H), 3.22 (s, 3 H), 2.29
(s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 177.3, 140.9, 138.8, 134.1, 133.5,
131.3, 130.3, 128.7, 126.9, 125.6, 108.6, 77.8, 26.6, 21.0.
1-Ethyl-3-hydroxy-3-phenylindolin-2-one (2n)16
Yellow solid; yield: 20.2 mg (43%); mp 151–152 °C (Lit. 153–154 °C).
1H NMR (600 MHz, CDCl3): δ = 7.41–7.28 (m, 7 H), 7.11–7.05 (m, 1 H),
6.95 (d, J = 7.8 Hz, 1 H), 3.90–3.73 (m, 2 H), 3.43 (s, 1 H), 1.34 (t, J = 7.2
Hz, 3 H).
13C NMR (151 MHz, CDCl3): δ = 177.2, 142.6, 140.3, 131.9, 129.8,
128.6, 128.2, 125.2, 125.1, 123.3, 108.8, 77.9, 35.0, 12.6.
LRMS (EI, 70 eV): m/z (%) = 289 (28), 287 (82), 261 (25), 260 (43), 259
(24), 258 (100), 244 (26), 242 (100), 207 (21), 918 (25).
HRMS (ESI): m/z [M + H]+ calcd for C16H15ClNO2: 288.0785; found:
288.0788.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
Y.-Y. Liao et al.
Paper
Synthesis
LRMS (EI, 70 eV): m/z (%) = 253 (79), 225 (50), 224 (36), 210 (100),
208 (26), 206 (22), 146 (30), 132 (26), 105 (30), 91 (19), 77 (49).
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1-Ethyl-3-hydroxy-3-(4-methoxyphenyl)indolin-2-one (2o)
White solid; yield: 22.1 mg (39%); mp 127.1–127.7 °C.
IR (KBr): 3386, 1709, 1617, 1506, 1468, 1253, 1174, 914 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.33 (dt, J = 9.4, 4.3 Hz, 4 H), 7.11–7.06
(m, 1 H), 6.92 (d, J = 7.8 Hz, 1 H), 6.88–6.82 (m, 2 H), 3.89–3.70 (m, 5
H), 3.62 (s, 1 H), 1.31 (t, J = 7.2 Hz, 3 H).
13C NMR (151 MHz, CDCl3): δ = 177.3, 159.5, 142.5, 132.3, 132.0,
129.7, 126.7, 125.1, 123.3, 114.0, 108.8, 77.5, 55.3, 35.0, 12.6.
LRMS (EI, 70 eV): m/z (%) = 283 (91), 267 (20), 255 (92), 254 (62), 240
(100), 238 (53).
HRMS (ESI): m/z [M + H]+ calcd for C17H18NO3: 284.1281; found:
284.1283.
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71, 5776. (c) Yin, L.; Kanai, M.; Shibasaki, M. Angew. Chem. Int.
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Jia, Y.-X.; Gao, J.-R. Chem. Eur. J. 2011, 17, 5234.
2-[(3-Chlorophenyl)(methyl)amino]-1-p-tolylethanone (1l)
White solid; yield: 202 mg (78%); mp 76.0–76.9 °C.
IR (KBr): 1688, 1599, 1559, 1500, 1222, 983, 953 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.89 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.0
Hz, 2 H), 7.11 (t, J = 8.1 Hz, 1 H), 6.69 (dd, J = 7.8, 1.2 Hz, 1 H), 6.65 (t,
J = 2.1 Hz, 1 H), 6.52 (dd, J = 8.4, 2.5 Hz, 1 H), 4.76 (s, 2 H), 3.10 (s, 3 H),
2.46 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 195.3, 150.4, 144.6, 135.1, 132.8,
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Otsuka, M.; Tsuchikama, K.; Endo, K. Synlett 2011, 2075.
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130.1, 129.5, 127.9, 116.8, 112.1, 110.3, 58.5, 39.6, 21.7.
LRMS (EI, 70 eV): m/z (%) = 275 (6), 273 (19), 156 (64), 155 (19), 154
(100), 141 (4), 140 (12), 139 (12), 138 (15).
HRMS (ESI): m/z [M + H]+ calcd for C16H17ClNO: 274.0993; found:
274.0996.
Funding Information
We gratefully acknowledge the financial support of South China Agri-
cultural University and the Science Technology Program Project of
Guangdong Province (No. 2016B020204005).
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Supporting Information
(13) Liu, M.; Zhang, C.; Ding, M.; Tang, B.; Zhang, F. Green Chem.
2017, 19, 4509.
(14) Zhu, F.; Zhou, F.; Cao, Z.-Y.; Wang, C.; Zhang, Y.-X.; Wang, C.-H.;
Zhou, J. Synthesis 2012, 44, 3129.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610537.
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(15) Yamamoto, Y.; Yohda, M.; Shirai, T.; Ito, H.; Miyaura, N. Chem.
Asian J. 2012, 7, 2446.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F