Synthesis of 3-amino-3-hydroxymethyloxindoles and 3-hydroxy-3- hydroxymethyloxindoles by Rh2(OAc)4-catalyzed three-component reactions of 3-diazooxindoles with formaldehyde and anilines or water

Article abstract of DOI:10.1021/jo500307n

Efficient Rh(II)-catalyzed three-component reactions of 3-diazooxindoles and formaldehyde with either anilines or water were developed to give a series of substituted 3-amino-3-hydroxymethyloxindoles or 3-hydroxy-3- hydroxymethyloxindoles in good to excellent yields. In this atom- and step-economic transformation, Rh₂(OAc)₄-catalyzed decomposition of 3-diazooxindoles with anilines or water forms the corresponding active ammonium or oxonium ylides. Electrophilic trapping of the resulting ammonium ylides or oxonium ylides by formaldehyde in the form of formalin efficiently produces the title compounds in one step.

Full text of DOI:10.1021/jo500307n

Article
pubs.acs.org/joc
Synthesis of 3‑Amino-3-hydroxymethyloxindoles and 3‑Hydroxy-3-
hydroxymethyloxindoles by Rh2(OAc)4‑Catalyzed Three-Component
Reactions of 3‑Diazooxindoles with Formaldehyde and Anilines or
Water
Chengjin Wang, Dong Xing,* Dongwei Wang, Xiang Wu, and Wenhao Hu*
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, and Department of Chemistry, East
China Normal University, Shanghai, 200062, China
S
* Supporting Information
ABSTRACT: Efficient Rh(II)-catalyzed three-component reactions of 3-diazooxindoles and formaldehyde with either anilines
or water were developed to give a series of substituted 3-amino-3-hydroxymethyloxindoles or 3-hydroxy-3-hydroxymethylox-
indoles in good to excellent yields. In this atom- and step-economic transformation, Rh2(OAc)4-catalyzed decomposition of 3-
diazooxindoles with anilines or water forms the corresponding active ammonium or oxonium ylides. Electrophilic trapping of the
resulting ammonium ylides or oxonium ylides by formaldehyde in the form of formalin efficiently produces the title compounds
in one step.
alkyloxindoles and 3-hydroxy-3-alkyloxindoles are still in great
demand. Herein, we describe efficient rhodium(II)-catalyzed
three-component reactions of 3-diazooxindoles with form-
aldehyde and anilines or water via aldol-type trapping of either
ammonium or oxonium ylides, leading to both 3-amino-3-
hydroxymethyloxindoles and 3-hydroxy-3-hydroxymethyloxin-
doles in an atom- and step-economic fashion (Scheme 1). The
3-hydroxymethyl group existed in these products could be
easily functionalized into different types of 3-amino-3-
alkyloxindoles or 3-hydroxy-3-alkyloxindoles.
In the past few years, our research group has developed a
series of multicomponent reactions (MCRs) via electrophilic
trapping of active onium ylides or zwitterionic intermediates
that generated from metal carbenes.6 Among those trans-
formations, aldol-type trapping of ammonium or oxonium
ylides with active aromatic ketones or aldehydes has been
extensively developed as efficient methods for the synthesis of
nitrogen- and/or oxygen-containing molecules,7,8 such as
different types of amino acid derivatives and heterocycles.
However, aliphatic aldehydes were seldom applied as the
trapping reagents owing to their weak electrophilicity. Very
recently, we disclosed that aqueous formaldehyde solution
(formalin) could efficiently trap the ammonium ylides
generated from aryl diazoacetate derived metal carbenes and
anilines to establish three-component transformations.9 With
INTRODUCTION
■
3,3-Disubstituted oxindoles are widely recognized as valuable
structural motifs, forming the core structure of a large number
of natural products and pharmaceutical agents.1,2 Among those
compounds, 3-amino-3-alkyloxindoles and 3-hydroxy-3-alkylox-
indoles are readily derivatized to the central framework of an
array of alkaloids that display novel biological activities.3 For
example, AG-041R has been reported as a potent gastrin/
CCKB receptor antagonist that exhibits selective binding to
CCKB rather than CCKA.3a,b Compound A has been used as
the key precursor leading to unusual marine alkaloid chartelline
A.3c YK-4-279 can block RNA helicase A binding to EWS-FLI1
and, therefore, shows potent anti-EWS activity.3d Convoluta-
mydine A shows a potent activity in the differentiation of HL-
60 human promyelocytic leukemia cells (Figure 1).3e
Owing to their structural importance in medicinal chemistry,
a number of strategies have been developed for the synthesis of
3-amino-3-alkyloxindoles and 3-hydroxy-3-alkyloxindoles.
Methods for the synthesis of 3-amino-3-alkyloxindoles include
nucleophilic additions to isatin imines,4a−c the Ritter reaction,4d
alkylation of 3-aminooxindoles,4e amination of 3-substituted
oxindoles,4f intramolecular arylation,4g,h and [3 + 2] dipolar
cycloadditions.4i On the other hand, nucleophilic addition to
isatins,5a−e arylation and allylation of isatins,5f−k and direct
hydroxylation of 3-alkyl-substituted oxindoles5l−q were gen-
erally applied for the synthesis of 3-hydroxy-3-alkyloxindole
derivatives. Despite these advances, highly efficient synthetic
strategies that can conveniently lead to both 3-amino-3-
Received: February 13, 2014
Published: April 4, 2014
© 2014 American Chemical Society
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Figure 1. Representative biologically active molecules containing 3-amino-3-alkyloxindole or 3-hydroxy-3-alkyloxindole motifs.
Scheme 1. Rh2(OAc)4-Catalyzed Three-Component Strategy
for the Synthesis of 3-Amino-3-hydroxymethyloxindoles and
3-Hydroxy-3-hydroxymethyloxindoles
Table 1. Condition Optimization for the Ammonium Ylide
Trapping Process
a
b
entry
solvent
THF
temp (°C)
T (h)
yield (%)
1
2
3
4
5
6
7
60
60
60
60
40
60
60
12
11
1
70
49
84
89
75
72
94
dioxane
DME
these preliminary results, we envisioned that formalin could be
applied as the suitable electrophile to trap active ylide
intermediates derived from 3-diazooxindoles for the synthesis
of 3,3-disubstituted oxindoles. However, the use of formalin as
the trapping reagent may cause an array of undesired side
reactions. For example, water and methanol that existed in the
solution may act as nucleophiles to react with 3-diazooxindoles
to afford O−H insertion products or oxonium ylide trapping
products,10a and under such reaction conditions, oxidation and
polymerization of 3-diazooxindoles are also possible side
reactions.10b,c On the other hand, 3-diazooxindoles were less
reactive diazo sources;11 as a result, the generated ammonium
ylide or oxonium ylide intermediates may undergo rapid N−H
or O−H insertions instead of being trapped by formaldehyde to
establish three-component transformations.
diethoxyethane
CH2Cl2
toluene
1
1
1
EtOAc
1
a
Reaction conditions: To a mixture of 2a (0.10 mmol), 3 (37%
aqueous formaldehyde solution, 0.60 mmol), Rh2(OAc)4 (0.001
mmol), and the corresponding solvent (1 mL) at the given
temperature was added 1a (0.10 mmol) in the corresponding solvent
(1 mL) via a syringe pump over 1 h. After completion of the addition,
the reaction mixture was stirred for the given time until complete
b
decomposition of diazo compound. Isolated yield of 4a after column
chromatography.
other hand, solvents immiscible with water, such as CH2Cl2 or
toluene, were also applied, giving 4a in slightly reduced yields
(Table 1, entries 5 and 6). The best result was obtained when
ethyl acetate (EA) was used as the solvent, affording 4a in 94%
yield within 1 h (Table 1, entry 7).
RESULTS AND DISCUSSION
■
Our studies commenced with the ammonium ylide trapping
process with formalin. N-Benzyl-3-diazooxindole 1a and 2,6-
dichloroaniline 2a were allowed to react with formalin 3 in the
presence of rhodium catalyst. Since our initial investigation
indicated that the Rh2(OAc)4-catalyzed decomposition of 1a
was very slow at room temperature, the reaction was allowed to
react at 60 °C. Under such reaction conditions, the desired
three-component product 4a was obtained in 70% yield after
reacting for 12 h (Table 1, entry 1). The major side products
being observed for this reaction included N-benzyl isatin
produced by oxidation of 1a, as well as the N−H and O−H
insertion products of 3-diazooxindole generated from aniline
and water, respectively. Encouraged by this preliminary result,
further condition optimizations were conducted. Among
different water-miscible solvents being screened, the use of
dioxane as the solvent gave relatively poor yield after reacting
for 11 h (Table 1, entry 2). When dimethoxyethane (DME) or
diethoxyethane was used as the solvent, the desired three-
component reaction was completed within 1 h and afforded 4a
in much improved yields (Table 1, entries 3 and 4). On the
With the optimized reaction conditions in hand, the substrate
scope of this Rh(II)-catalyzed ammonium ylide trapping
process was investigated. Different protecting groups on the
nitrogen atom of 3-diazooxindoles, including benzyl (1a),
methyl (1b), and acetyl (1c), proved to be effective in
providing the corresponding three-component products in
good yields (Table 2, entries 1−3). Different substituents on
the aromatic ring of 3-diazooxindoles were also tested, and the
corresponding three-component products were generally
afforded in good yields regardless of their electronic features
(Table 2, entries 4−7, 15, and 21). On the other hand, different
substituted anilines were also investigated. With aniline as the
substrate, the desired three-component product 4h was
obtained in relatively low yield (Table 2, entry 8). Anilines
bearing halogen substituents at the para-position were suitable
substrates, giving the corresponding three-component products
in high yields (Table 2, entries 9−11). When 4-nitroaniline or
3-nitroaniline were used as the substrates, even higher yields of
the desired products were obtained (Table 2, entries 12 and
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Table 2. Substrate Scope of the Ammonium Ylide Trapping
a
Process
b
entry
1 (R1, R2)
R3
4
yield (%)
Figure 2. X-ray crystal structure of 4a.
1
2
1a (Bn, H)
1b (Me, H)
1c (Ac, H)
1d (Bn, 5-Me)
1e (Bn, 5-Br)
1f (Bn, 4-Cl)
1g (Bn, 7-Cl)
1a (Bn, H)
1a (Bn, H)
1a (Bn, H)
1a (Bn, H)
1a (Bn, H)
1a (Bn, H)
1a (Bn, H)
1d (Bn, 5-Me)
1a (Bn, H)
1a (Bn, H)
1a (Bn, H)
1a (Bn, H)
1a (Bn, H)
1d (Bn, 5-Me)
2,6-dichloro
2,6-dichloro
2,6-dichloro
2,6-dichloro
2,6-dichloro
2,6-dichloro
2,6-dichloro
H
4a
4b
4c
4d
4e
4f
94
78
89
84
89
74
93
42
89
86
88
94
95
84
73
76
82
98
94
64
84
3
a 37% aqueous solution of formaldehyde, formalin contains a
considerable amount of water, which could be directly used as
the precursor to generate the corresponding oxonium ylide, and
the reaction between 3-diazooxindoles and formalin could
potentially lead to a three-component oxonium ylide trapping
transformation. With this hypothesis, N-benzyl-3-diazooxindole
1a and formalin 3 were allowed to react in the presence of
Rh2(OAc)4 in EtOAc at 60 °C, and the desired oxonium ylide
trapping product 5a was obtained in 70% yield along with the
formation of N-benzyl isatin derived from oxidation of 1a, N-
benzyl-3-hydroxyoxindole, and N-benzyl-3-methoxyoxindole
(O−H insertion products from H2O and MeOH, respectively)
as the major side products (Table 3, entry 1). This is the first
time that a three-component reaction based on trapping of
oxonium ylides with formaldehyde was realized. With this
preliminary result in hand, further condition optimizations were
conducted. However, among different solvents being tested,
only the use of EtOAc provided the most satisfactory result
(Table 3, entries 1−6). Other transition-metal catalysts,
including copper(I) and copper(II) salts, iron porphyrin, and
palladium(II) complex, were also screened, but no encouraging
results were achieved (Table 3, entries 7−13). Therefore, the
use of Rh2(OAc)4 as the catalyst and EtOAc as the solvent was
chosen as the conditions for investigating the substrate scope.
Under standard reaction conditions, the substrate scope of
this oxonium ylide trapping three-component reaction was
tested. N-Alkyl or N-acetyl substituted 3-diazooxindoles were
applicable to the desired three-component reaction, yielding
the desired three-component products in moderate to good
yields (Table 4, entries 1−3). Substrates bearing ester
substituents, such as N-methoxycarbonyl, N-ethoxycarbonyl,
and N-Boc substituted 3-diazooxindoles, were also suitable
substrates to give the desired three-component products in
moderate to good yields (Table 4, entries 4−6). On the other
hand, different substituents on the aromatic ring of 3-
diazooxindoles were also tested. 5-Methyl substituted 3-
diazooxindole gave the desired three-component product in
73% yield (Table 4, entry 7); however, halogen substituents at
the 5-position of 3-diazooxindoles caused declined yields, while
relatively poor yields were observed when 5-fluoro 3-
diazooxindoles were used as the substrates (Table 4, entries
8−11). Substituents on other positions of 3-diazooxindoles
were also proved to be suitable for the desired three-
component reaction, giving the desired products in moderate
to good yields (Table 4, entries 12−14). Similar to the
previously developed ammonium ylide trapping process, the
use of other aliphatic aldehydes, including ethanal, propanal,
and butanal, failed to afford the desired three-component
products in this oxonium ylide trapping process.
4
5
6
7
4g
4h
4i
8
9
4-Cl
10
11
12
13
14
15
16
17
18
19
20
21
4-Br
4j
4-I
4k
4l
4-NO2
3-NO2
4m
4n
4o
4p
4q
4r
4s
4t
2-Cl
2-Cl
2-I
3-Cl
2,4-dichloro
2,5-dichloro
4-F-2-NO2
2,4,6-tribromo
4u
a
Reaction conditions: To a mixture of 2 (0.1 mmol), 3 (37% aqueous
formaldehyde solution, 0.6 mmol), Rh2(OAc)4 (0.001 mmol), and
EtOAc (1 mL) at 60 °C was added 1 (0.1 mmol) in EtOAc (1 mL) via
a syringe pump over 1 h. After the completion of the addition, the
reaction mixture was stirred for an additional 1 h. Isolated yield of 4
after column chromatography.
b
13). These results indicated that electron-deficient anilines
favored the desired three-component reactions. This might be
explained by the fact that electron-deficient aniline had
decreased electron density on the nitrogen atom; therefore,
preventing the unwanted formation of a hemiacetal resulted
from the addition to formaldehyde. Changing the position of
the halogen substituent had little effect on the yields of the
desired three-component products (Table 2, entries 14−17).
The reaction conditions were also compatible with other
disubstituted anilines, which gave the desired three-component
products in good yields (Table 2, entries 18−20). 2,4,6-
Tribromoaniline was also applicable to this three-component
reaction, affording the desired product 4u in 84% yield (Table
2, entry 21). The structures of the three-component products
were further confirmed by the single-crystal X-ray analysis of
compound 4a (Figure 2). It was also worth mentioning that,
when other aliphatic aldehydes, such as ethanal, propanal, or
butanal, were applied, no desired three-component products
were observed. This might be caused by the relatively weak
electrophilicities of other aliphatic aldehydes or increased steric
hindrance. These results indicated the unique feature of
formaldehyde as the suitable trapping agent.
Having successfully established the Rh(II)-catalyzed ammo-
nium ylide trapping process with formalin, we set out to further
expand this electrophilic trapping process to oxonium ylides. As
A plausible reaction pathway for this Rh(II)-catalyzed three-
component approach is shown in Scheme 2. Rh2(OAc)4
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a
Table 3. Condition Optimization for the Oxonium Ylide Trapping Process
b
entry
solvent
cat.
temp (°C)
T (h)
yield (%)
1
2
EtOAc
THF
Rh2(OAC)4 (2%)
Rh2(OAC)4 (2%)
Rh2(OAC)4 (2%)
Rh2(OAC)4 (2%)
Rh2(OAC)4 (2%)
Rh2(OAC)4 (2%)
CuOTf (10%)
60
60
60
60
35
60
60
60
60
60
60
60
60
1
9
70
47
22
41
45
44
<5
<5
0
3
dioxane
DME
9
4
1
5
DCM
1
6
toluene
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
1
7
12
12
12
30
12
18
18
8
Cu(OTf)2 (10%)
Cu(OAc)2·H2O (10%)
CuSO4 (50%)
9
10
11
12
13
<5
14
<5
15
CuPF6(MeCN)4 (10%)
Fe(TPP)Cl (1%)
(η3-C3H5)2Pd2Cl2 (2.5%)
a
Reaction conditions: To a mixture of the catalyst and formalin 3 (1.2 mmol) (37% aqueous formaldehyde solution) in the corresponding solvent
(2.0 mL) at 60 °C was added 1a (0.20 mmol) in the corresponding solvent (2.0 mL) via a syringe pump over 1 h. After the completion of the
b
addition, the reaction mixture was stirred for the given time. Isolated yield of 5a after column chromatography.
3,3-disubstituted oxindole derivatives, the three-component
product 4t derived from 3-diazooxindole, 4-fluoro-2-nitroani-
line, and formaldehyde was first converted into the
corresponding Boc-protected product 6t in 90% yield.
Compound 6t then underwent Pd/C-catalyzed hydrogenation
to afford 7t (95%), which was further cyclized into novel
benzimidazole 8t (96% yield) (Scheme 3).
Table 4. Substrate Scope of the Oxonium Ylide Trapping
Process
a
b
entry
R1
Bn
R2
5
yield (%)
CONCLUSION
■
1
2
H (1a)
5a
5b
5c
5d
5e
5f
70
46
54
62
31
45
73
54
30
26
55
74
46
73
In conclusion, we have developed an efficient Rh(II)-catalyzed
three-component reaction of 3-diazooxindoles with anilines and
formalin. This transformation proceeded through an electro-
philic trapping of the ammonium ylides generated from 3-
diazooxindoles and anilines with formaldehyde. A series of
substituted 3-amino-3-hydroxymethyloxindoles were synthe-
sized in high to excellent yields. On the other hand, the reaction
between 3-diazooxindoles and formalin in the presence of
Rh(II) catalyst also resulted in an efficient oxonium ylide
trapping three-component reaction, yielding a series of 3-
hydroxy-3-hydroxymethyloxindoles in moderate to good yields.
This three-component approach provides an efficient and
convenient way for the synthesis of both 3-amino-3-
hydroxymethyloxindoles and 3-hydroxy-3-hydroxymethyloxin-
doles. Exploration of the asymmetric version of the reactions is
currently underway in our laboratory.
Me
Ac
H (1b)
3
H (1c)
4
CO2Me
CO2Et
Boc
Bn
H (1h)
5
H (1i)
6
H (1j)
7
5-Me (1d)
5-Br (1e)
5-F (1k)
5-F (1l)
5-Cl (1m)
4-Cl (1f)
6-Cl (1n)
7-Cl (1g)
5g
5h
5i
8
Bn
9
Bn
10
11
12
13
14
Me
5j
Bn
5k
5l
Bn
Bn
5m
5n
Bn
a
Reaction conditions: To a mixture of Rh2(OAc)4 (0.004 mmol) and
formalin 3 (1.2 mmol) (37% aqueous formaldehyde solution) in
EtOAc (2.0 mL) at 60 °C was added 1 (0.20 mmol) in EtOAc (4.0 mL
for 5-substituted 3-diazooxindoles and 2.0 mL for other 3-diazo
oxindoles) via a syringe pump over 1 h. After the completion of the
addition, the reaction mixture was stirred for an additional 1 h.
EXPERIMENTAL SECTION
■
General Information. Diazo compounds 1a−1n were prepared
b
according to the literature methods.11b,12 All isolated compounds were
Isolated yields after column chromatography.
1
characterized on the basis of H NMR and 13C NMR spectroscopic
1
data and HRMS (TOF-Q) data. H NMR and 13C NMR chemical
decomposes 3-diazooxindole 1 to form the corresponding
rhodium carbene species I, which further reacts with aniline or
water to give active ammonium ylides or oxonium ylides IIa/
IIb. In the presence of formaldehyde, the active ylide species
undergo aldol-type addition to afford the desired three-
component products.
shifts are reported in parts per million (ppm) using tetramethylsilane
(TMS) as an internal standard. All reactions were run in open flasks,
and an inert atmosphere was not required. A.R. grade solvents were
directly used, and further purification or degas of the solvents was not
required.
General Procedure for the Synthesis of 3-Amino-3-hydrox-
ymethyloxindoles. To a mixture of Rh2(OAc)4 (0.001 mmol),
aniline 2 (0.10 mmol), and formalin 3 (37% aqueous solution of
To further demonstrate the synthetic potential of this Rh(II)-
catalyzed three-component strategy in synthesizing valuable
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Scheme 2. Proposed Reaction Pathways
Scheme 3. Synthesis of Valuable 3,3-Disubstituted Oxindoles
formaldehyde, 0.60 mmol) in EtOAc (1.0 mL) at 60 °C was added
diazo compound 1 (0.1 mmol) in EtOAc (1.0 mL) via a syringe pump
for 1 h. After the completion of the addition, the reaction mixture was
stirred for an additional 1 h. Solvents were removed under reduced
pressure to give crude products, which were purified by flash
chromatography on silica gel (ethyl acetate/petroleum ether = 1:10
to 1:1).
124.9, 123.6, 109.3, 69.8, 66.5, 44.1, 20.9. HRMS (ESI) calcd for
C23H20Cl2N2NaO2 [M + Na]+ = 449.0800, found 449.0822.
1-Benzyl-5-bromo-3-((2,6-dichlorophenyl)amino)-3-(hydroxy-
methyl)indolin-2-one (4e). A light yellow solid (44 mg, 89% yield).
1H NMR (400 MHz, CDCl3): δ 7.39−7.27 (m, 6H), 7.14 (d, J = 8.0
Hz, 2H), 6.83 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 6.64 (d, J =
8.3 Hz, 1H), 5.18 (s, 1H), 5.01 (d, J = 15.4 Hz, 1H), 4.79 (d, J = 15.5
Hz, 1H), 3.91 (dd, J = 24.3, 11.0 Hz, 2H), 3.08 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 177.3, 142.0, 139.4, 135.0, 132.2, 129.7, 128.90
128.3, 128.0, 127.7, 127.4, 124.2, 115.1, 111.0, 69.4, 66.6, 44.2. HRMS
(ESI) calcd for C22H17BrCl2N2NaO2 [M + Na]+ = 512.9748, found
512.9773.
1-Benzyl-4-chloro-3-((2,6-dichlorophenyl)amino)-3-(hydroxy-
methyl)indolin-2-one (4f). A white solid (33 mg, 74% yield). 1H
NMR (400 MHz, CDCl3): δ 7.36−7.27 (m, 5H), 7.13 (t, J = 8.1 Hz,
1H), 7.09 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.74 (t, J = 8.0
Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 5.50 (s, 1H), 4.99 (d, J = 15.5 Hz,
1H), 4.81 (d, J = 15.5 Hz, 1H), 4.43 (t, J = 11.0 Hz, 1H), 3.98−3.85
(m, 1H), 3.18−2.99 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 177.0,
145.0, 140.1, 135.0, 131.5, 130.7, 128.9, 128.3, 128.0, 127.7, 127.2,
124.1, 123.7, 122.5, 108.1, 67.3, 66.7, 44.3. HRMS (ESI) calcd for
C22H17Cl3N2NaO2 [M + Na]+ = 469.0253, found 469.0248.
1-Benzyl-3-((2,6-dichlorophenyl)amino)-3-(hydroxymethyl)-
1
indolin-2-one (4a). A white solid (39 mg, 94% yield). H NMR (400
MHz, CDCl3): δ 7.40−7.27 (m, 5H), 7.15 (td, J = 7.8, 1.0 Hz, 1H),
7.09 (d, J = 8.0 Hz, 2H), 6.78 (dt, J = 12.4, 4.1 Hz, 3H), 6.69−6.59 (m,
1H), 5.27 (s, 1H), 5.04 (d, J = 15.4 Hz, 1H), 4.82 (d, J = 15.4 Hz, 1H),
3.97 (t, J = 10.9 Hz, 1H), 3.87 (dd, J = 11.3, 3.0 Hz, 1H), 3.15 (dd, J =
10.4, 3.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 178.1, 143.0,
140.0, 135.5, 129.7, 129.4, 128.8, 128.1, 127.9, 127.8, 125.8, 124.1,
123.7, 122.3, 109.6, 69.8, 66.5, 44.1. HRMS (ESI) calcd for
C22H19Cl2N2O2 [M + H]+ = 413.0824, found 413.0838.
3-((2,6-Dichlorophenyl)amino)-3-(hydroxymethyl)-1-methyl-
1
indolin-2-one (4b). A white solid (26 mg, 78% yield). H NMR (400
MHz, CDCl3): δ 7.26 (d, J = 6.5 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H),
6.86−6.73 (m, 3H), 6.68 (d, J = 7.3 Hz, 1H), 5.22 (s, 1H), 3.92 (t, J =
10.8 Hz, 1H), 3.83 (dd, J = 11.3, 3.2 Hz, 1H), 3.24 (s, 3H), 3.15 (d, J =
9.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 178.1, 143.8, 140.0,
129.6, 129.5, 128.2, 125.9, 124.1, 123.7, 122.3, 108.6, 69.5, 66.5, 26.3.
HRMS (ESI) calcd for C16H14Cl2N2NaO2 [M + Na]+ = 359.0330,
found 359.0323.
1-Benzyl-7-chloro-3-((2,6-dichlorophenyl)amino)-3-(hydroxy-
methyl)indolin-2-one (4g). A white solid (42 mg, 93% yield). 1H
NMR (400 MHz, CDCl3): δ 7.31 (q, J = 8.1 Hz, 4H), 7.25 (dd, J =
8.4, 5.1 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H),
6.77 (dt, J = 15.7, 8.0 Hz, 2H), 6.60 (t, J = 8.0 Hz, 1H), 5.43 (d, J =
15.9 Hz, 1H), 5.36−5.25 (m, 1H), 5.22 (s, 1H), 3.96−3.88 (m, 1H),
3.85 (d, J = 11.2 Hz, 1H), 3.10 (d, J = 36.6 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 178.6, 139.6, 139.1, 137.2, 132.0, 129.5, 128.6, 128.3,
127.4, 127.2, 123.9, 123.3, 122.7, 115.8, 69.8, 66.0, 45.01. HRMS (ESI)
calcd for C22H17Cl3N2NaO2 [M + Na]+ = 469.0253, found 469.0276.
1-Benzyl-3-(hydroxymethyl)-3-(phenylamino)indolin-2-one (4h).
1-Acetyl-3-((2,6-dichlorophenyl)amino)-3-(hydroxymethyl)-
1
indolin-2-one (4c). A white solid (32 mg, 89% yield). H NMR (400
MHz, CDCl3): δ 8.23 (d, J = 8.2 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H),
7.13 (d, J = 8.0 Hz, 2H), 6.98 (t, J = 7.5 Hz, 1H), 6.81 (t, J = 8.0 Hz,
1H), 6.74 (d, J = 7.5 Hz, 1H), 5.12 (s, 1H), 3.92 (s, 2H), 2.73 (s, 3H),
2.62 (d, J = 5.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 178.5,
170.8, 140.3, 139.0, 129.9, 129.7, 128.3, 125.2, 124.9, 124.1, 123.7,
116.9, 69.6, 66.6, 26.7. HRMS (ESI) calcd for C17H16Cl2N2NaO3 [M +
Na]+ = 389.0436, found 389.0443.
1
A sticky oil (14 mg, 42% yield). H NMR (400 MHz, CDCl3): δ
7.40−7.16 (m, 8H), 7.06 (t, J = 7.5 Hz, 1H), 6.95 (t, J = 7.8 Hz, 2H),
6.84 (d, J = 7.8 Hz, 1H), 6.70 (t, J = 7.3 Hz, 1H), 6.27 (d, J = 8.0 Hz,
2H), 5.18 (s, 1H), 5.11 (d, J = 15.5 Hz, 1H), 4.76 (d, J = 15.5 Hz, 1H),
3.92 (t, J = 10.9 Hz, 1H), 3.75−3.64 (m, 1H), 3.12 (d, J = 10.4 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 178.0, 145.6, 141.9, 135.3,
129.6, 129.1, 128.8, 127.9, 127.6, 124.0, 123.6, 119.6, 115.5, 110.1,
1-Benzyl-3-((2,6-dichlorophenyl)amino)-3-(hydroxymethyl)-5-
methylindolin-2-one (4d). A light yellow solid (36 mg, 84% yield). 1H
NMR (400 MHz, CDCl3): δ 7.38−7.23 (m, 5H), 6.94 (dd, J = 8.0, 0.8
Hz, 1H), 6.77 (t, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.44 (d, J =
0.6 Hz, 1H), 5.25 (s, 1H), 5.00 (d, J = 15.4 Hz, 1H), 4.80 (d, J = 15.4
Hz, 1H), 3.95 (t, J = 10.7 Hz, 1H), 3.85 (d, J = 10.1 Hz, 1H), 3.19 (d, J
= 9.9 Hz, 1H), 2.08 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 178.0,
140.5, 140.0, 135.6, 132.0, 129.7, 129.6, 128.8, 128.1, 127.8, 126.0,
68.1, 65.0, 44.1. HRMS (ESI) calcd for C22H21N2O2 [M + H]+
345.1603, found 345.1598.
=
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1-Benzyl-3-((4-chlorophenyl)amino)-3-(hydroxymethyl)-indolin-
HRMS (ESI) calcd for C23H21ClN2NaO2 [M + Na]+ = 415.1189,
found 415.1181.
1
2-one (4i). A white solid (32 mg, 89% yield). H NMR (400 MHz,
CDCl3): δ 7.30 (dd, J = 8.7, 4.9 Hz, 4H), 7.26−7.22 (m, 1H), 7.22−
7.16 (m, 2H), 7.06 (t, J = 7.5 Hz, 1H), 6.88 (t, J = 6.0 Hz, 2H), 6.84
(d, J = 7.9 Hz, 1H), 6.24−6.12 (m, 2H), 5.24 (s, 1H), 5.09 (d, J = 15.4
Hz, 1H), 4.73 (d, J = 15.4 Hz, 1H), 3.97−3.82 (m, 1H), 3.75−3.66
(m, 1H), 3.46 (d, J = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
177.7, 144.2, 141.9, 135.2, 129.8, 129.0, 128.9, 128.0, 127.6, 127.3,
124.4, 124.1, 123.7, 117.0, 110.1, 67.9, 65.2, 44.1. HRMS (ESI) calcd
for C22H20ClN2O2 [M + H]+ = 379.1213 found 379.1216.
1-Benzyl-3-(hydroxymethyl)-3-((2-iodophenyl)amino)indolin-2-
1
one (4p). A white solid (36 mg, 76% yield). H NMR (400 MHz,
CDCl3): δ 7.66 (dd, J = 7.8, 1.3 Hz, 1H), 7.34−7.27 (m, 7H), 7.07 (t, J
= 7.4 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.72 (dd, J = 11.3, 4.2 Hz,
1H), 6.45−6.34 (m, 1H), 5.72 (s, 1H), 5.64 (dd, J = 8.1, 1.1 Hz, 1H),
5.13 (d, J = 15.3 Hz, 1H), 4.81 (d, J = 15.3 Hz, 1H), 4.00 (t, J = 11.4
Hz, 1H), 3.72 (dd, J = 11.5, 2.5 Hz, 1H), 2.95 (dd, J = 11.3, 2.5 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 177.3, 145.0, 141.8, 139.4,
135.4, 129.7, 129.1, 128.9, 128.0, 127.8, 126.9, 123.9, 123.7, 120.4,
112.5, 110.1, 87.1, 68.3, 65.0, 44.2. HRMS (ESI) calcd for
C22H19IN2NaO2 [M + Na]+ = 493.0389, found 493.0367.
1-Benzyl-3-(hydroxymethyl)-3-((4-bromophenyl)amino)indolin-
1
2-one (4j). A white solid (36 mg, 86% yield). H NMR (400 MHz,
CDCl3): δ 7.23 (d, J = 6.2 Hz, 4H), 7.18 (d, J = 6.3 Hz, 1H), 7.14 (d, J
= 6.0 Hz, 2H), 6.99 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.8 Hz, 2H), 6.78
(d, J = 7.7 Hz, 1H), 6.05 (d, J = 7.9 Hz, 2H), 5.18 (s, 1H), 5.02 (d, J =
15.4 Hz, 1H), 4.67 (d, J = 15.4 Hz, 1H), 3.83 (s, 1H), 3.63 (d, J = 11.5
Hz, 1H), 3.25 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 177.7, 144.6,
141.8, 135.2, 131.9, 129.8, 128.9, 128.0, 127.6, 127.2, 124.0, 123.7,
117.3, 111.6, 110.2, 67.9, 65.0, 44.1. HRMS (ESI) calcd for
C22H19BrNaN2O2 [M + Na]+ = 445.0528, found 445.0529.
1-Benzyl-3-((3-chlorophenyl)amino)-3-(hydroxymethyl)indolin-2-
1
one (4q). A white solid (31 mg, 82% yield). H NMR (400 MHz,
CDCl3): δ 7.31−7.11 (m, 8H), 6.99 (t, J = 7.5 Hz, 1H), 6.75 (t, J = 8.2
Hz, 2H), 6.57 (d, J = 7.8 Hz, 1H), 6.21 (s, 1H), 6.01 (d, J = 8.1 Hz,
1H), 5.26 (s, 1H), 5.06 (d, J = 15.5 Hz, 1H), 4.70 (d, J = 15.5 Hz, 1H),
3.86−3.75 (m, 1H), 3.62 (d, J = 11.5 Hz, 1H), 3.24 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 177.6, 141.7, 135.4, 129.8, 129.4, 128.9, 128.0,
127.8, 127.5, 127.1, 124.0, 123.7, 119.2, 113.1, 110.1, 68.2, 64.5, 44.2.
HRMS (ESI) calcd for C22H19ClNaN2O2 [M + Na]+ = 401.1033,
found 401.1025.
1-Benzyl-3-(hydroxymethyl)-3-((4-iodophenyl)amino)indolin-2-
1
one (4k). A yellow solid (41 mg, 88% yield). H NMR (400 MHz,
CDCl3): δ 7.21 (d, J = 7.1 Hz, 4H), 7.17 (dd, J = 10.7, 4.9 Hz, 3H),
7.11 (d, J = 7.7 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.78 (d, J = 7.7 Hz,
1H), 5.94 (d, J = 7.6 Hz, 2H), 5.18 (s, 1H), 5.02 (d, J = 15.4 Hz, 1H),
4.68 (d, J = 15.4 Hz, 1H), 3.82 (s, 1H), 3.63 (d, J = 11.5 Hz, 1H), 3.25
(d, J = 43.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 177.7, 145.3,
141.8, 137.8, 135.2, 129.8, 128.9, 128.1, 127.7, 127.1, 124.0, 123.7,
117.6, 110.2, 81.0, 68.0, 64.9, 44.2. HRMS (ESI) calcd for
C22H19IN2NaO2 [M + Na]+ = 493.0389, found 493.0372.
1-Benzyl-3-((2,4-dichlorophenyl)amino)-3-(hydroxymethyl)-
1
indolin-2-one (4r). A white solid (40 mg, 98% yield). H NMR (400
MHz, CDCl3): δ 7.19 (dd, J = 17.6, 10.1 Hz, 8H), 6.98 (t, J = 7.4 Hz,
1H), 6.83 (d, J = 7.9 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 5.77 (s, 1H),
5.50 (d, J = 8.7 Hz, 1H), 5.04 (d, J = 15.3 Hz, 1H), 4.70 (d, J = 15.3
Hz, 1H), 3.88 (t, J = 10.6 Hz, 1H), 3.66 (d, J = 11.4 Hz, 1H), 3.11 (s,
1H). 13C NMR (100 MHz, CDCl3): δ 177.1, 141.7, 140.5, 135.3,
130.0, 129.1, 128.9, 128.2, 127.9, 127.5, 126.7, 124.0, 123.8, 123.3,
121.4, 113.8, 110.2, 68.0, 64.6, 44.3. HRMS (ESI) calcd for
C22H18Cl2NaN2O2 [M + Na]+ = 435.0643, found 435.0625.
1-Benzyl-3-(hydroxymethyl)-3-((4-nitrophenyl)amino)indolin-2-
1
one (4l). A yellow solid (39 mg, 94% yield). H NMR (400 MHz,
CDCl3): δ 7.80 (d, J = 9.0 Hz, 2H), 7.40−7.28 (m, 6H), 7.26 (s, 1H),
7.07 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.14 (d, J = 9.0 Hz,
2H), 6.03 (s, 1H), 5.11 (d, J = 15.3 Hz, 1H), 4.85 (d, J = 15.3 Hz, 1H),
3.92 (d, J = 11.5 Hz, 1H), 3.78 (d, J = 11.6 Hz, 1H), 3.51 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 176.5, 151.1, 141.6, 139.6, 135.1, 130.3,
129.0, 128.9, 127.9, 125.9, 124.0, 123.8, 113.2, 110.5, 67.9, 64.1, 44.4.
HRMS (ESI) calcd for C22H19N3NaO4 [M + Na]+ = 412.1273, found
412.1264.
1-Benzyl-3-((2,5-dichlorophenyl)amino)-3-(hydroxymethyl)-
1
indolin-2-one (4s). A white solid (39 mg, 94% yield). H NMR (400
MHz, CDCl3): δ 7.32−7.14 (m, 7H), 7.07 (d, J = 8.4 Hz, 1H), 7.00 (t,
J = 7.4 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H),
5.88 (s, 1H), 5.67 (s, 1H), 5.09 (d, J = 15.6 Hz, 1H), 4.73 (d, J = 15.6
Hz, 1H), 3.88 (t, J = 9.7 Hz, 1H), 3.66 (d, J = 11.4 Hz, 1H), 3.11 (d, J
= 8.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 176.9, 142.6, 141.7,
135.1, 130.2, 130.1, 129.2, 127.9, 127.3, 126.2, 123.9, 123.9, 119.1,
119.0, 112.9, 110.4, 68.2, 64.4, 44.4. HRMS (ESI) calcd for
C22H18Cl2NaN2O2 [M + Na]+ = 435.0643, found 435.0642.
1-Benzyl-3-(hydroxymethyl)-3-((3-nitrophenyl)amino)indolin-2-
1
one (4m). A yellow solid (37 mg, 95% yield). H NMR (400 MHz,
CDCl3): δ 7.40 (d, J = 8.0 Hz, 1H), 7.28−7.13 (m, 8H), 6.98 (dt, J =
16.0, 7.6 Hz, 3H), 6.86 (d, J = 7.8 Hz, 1H), 6.43 (d, J = 8.1 Hz, 1H),
5.64 (s, 1H), 4.96 (d, J = 15.5 Hz, 1H), 4.86 (d, J = 15.5 Hz, 1H), 3.87
(t, J = 10.0 Hz, 1H), 3.69 (d, J = 11.5 Hz, 1H), 3.41 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 177.3, 146.5, 141.8, 135.1, 130.2, 129.7, 129.0,
128.1, 127.5, 126.3, 123.9, 120.6, 113.7, 110.5, 108.8, 67.9, 64.7, 44.3.
HRMS (ESI) calcd for C22H20N3O4 [M + H]+ = 390.1454, found
390.1460.
1-Benzyl-3-((4-fluoro-2-nitrophenyl)amino)-3-(hydroxymethyl)-
indolin-2-one (4t). A yellow solid (26 mg, 64% yield). 1H NMR (400
MHz, CDCl3): δ 8.89 (s, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.27 (dd, J =
13.3, 6.2 Hz, 6H), 7.19 (d, J = 7.3 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H),
6.93 (d, J = 7.9 Hz, 1H), 6.61 (dd, J = 11.0, 5.3 Hz, 1H), 5.63 (dd, J =
9.1, 3.9 Hz, 1H), 5.09 (d, J = 15.2 Hz, 1H), 4.77 (d, J = 15.2 Hz, 1H),
3.92 (t, J = 10.2 Hz, 1H), 3.76 (d, J = 11.4 Hz, 1H), 2.91 (d, J = 7.6
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 175.9, 153.3 (d, JC‑F = 239.0
Hz), 141.5, 139.9, 135.3, 133.0 (d, JC‑F = 8.2 Hz), 130.2, 129.0, 128.3,
128.1, 126.3, 123.9 (d, JC‑F = 7.0 Hz), 123.9, 116.2 (d, JC‑F = 7.1 Hz),
112.7 (d, JC‑F = 26.0 Hz), 110.4, 68.2, 64.6, 44.4. HRMS (ESI) calcd
for C22H18FNaN3O4 [M + Na]+ = 430.1179, found 430.1186.
1-Benzyl-3-(hydroxymethyl)-5-methyl-3-((2,4,6-tribromophenyl)-
1-Benzyl-3-((2-chlorophenyl)amino)-3-(hydroxymethyl)indolin-2-
1
one (4n). A light yellow solid (32 mg, 84% yield). H NMR (400
MHz, CDCl3): δ 7.28−7.12 (m, 8H), 6.98 (t, J = 7.4 Hz, 1H), 6.82 (d,
J = 7.8 Hz, 1H), 6.55 (dt, J = 23.2, 7.4 Hz, 2H), 5.81 (s, 1H), 5.62 (d, J
= 7.9 Hz, 1H), 5.06 (d, J = 15.4 Hz, 1H), 4.72 (d, J = 15.3 Hz, 1H),
3.91 (t, J = 10.8 Hz, 1H), 3.66 (d, J = 11.4 Hz, 1H), 3.01 (d, J = 10.5
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 177.4, 146.8, 141.7, 135.2,
134.8, 129.8, 129.0, 127.9, 127.5, 123.7, 120.9, 119.3, 115.0, 113.1,
110.3, 68.1, 64.7, 44.2. HRMS (ESI) calcd for C22H19ClN2O2 [M +
H]+ = 379.1213, found 379.1221.
1-Benzyl-3-((2-chlorophenyl)amino)-3-(hydroxymethyl)-5-
methylindolin-2-one (4o). A light yellow solid (36 mg, 73% yield). 1H
NMR (400 MHz, CDCl3): δ 7.36−7.27 (m, 5H), 7.24 (dd, J = 8.1, 1.9
Hz, 1H), 7.12 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz,
1H), 6.66 (td, J = 7.8, 1.5 Hz, 1H), 6.60 (td, J = 7.6, 1.5 Hz, 1H), 5.87
(s, 1H), 5.71 (dd, J = 8.0, 1.4 Hz, 1H), 5.12 (d, J = 15.3 Hz, 1H), 4.78
(d, J = 15.3 Hz, 1H), 3.97 (d, J = 11.5 Hz, 1H), 3.72 (d, J = 11.5 Hz,
1H), 3.05 (s, 1H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
177.3, 141.8, 139.3, 135.5, 133.5, 130.1, 129.4, 128.9, 127.9, 127.8,
127.5, 127.0, 124.6, 120.8, 119.1, 113.1, 109.9, 68.2, 64.4, 44.2, 21.1.
1
amino)oxindole (4u). A light yellow solid (50 mg, 84% yield). H
NMR (400 MHz, CDCl3): δ 7.48 (s, 2H), 7.40−7.35 (m, 2H), 7.29
(dt, J = 14.1, 6.6 Hz, 3H), 6.98 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 8.0 Hz,
1H), 6.34 (s, 1H), 5.27 (s, 1H), 5.00 (d, J = 15.3 Hz, 1H), 4.79 (d, J =
15.3 Hz, 1H), 3.99 (t, J = 10.6 Hz, 1H), 3.80 (d, J = 11.3 Hz, 1H), 3.26
(s, 1H), 2.11 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 177.9, 141.9,
140.7, 135.4, 134.2, 132.1, 129.9, 128.8, 128.0, 127.9, 125.2, 121.0,
115.8, 109.4, 70.0, 66.4, 44.1, 21.0. HRMS (ESI) calcd for
C23H19Br3N2NaO2 [M + Na]+ = 614.8894, found 614.8865.
General Procedure for the Synthesis of 3-Hydroxy-3-
hydroxymethyloxindoles. To a mixture of Rh2(OAc)4 (0.004
mmol) and formalin 3 (37% aqueous formaldehyde solution, 1.2
mmol of formaldehyde) in EtOAc (2.0 mL) at 60 °C was added diazo
compound 1 (0.20 mmol) in EtOAc (4.0 mL for 5-substituted 3-diazo
3913
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Article
oxindoles and 2.0 mL for other 3-diazo oxindoles) via a syringe pump
for 1 h. After the completion of the addition, the reaction mixture was
stirred for an additional 1 h. Solvents were removed under reduced
pressure to give the crude products, which were purified by flash
chromatography on silica gel (ethyl acetate/petroleum ether = 1:10 to
3:1).
1H), 3.90 (s, 2H), 3.64 (s, 1H). 13C NMR (100 MHz, CDCl3): δ
177.7, 159.6 (d, JC‑F = 241.0 Hz), 138.3, 134.77, 129.7 (d, JC‑F = 9.0
Hz), 129.0, 127.9, 127.1, 116.2 (d, JC‑F = 24.0 Hz), 112.8 (d, JC‑F
=
25.0 Hz), 110.5 (d, JC‑F = 8.0 Hz), 76.2, 66.8, 43.9. HRMS (ESI) calcd
for C16H14FNNaO3 [M + Na]+ = 310.0855, found 310.0865.
5-Fluoro-3-hydroxy-3-(hydroxymethyl)-1-methylindolin-2-one
(5j). A white solid (12 mg, 26% yield). 1H NMR (400 MHz, MeOD):
δ 7.21 (dd, J = 7.9, 2.6 Hz, 1H), 7.08 (td, J = 9.1, 2.6 Hz, 1H), 6.95
(dd, J = 8.5, 4.1 Hz, 1H), 3.80 (q, J = 10.7 Hz, 2H), 3.17 (s, 3H). 13C
NMR (101 MHz, MeOD): δ 179.1, 161.0 (d, JC‑F = 268 Hz), 141.5,
1-Benzyl-3-hydroxy-3-(hydroxymethyl)indolin-2-one (5a). A light
yellow solid (38 mg, 70% yield). 1H NMR (400 MHz, CDCl3): δ 7.32
(d, J = 7.2 Hz, 1H), 7.15 (s, 5H), 7.08 (t, J = 8.0 Hz, 1H), 6.92 (t, J =
7.4 Hz, 1H), 6.57 (d, J = 7.7 Hz, 1H), 4.91 (s, 1H), 4.81 (d, J = 15.8
Hz, 1H), 4.63 (d, J = 15.8 Hz, 1H), 3.79 (s, 2H), 3.73 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 177.9, 142.6, 135.2, 129.9, 128.9, 128.3,
127.7, 127.2, 124.6, 123.4, 109.7, 76.2, 66.9, 43.7. HRMS (ESI) calcd
for C16H15NNaO3 [M + Na]+ = 292.0950, found 292.0953.
3-Hydroxy-3-(hydroxymethyl)-1-methylindolin-2-one (5b). A
white solid (18 mg, 46% yield). 1H NMR (400 MHz, CDCl3): δ
7.39−7.23 (m, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.80 (t, J = 9.6 Hz, 1H),
4.01 (s, 1H), 3.76 (q, J = 11.6 Hz, 2H), 3.13 (s, 3H), 2.98 (d, J = 25.1
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 177.60, 143.61, 130.2,
127.5, 124.3, 123.4, 108.7, 75.4, 66.9, 26.2. HRMS (ESI) calcd for
C10H11NNaO3 [M + Na]+ = 216.0645, found 216.0637.
133.2 (d, JC‑F = 8.0 Hz), 116.6 (d, JC−F = 24.0 Hz), 113.3 (d, JC‑F
=
25.0 Hz), 110.4 (d, JC‑F = 8.0 Hz), 78.0, 66.8, 26.6. HRMS (ESI) calcd
for C10H10FNaNO3 [M + Na]+ = 234.0542, found 234.0541.
1-Benzyl-5-chloro-3-hydroxy-3-(hydroxymethyl)indolin-2-one
(5k). A white solid (33 mg, 55% yield). 1H NMR (400 MHz, MeOD):
δ 8.86 (s, 1H), 8.81−8.69 (m, 4H), 8.65 (dd, J = 15.5, 7.8 Hz, 2H),
8.15 (d, J = 8.3 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 6.32−6.19 (m,
5H), 5.31 (s, 2H). 13C NMR (100 MHz, MeOD): δ 179.1, 143.3,
136.8, 133.3, 130.3, 129.8, 129.4, 128.7, 128.3, 125.82, 111.8, 77.9,
66.9, 44.4. HRMS (ESI) calcd for C16H14ClNNaO3 [M + Na]+
326.0560, found 326.0548.
=
1-Benzyl-4-chloro-3-hydroxy-3-(hydroxymethyl)indolin-2-one
(5l). A white solid (45 mg, 74% yield). 1H NMR (400 MHz, MeOD):
δ 8.78 (d, J = 7.2 Hz, 2H), 8.68 (dt, J = 23.3, 6.9 Hz, 3H), 8.59 (t, J =
8.0 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 6.44
(d, J = 16.0 Hz, 1H), 6.25 (s, 1H), 5.82 (d, J = 10.1 Hz, 1H), 5.41 (d, J
= 10.1 Hz, 1H). 13C NMR (100 MHz, MeOD): δ 179.2, 146.9, 136.8,
132.8, 132.0, 129.7, 128.6, 128.2, 127.2, 125.1, 109.3, 79.0, 64.0, 44.5.
HRMS (ESI) calcd for C16H14ClNNaO3 [M + Na]+ = 326.0560, found
326.0560.
1-Acetyl-3-hydroxy-3-(hydroxymethyl)indolin-2-one (5c). A sticky
oil (24 mg, 54% yield). H NMR (400 MHz, CDCl3): δ 8.12 (d, J =
1
8.2 Hz, 1H), 7.32 (dd, J = 14.5, 7.6 Hz, 2H), 7.17 (dd, J = 13.2, 5.7 Hz,
1H), 3.75 (q, J = 11.7 Hz, 2H), 2.54 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 178.3, 170.6, 140.1, 130.6, 126.9, 125.8, 123.9, 116.8, 75.7,
67.0, 26.5. HRMS (ESI) calcd for C11H11NNaO4 [M + Na]+
244.0586, found 244.0595.
=
Methyl 3-Hydroxy-3-(hydroxymethyl)-2-oxoindoline-1-carboxy-
1
late (5d). A white solid (29 mg, 62% yield). H NMR (400 MHz,
1-Benzyl-6-chloro-3-hydroxy-3-(hydroxymethyl)indolin-2-one
(5m). A white solid (28 mg, 46% yield). 1H NMR (400 MHz,
MeOD): δ 7.43−7.19 (m, 6H), 7.07 (dd, J = 7.9, 1.2 Hz, 1H), 6.76 (s,
1H), 4.99 (d, J = 16.0 Hz, 1H), 4.86 (d, J = 9.4 Hz, 1H), 3.89 (s, 2H).
13C NMR (100 MHz, MeOD): δ 179.5, 146.0, 136.7, 136.2, 130.0,
129.8, 128.7, 128.2, 126.5, 123.8, 111.1, 77.5, 66.8, 44.4. HRMS (ESI)
calcd for C16H14ClNNaO3 [M + Na]+ = 326.0560, found 326.0551.
1-Benzyl-7-chloro-3-hydroxy-3-(hydroxymethyl)indolin-2-one
(5n). A white solid (44 mg, 73% yield). 1H NMR (400 MHz, MeOD):
δ 7.40 (d, J = 7.3 Hz, 1H), 7.26 (t, J = 6.2 Hz, 4H), 7.21 (dd, J = 8.3,
3.7 Hz, 2H), 7.07 (t, J = 7.7 Hz, 1H), 5.32 (q, J = 16.5 Hz, 2H), 3.91
(q, J = 10.4 Hz, 2H). 13C NMR (100 MHz, MeOD): δ 180.2, 140.7,
138.8, 134.7, 133.0, 129.5, 128.0, 127.3, 125.3, 124.2, 116.6, 77.2, 67.1,
45.8. HRMS (ESI) calcd for C16H14ClNNaO3 [M + Na]+ = 326.0560,
found 326.0562.
MeOD): δ 7.90 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 7.4 Hz, 1H), 7.39 (t, J
= 7.9 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 3.97 (s, 3H), 3.89 (d, J = 10.5
Hz, 1H), 3.81 (d, J = 10.5 Hz, 1H). 13C NMR (100 MHz, MeOD): δ
176.6, 151.2, 140.0, 129.5, 129.0, 124.8, 124.0, 114.7, 76.2, 66.0, 52.8.
HRMS (ESI) calcd for C11H11NNaO5 [M + Na]+ = 260.0535, found
260.0548.
Ethyl 3-Hydroxy-3-(hydroxymethyl)-2-oxoindoline-1-carboxylate
(5e). A white solid (16 mg, 31% yield). 1H NMR (400 MHz, CDCl3):
δ 7.84 (d, J = 8.1 Hz, 1H), 7.35 (dd, J = 12.2, 7.6 Hz, 2H), 7.20−7.15
(m, 1H), 4.39 (q, J = 7.0 Hz, 2H), 3.77 (s, 2H), 1.37 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 176.3, 150.5, 139.4, 130.7,
126.4, 125.4, 124.2, 115.5, 75.2, 67.0, 63.8, 29.7. HRMS (ESI) calcd for
C12H13NNaO5 [M + Na]+ = 274.0691, found 274.0691.
tert-Butyl 3-hydroxy-3-(hydroxymethyl)-2-oxoindoline-1-carbox-
1
ylate (5f). A white solid (25 mg, 45% yield). H NMR (400 MHz,
(1-Benzyl-3-((4-fluoro-2-nitrophenyl)amino)-2-oxoindolin-3-
yl)methyl tert-Butyl Carbonate (6t). To a solution of alcohol 4t
(83 mg, 0.2 mmol), DMAP (2 mg, 0.02 mmol), and Et3N (61 mg, 0.60
mmol) in CH2Cl2 (15 mL) was added Boc2O (87 mg, 0.40 mmol) in
CH2Cl2 (5 mL) at room temperature. The reaction mixture was stirred
at room temperature for 12 h. After the completion of the reaction, the
mixture was diluted with sat. NaHCO3 (20 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
Purification on silica gel (hexanes:EtOAc, 20:1 → 8:1) provided 6t
as a yellow solid (93 mg, 90% yield). 1H NMR (400 MHz, CDCl3): δ
8.76 (s, 1H), 7.87 (dd, J = 8.9, 3.0 Hz, 1H), 7.41 (d, J = 7.3 Hz, 2H),
7.38−7.29 (m, 5H), 7.05 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H),
6.73−6.62 (m, 1H), 5.73 (dd, J = 9.4, 4.4 Hz, 1H), 5.10 (d, J = 15.3
Hz, 1H), 4.91 (d, J = 15.3 Hz, 1H), 4.62 (d, J = 11.1 Hz, 1H), 4.33 (d,
J = 11.1 Hz, 1H), 1.45 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 173.6,
153.4 (d, J = 239.0 Hz), 152.8, 141.7, 139.3, 135.2, 133.1 (d, J = 8.0
Hz), 130.3, 129.0, 128.2, 128.1, 125.9, 124.6, 124.0 (d, J = 23.0 Hz),
123.6, 116.3 (d, J = 7.1 Hz), 112.6 (d, J = 26.0 Hz), 110.2, 83.4, 69.4,
63.8, 44.6, 27.6; HRMS (ESI) calcd for C27H26FN3NaO6 [M + Na]+ =
530.1703, found 530.1707.
CDCl3): δ 7.75 (d, J = 8.0 Hz, 1H), 7.42−7.24 (m, 2H), 7.13 (t, J =
7.4 Hz, 1H), 3.75 (s, 2H), 1.58−1.45 (m, 9H). 13C NMR (100 MHz,
CDCl3): δ 176.50, 148.80, 139.64, 130.39, 125.09, 124.28, 115.32,
85.05, 75.33, 66.98, 28.04. HRMS (ESI) calcd for C14H17NNaO5 [M +
Na]+ = 302.1004, found 302.1013.
1-Benzyl-3-hydroxy-3-(hydroxymethyl)-5-methylindolin-2-one
(5g). A white solid (41 mg, 73% yield). 1H NMR (400 MHz, CDCl3):
δ 7.34−7.16 (m, 6H), 7.00 (d, J = 7.9 Hz, 1H), 6.58 (d, J = 7.9 Hz,
1H), 4.91 (d, J = 15.7 Hz, 1H), 4.76 (d, J = 15.7 Hz, 1H), 4.48 (s, 1H),
3.88 (q, J = 11.8 Hz, 2H), 3.36 (s, 1H), 2.28 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 177.8, 140.2, 135.3, 133.1, 130.3, 128.9, 127.8, 127.7,
127.1, 125.2, 109.5, 75.8, 67.0, 43.7, 21.0. HRMS (ESI) calcd for
C17H17NNaO3 [M + Na]+ = 306.1111, found 306.1106.
1-Benzyl-5-bromo-3-hydroxy-3-(hydroxymethyl)indolin-2-one
(5h). A white solid (38 mg, 54% yield). 1H NMR (400 MHz, CDCl3):
δ 7.47 (s, 1H), 7.21 (ddd, J = 21.5, 15.1, 7.8 Hz, 6H), 6.49 (d, J = 8.3
Hz, 1H), 4.85 (d, J = 15.8 Hz, 1H), 4.69 (d, J = 15.8 Hz, 1H), 4.42 (s,
1H), 3.81 (s, 2H), 3.22 (s, 1H).13C NMR (100 MHz, CDCl3): δ
177.3, 141.6, 134.7, 132.8, 129.9, 129.0, 128.0, 127.9, 127.1, 116.2,
111.2, 75.8, 66.8, 43.9. HRMS (ESI) calcd for C16H14BrNNaO3 [M +
Na]+ = 370.0055, found 370.0061.
1-Benzyl-5-fluoro-3-hydroxy-3-(hydroxymethyl)indolin-2-one
(5i). A white solid (17 mg, 30% yield). 1H NMR (400 MHz, CDCl3):
δ 7.34−7.21 (m, 5H), 7.21−7.15 (m, 1H), 6.90 (t, J = 8.4 Hz, 1H),
6.68−6.55 (m, 1H), 4.92 (d, J = 16.3 Hz, 2H), 4.76 (d, J = 15.8 Hz,
(3-((2-Amino-4-fluorophenyl)amino)-1-benzyl-2-oxoindolin-
3-yl)methyl tert-Butyl Carbonate (7t). To a solution of compound
6t (80 mg, 0.16 mmol) in MeOH (10 mL) was added 5% Pd/C, and
the mixture was stirred at room temperature under a hydrogen balloon
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Article
for 4 h. Then the catalyst was filtered off through a Celite bed and
washed with MeOH (20 mL). The filtrate was concentrated in vacuo
to give crude product, which was purified on silica gel
(hexanes:EtOAc, 10:1 → 2:1) to provide 7t as a white solid (72
Chem. 2003, 2209−2219. (f) Trost, B. M.; Brennan, M. K. Synthesis
2009, 18, 3003−3025.
(2) For selected examples, see: (a) Antonchick, A. P.; Gerding-
Reimers, C.; Catarinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.;
̈
1
mg, 95% yield). H NMR (400 MHz, CDCl3): δ 7.49 (d, J = 7.3 Hz,
Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2, 735−740. (b) Nicolaou,
K. C.; Chen, D. Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder, S. A. J.
Am. Chem. Soc. 2004, 126, 12888−12896. (c) Netz, A.; Oost, T.;
Geneste, H.; Braje, W. M.; Wernet, W.; Unger, L.; Hornberger, W.;
Lubisch, W. PCT Int. Appl. WO2008080971. (d) Lin, X.-C.; Weinreb,
S. M. Tetrahedron Lett. 2001, 42, 2631−2633. (e) Silverio, D. L.;
Torker, S.; Pilyugina, T.; Vieira, E. M.; Snapper, M. L.; Haeffner, F.;
Hoveyda, A. H. Nature 2013, 494, 216−221. (f) Bergonzini, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 971−974.
1H), 7.24−7.19 (m, 3H), 7.17 (d, J = 7.7 Hz, 1H), 7.05 (t, J = 7.5 Hz,
1H), 6.97 (dd, J = 5.3, 3.6 Hz, 2H), 6.62 (d, J = 7.8 Hz, 1H), 6.34 (dd,
J = 10.1, 2.8 Hz, 1H), 6.25 (dd, J = 8.7, 5.9 Hz, 1H), 6.01 (td, J = 8.5,
2.8 Hz, 1H), 5.02 (d, J = 15.9 Hz, 1H), 4.72 (d, J = 15.8 Hz, 1H), 4.63
(d, J = 10.9 Hz, 1H), 4.31 (d, J = 10.9 Hz, 1H), 4.15 (s, 2H), 3.89 (s,
1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 176.9, 160.2 (d, J
= 239.0 Hz), 153.1, 143.6 (d, J = 10.8 Hz), 142.8, 134.9, 129.7, 128.7,
127.6, 126.9, 126.9, 126.7, 125.5 (d, J = 9.7 Hz), 125.1, 123.0, 109.7,
104.8 (d, J = 22.0 Hz), 103.3 (d, J = 25.0 Hz), 82.8, 69.4, 66.5, 43.9,
27.7; HRMS (ESI) calcd for C27H28FN3NaO4 [M + Na]+ = 500.1962,
found 500.1938
(1-Benzyl-3-(5-fluoro-1H-benzo[d]imidazol-1-yl)-2-oxo-
indolin-3-yl)methyl tert-Butyl Carbonate (8t). To a 25 mL round-
bottom flask equipped with a magnetic stir bar was added 7t (72 mg,
0.15 mmol), 10.0 mL of triethyl orthoformate, and p-toluenesulfonic
acid monohydrate (3 mg, 0.015 mmol), and the resulting solution was
stirred for 8 h. The solution was then diluted with ethyl acetate (15
mL) and washed with NaHCO3 (15 mL). The aqueous layer was back-
extracted with ethyl acetate (3 × 15 mL), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated in vacuo to
give a brown solid (70 mg, 96% yield). 1H NMR (400 MHz, CDCl3):
δ 8.30 (s, 1H), 7.45 (dt, J = 9.1, 4.7 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H),
7.33 (dt, J = 9.4, 5.0 Hz, 5H), 7.28 (d, J = 7.5 Hz, 1H), 7.06 (dd, J =
17.0, 9.5 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.71 (td, J = 9.1, 2.4 Hz,
1H), 6.45 (dd, J = 9.0, 4.5 Hz, 1H), 5.16 (d, J = 11.8 Hz, 1H), 5.06−
4.94 (m, 2H), 4.82 (d, J = 11.8 Hz, 1H), 1.40 (s, 9H). 13C NMR (100
MHz, CDCl3): δ 171.2, 159.4 (d, J = 238.0 Hz), 152.4, 144.8 (d, J =
13.0 Hz), 143.0, 142.5, 134.6, 131.2, 129.0, 128.2, 127.7, 125.8, 124.4,
123.8, 111.9 (d, J = 9.0 Hz), 119.6 (d, J = 26.0 Hz), 110.5, 106.3 (d, J
= 24.0 Hz), 83.6, 66.3, 65.5, 44.6, 27.6. HRMS (ESI) calcd for
C28H26FN3NaO4 [M + Na]+ = 510.1805, found 510.1812.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for compounds 4a−4u, 5a−5n, 6t, 7t,
and 8t; and X-ray crystal data for compound 4a. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: dxing@sat.ecnu.edu.cn (D.X.).
*E-mail: whu@chem.ecnu.edu.cn. Fax: (+86) 21-62233176
(W.H.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Martínez del Campo, T.; Quiros
́
, M. Chem.Eur. J. 2009, 15, 3344−
We acknowledge the financial support from the NSF of China
(21125209 and 21332003), the MOST of China
(2011CB808600), STCSM (12JC1403800), the specialized
Research Fund for the Doctoral Program of Higher Education
(20130076120031), and the Shanghai Postdoctoral Scientific
Program (13R21412800).
3346. (l) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41,
512−515. (m) Ueda, T.; Inada, M.; Okamoto, I.; Morita, N.; Tamura,
O. Org. Lett. 2008, 10, 2043−2046. (n) Sano, D.; Nagata, K.; Itoh, T.
Org. Lett. 2008, 10, 1593−1595. (o) Bui, T.; Candeias, N. R.; Barbas,
C. F., III J. Am. Chem. Soc. 2010, 132, 5574−5575. (p) Zhang, Z.;
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(q) Yadav, J. S.; Subba Reddy, B. V.; Suresh Reddy, Ch.; Krishna, A. D.
Tetrahedron Lett. 2007, 48, 2029−2032.
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