Regiospecific epoxide opening: A facile approach for the synthesis of 3-hydroxy-3-aminomethylindolin-2-one derivatives

Article abstract of DOI:10.1039/c1gc15416h

A mild and eco-friendly method has been developed for aminolysis of 3-oxirane-indolin-2-ones with aliphatic and aromatic amines to afford 3-hydroxy-3-aminomethylindolin-2-ones. An enhancement in reaction rate was observed when water was used as the reaction medium. The reactions proceed regiospecifically to open the epoxide ring from the less-substituted end.

Full text of DOI:10.1039/c1gc15416h

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PAPER
Regiospecific epoxide opening: a facile approach for the synthesis of
3-hydroxy-3-aminomethylindolin-2-one derivatives
Mangilal Chouhan,a Kishna Ram Senwar,a Ratnesh Sharma,a Vikas Groverb and Vipin A. Nair*a
Received 15th April 2011, Accepted 6th June 2011
DOI: 10.1039/c1gc15416h
A mild and eco-friendly method has been developed for aminolysis of 3-oxirane-indolin-2-ones
with aliphatic and aromatic amines to afford 3-hydroxy-3-aminomethylindolin-2-ones. An
enhancement in reaction rate was observed when water was used as the reaction medium. The
reactions proceed regiospecifically to open the epoxide ring from the less-substituted end.
fully tried, although these methodologies suffer from one or
Introduction
more reaction constraints, such as longer reaction times, high
Controls on the safe use and disposal of hazardous chemicals
temperatures, high pressure, moderate yields, poor regioselectiv-
has forced the scientific community to adopt environmentally
ity, the use of air- and moisture-sensitive catalysts, stoichiometric
benign reactions and conditions. The largest contributor to the
magnitude of the E factor1 for a reaction is an organic solvent,
many of which are ecologically harmful and require additional
amounts of catalyst, costly reagents/catalysts and the fact that
they mostly use organic halogenated solvents. Recent reports
have indicated the use of water as a solvent for epoxide opening,
expense for their proper disposal. Modern approaches to reduce
providing much cleaner reaction conditions.
the environmental hazards of organic solvents are either to run
reactions in solvent free conditions or to use solvents which have
One-carbon higher homologues, g-amino alcohols are found
in various natural products like arundaphine, donaxaridine and
lesser or no detrimental effects on ecosystems.2 Thus, organic
paratunamide D, denoted as 3-substituted-3-hydroxyindolin-2-
reactions in water3 have drawn the attention of researchers due to
one alkaloids (Fig. 1).21 3-Substituted-3-hydroxyindolin-2-ones
its unique characteristics like non-flammability, high dielectric
are known to possess antibacterial, antiprotozoal and anti-
constant, high boiling point, hydrogen bond donor/acceptor
inflammatory activities, and have also demonstrated agonistic
properties and above all economic benefits. Greener reactions
activity with progesterone receptors, their activity being influ-
are therefore of prime importance in organic chemistry.
enced by the substituent at the C-3 position as well as the
absolute configuration at the stereogenic centre.22
b-Amino alcohols are important precursors in several syn-
thetic drugs and natural products,4 and are also employed for
preparation of amino acids5 and chiral auxiliaries.6 One of the
most straightforward methods to synthesize these templates
would be the direct aminolysis of epoxides (oxiranes). However,
the strategy is limited by sluggish reactions with weakly nucle-
ophilic amines, poor regioselectivity and difficulties in handling
sensitive epoxides. The electrophilic activation of epoxides is
often carried out as a viable strategy to facilitate nucleophilic
attack. Thus, the use of alumina,7 alkali metal perchlorates
and tetrafluoroborate,8 silica gel in solvent free conditions,9
metal triflates,10 metal alkoxides,11 metal halides,12 zirconium
sulfophenyl phosphonate,13 microwave irradiation,14 ultrasonifi-
cation in water,15 refluxing with hexafluoro-2-propanol,16 ionic
liquids,17 iron(III) trifluoroacetate,18 Yb(OTf)3/supercritical car-
bon dioxide,19 metal amides and triflamide20 have been success-
aDepartment of Medicinal Chemistry,
bCentral Instrumentation Laboratory, National Institute of
Pharmaceutical Education and Research, Sector 67, Mohali, Punjab,
160062, India. E-mail: vn74nr@yahoo.com; Tel: +91 172-2292045
Fig. 1 Natural products containing the indolin-2-one scaffold.
Green Chem., 2011, 13, 2553–2560 | 2553
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Table 1 Effect of solventsa
In continuation of our work on bioactive heterocycles,23
the current investigations are mainly focused on 3-substituted-
3-hydroxyindolin-2-one derivatives.23e The previously available
report for the preparation of 3-hydroxy-3-aminomethylindolin-
2-one employed hazardous conditions involving nitromethane
and tin or palladium, and also needed a high temperature and
a long reaction time (Scheme 1).24 This prompted us to employ
water as the reaction medium for the aminolysis of 3-oxirane-
indolin-2-ones to obtain 3-hydroxy-3-aminomethylindolin-2-
ones under very mild conditions. The reactions proceeded with
high yields and regiospecificities, opening the oxirane ring from
the less-substituted end.
Entry
Solvent
Conversionb (%)
1
2
3
4
5
6
7
8
Toluene
CH3CN
EtOAc
THF
DCM
EtOH
EtOH : H2O (7 : 3)
H2O
10
25
35
30
20
60
76
85
a Oxirane (1.0 mmol), amine (1.0 mmol), distilled water (5 mL), time 2
h, temp. 30 ◦C; b Determined by 1H NMR.
Scheme 1 Reported method for the preparation of 3-hydroxy-3-
aminomethylindolin-2-one.
Table 2 Reactions with various aliphatic aminesa
Results and discussion
The oxirane derivatives of isatin were prepared as illustrated
in Scheme 2. Isatins were synthesised from aniline by the
Sandmeyer25a reaction using chloral hydrate under acidic condi-
tions in a polar medium. Furthermore, it was N-methylated25b
using NaH and methyl iodide in dry THF. Formation of
the oxirane ring at the 3-position using trimethylsulfoxonium
iodide and cesium carbonate at 50 ◦C in acetonitrile afforded
the spiro[indolin3,2¢-oxiran]-2-ones, which were subjected to
aminolysis.
Entry R1
R2
Product Yieldb (%)
1
2
3
4
5
6
CH3
H
H
H
H
H
CH3
CH3
6(a)(i)
95
95
97
97
94
98
i-C3H7
t-C4H9
C6H5CH2
cy-C6H11
CH3
6(a)(ii)
6(a)(iii)
6(a)(iv)
6(a)(v)
6(a)(vi)
7
8
C6H5
C6H5CH2
6(a)(vii) 97
C6H5CH2 6(a)(viii) 98
9
10
11
(–CH2–)4
(–CH2–)5
6(a)(ix)
6(a)(x)
6(a)(xi)
98
99
99
(–CH2CH2OCH2CH2–)
a Oxirane (1.0 mmol), amine (1.0 mmol), distilled water (5 mL), time
30 min, temp. 30 ◦C. b Isolated yield.
The optimized conditions were further extended to different
aliphatic and aromatic amines to generalise the scope of the re-
action. The oxirane ring was opened from the less-hindered side,
affording the products regiospecifically. In the case of aliphatic
amines (Table 2), an acceleration in the course of the reaction
was observed◦. The reaction was complete in 30 min at room tem-
perature (30 C). For aromatic amines, the reactions tolerated
both electron withdrawing and electron donating groups alike,
affording high yields of the desired products (Table 3).
Due to its hydrogen bond donor and acceptor properties,
water is expected to activate both the reactants as they come
into close proximity and to assist in overcoming the transition
state barrier for bonding to occur.3j It can be speculated that
water enhances the electrophilicity of the oxirane ring through
hydrogen bonding, facilitating the nucleophilic attack of the
amine. The hydrogen bonding between the amine hydrogen
and oxygen of the amide carbonyl may provide additional
stabilization to the transition state, allowing the epoxide to be
Scheme 2 Synthesis of 1-methylspiro(indolin3,2¢-oxiran)-2-one.
To standardise the reaction conditions, a model reaction of
3-oxirane-indolin-2-one and aniline in different solvents was
performed at room temperature (30 ◦C), and the results are
summarized in Table 1. Non-polar solvents like toluene afforded
poor yields, while an improvement was observed with polar
solvents. Moderate yields were obtained with polar aprotic
solvents, while the polar protic solvent EtOH indicated an
enhancement in the reaction rate. The best result was obtained
in an aqueous medium. Furthermore, the thermal dependency
of the reaction in water was analyzed by carrying it out at five
different temperatures from 0 to 50 ◦C at intervals of 10 ◦C.
At low temperatures (0 and 10 ◦C), the reactions were sluggish,
affording poor conversion to the desired product. The course of
◦
the reaction demonstrated a drastic change at 50 C, attaining
completion in 2 h.
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Table 3 Reactions with various aromatic aminesa
relative to residual signals of the solvent. Coupling constants
are given in Hz. The following abbreviations are used to indicate
multiplicity: s, singlet; d, doublet; t, triplet; td, triple doublet; dt,
double triplet; q, quartet; m, multiplet; brs, broad signal. HRMS
were recorded on a Bruker Maxix TOF mass spectrometer.
Melting points are uncorrected.
Typical procedure for oxirane formation
Entry
R
R1
R2
Product
Yieldb (%)
A mixture of trimethylsulfoxonium iodide (1.0 mmol) and
cesium carbonate (2.0 mmol) in dry CH3CN was stirred at
50 ◦C for 1 h under a nitrogen atmosphere to generate the sulfur
ylide. To this, a solution of N-methylisatin (1.0 mmol) in dry
CH3CN (5 mL) was added dropwise over 10 min. The progress
of the reaction was monitored by TLC. After completion, the
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
F
F
F
F
F
H
4-CH3
4-F
4-Cl
4-Br
2-Cl
2-OH
3-NO2
H
H
H
H
H
8(a)(i)
95
97
98
98
97
95
98
96
96
95
98
97
96
97
96
98
98
96
97
99
98
96
98
97
96
95
98
97
98
98
96
96
8(a)(ii)
8(a)(iii)
8(a)(iv)
8(a)(v)
8(a)(vi)
8(a)(vii)
8(a)(viii)
8(b)(i)
H
4-F
5-NO2
H
H
H
H
H
H
4-F
5-NO2
H
H
H
H
H
H
4-F
5-NO2
H
H
H
H
H
H
R
reaction mixture was filtered through a Celiteꢀ bed and the
9
filtrate evaporated to dryness. The crude product thus obtained
was purified by column chromatography on silica gel (60–120
mesh) using EtOAc : hexane (20 : 80) mixture as the eluent to
afford the pure product.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
4-CH3
4-F
8(b)(ii)
8(b)(iii)
8(b)(iv)
8(b)(v)
8(b)(vi)
8(b)(vii)
8(b)(viii)
8(c)(i)
8(c)(ii)
8(c)(iii)
8(c)(iv)
8(c)(v)
8(c)(vi)
8(c)(vii)
8(c)(viii)
8(d)(i)
8(d)(ii)
8(d)(iii)
8(d)(iv)
8(d)(v)
8(d)(vi)
8(d)(vii)
8(d)(viii)
4-Cl
4-Br
2-Cl
2-OH
3-NO2
H
F
F
F
1-Methylspiro[indo◦line-3,2¢-oxiran]-2-one (4a). Pale yellow
1
solid; m.p. = 84–86 C; H NMR (CDCl3, 400 MHz) d 3.28
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
(s, 3H), 3.44 (d, 1H, J = 6.6 Hz), 3.59 (d, 1H, J = 6.7 Hz), 6.93
4-CH3
4-F
(d, 1H, J = 7.8 Hz), 7.07–7.13 (m, 2H), 7.37–7.41 (m, 1H); 13
C
4-Cl
4-Br
2-Cl
2-OH
3-NO2
H
4-CH3
4-F
4-Cl
4-Br
2-Cl
2-OH
3-NO2
NMR (CDCl3, 100 MHz) d 26.7, 54.1, 56.4, 108.9, 122.1, 122.7,
122.9, 130.4, 145.1, 172.8; ESI-HRMS(m/z): [M + Na]+ calc.
for C10H9NO2Na, 198.0531, found 198.0525.
5-Fluoro-1-methylspiro[indoline-3,2¢-oxiran]-2-one
(4b).
White solid; m.p. = 159–161 ◦C; 1H NMR (CDCl3, 400 MHz) d
3.27 (s, 3H), 3.42 (d, 1H, J = 6.6 Hz), 3.60 (d, 1H, J = 6.7 Hz),
6.83–6.88 (m, 2H), 7.09 (dt, 1H, J = 2.6, 9.0 Hz); 13C NMR
(CDCl3, 100 MHz) d 26.8, 54.3, 56.4, 109.5, 109.6, 110.2, 110.5,
116.6, 116.8, 124.4, 124.5, 141.0, 171.5; ESI-HRMS(m/z): [M
+ Na]+ calc. for C10H8FNO2Na, 216.0437, found 216.0431.
4-F
5-NO2
H
a Oxirane (1.0 mmol), amine (1.0 mmol), distilled water (5 mL), time 2
h, temp. 50 ◦C. b Isolated yield.
5-Chloro-1-methylspiro[indoline-3,2¢-oxiran]-2-one
(4c).
Pale yellow solid, m.p. = 163–165 ◦C; 1H NMR (CDCl3,
400 MHz) d 3.28 (s, 3H), 3.43 (d, 1H, J = 6.6 Hz), 3.59 (d, 1H,
J = 6.7 Hz), 6.85 (d, 1H, J = 8.3 Hz), 7.09 (d, 1H, J = 2.1 Hz),
7.36 (dd, 1H, J = 2.2, 8.4 Hz); 13C NMR (CDCl3, 100 MHz)
d 26.8, 54.2, 56.1, 109.8, 122.6, 124.5, 128.5, 130.3, 143.6,
171.3; ESI-HRMS(m/z): [M + Na]+ calc. for C10H8ClNO2Na,
232.0141, found 232.0136.
opened specifically from the less-hindered side. Based on these
assumptions, a plausible mechanism is proposed in Fig. 2.
5-Bromo-1-methylspiro[indoline-3,2¢-oxiran]-2-one
(4d).
Pale brown solid, m.p. = 167–169 ◦C; 1H NMR (CDCl3,
400 MHz) d 3.27 (s, 3H), 3.43 (d, 1H, J = 6.7 Hz), 3.59 (d, 1H,
J = 6.6 Hz), 6.80 (d, 1H, J = 8.3 Hz), 7.23 (d, 1H, J = 1.9 Hz),
7.51 (dd, 1H, J = 2.0, 8.3 Hz); 13C NMR (CDCl3, 100 MHz)
d 26.8, 54.3, 56.1, 108.5, 115.6, 124.8, 125.4, 133.2, 144.0,
171.2; ESI-HRMS(m/z): [M + Na]+ calc. for C10H8BrNO2Na,
275.9636, found 275.9631.
Fig. 2 A plausible mechanism for the reaction.
Experimental section
All reagents required for this study were purchased from
commercial sources and used as such without further purifi-
General procedure for epoxide aminolysis in water
cation. Solvents were distilled and dried before use. 1H and 13
C
A mixture of oxirane (1.0 mmol), amine (1.0 mmol) and distilled
water (5 mL) was stirred at 50 ◦C until complete conversion
of the epoxide was observed by TLC. The reaction mixture
was extracted into Et2O (10 mL), dried over anhydrous sodium
sulfate and concentrated to obtain the crude product. The crude
NMR spectra were recorded at 400 and 100 MHz, respectively,
on a Bruker Avance DPX 400 (400 MHz) spectrometer in
CDCl3/CD3OD using TMS as an internal standard. The
1
chemical shifts (d) for H and 13C spectra are given in ppm
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products were either washed with cold hexane or eluted through
a column of neutral alumina using EtOAc : hexane mixture as
the eluent to afford the pure products.
(CDCl3, 400 MHz) d 2.91 (s, 3H), 3.16 (s, 3H), 3.27 (brs, 1H),
3.64 (d, 1H, J = 15.2 Hz), 3.82 (d, 1H, J = 15.2 Hz), 6.72–6.84
(m, 4H), 7.06 (t, 1H, J = 7.5 Hz), 7.19 (t, 2H, J = 8.2 Hz), 7.33
(t, 1H, J = 7.6 Hz), 7.44 (d, 1H, J = 7.2 Hz); 13C NMR (CDCl3,
100 MHz) d 26.3, 40.4, 61.0, 76.4, 108.4, 113.3, 117.8, 123.1,
124.8, 128.9, 130.0, 137.0, 143.6, 150.5, 177.8; ESI-HRMS(m/z):
[M + Na]+ calc. for C17H18N2O2Na, 305.1266, found 305.1260.
3-Hydroxy-1-methyl-3-((methylamino)methyl)indolin-2-one
[6(a)(i)]. Colourless semisolid; 1H NMR (CDCl3, 400 MHz) d
2.49 (s, 3H), 2.91 (s, 2H), 3.17 (s, 3H), 3.70 (brs, 2H), 6.82 (d,
1H, J = 7.7 Hz), 7.09 (t, 1H, J = 7.6 Hz), 7.30–7.38 (m, 2H); 13
C
3 - ((Dibenzylamino)methyl) - 3 - hydroxy - 1 - methylindolin - 2-
one [6(a)(viii)]. Colourless liquid; 1H NMR (CDCl3, 400 MHz)
d 3.05 (d, 2H, J = 2.0 Hz), 3.08 (s, 3H), 3.52 (d, 2H, J = 13.6 Hz),
3.75 (brs, 1H), 3.82 (d, 2H, J = 13.6 Hz), 6.74 (d, 1H, J = 7.8 Hz),
6.83 (d, 1H, J = 7.3 Hz), 6.92 (t, 1H, J = 7.4 Hz), 7.17–7.19 (m,
4H), 7.21–7.31 (m, 7H); 13C NMR (CDCl3, 100 MHz) d 26.2,
52.9, 59.2, 59.5, 74.8, 108.1, 123.1, 124.1, 127.0, 127.2, 128.3,
128.4, 128.5, 129.2, 129.5, 130.5, 138.6, 140.2, 143.9, 178.8; ESI-
HRMS(m/z): [M + Na]+ calc. for C24H24N2O2Na, 395.1735,
found 395.1730.
NMR (CDCl3, 100 MHz) d 26.1, 36.5, 57.4, 73.9, 108.4, 123.1,
123.9, 129.2, 129.8, 143.7, 178.1; ESI-HRMS(m/z): [M + Na]+
calc. for C11H14N2O2Na, 229.0953, found 229.0947.
3 - Hydroxy - 3 - ((isopropylamino)methyl) - 1 - methy-
1
lindolin-2-one [6(a)(ii)]. Colourless liquid; H NMR (CDCl3,
400 MHz) d 1.12 (dd, 6H, J = 6.3, 8.3 Hz), 2.84–2.94 (m, 3H),
3.16 (s, 3H), 3.85 (brs, 2H), 6.82 (d, 1H, J = 7.8 Hz), 7.09 (dt,
1H, J = 0.9, 7.6 Hz), 7.31–7.34 (m, 2H); 13C NMR (CDCl3,
100 MHz) d 22.7, 23.0, 26.1, 49.3, 52.6, 73.2, 108.4, 123.1, 123.8,
129.4, 129.9, 143.7, 178.4; ESI-HRMS(m/z): [M + Na]+ calc. for
C13H18N2O2Na, 257.1266, found 257.1260.
3-Hydroxy-1-methyl-3-(pyrrolidin-1-ylmethyl)indolin-2-one
[6(a)(ix)]. Pale brown solid, m.p. = 134–135 ◦C; 1H NMR
(CDCl3, 400 MHz) d 1.74–1.79 (m, 4H), 2.65–2.71 (m, 2H),
2.84–2.90 (m, 3H), 2.99 (d, 1H, J = 13.4 Hz), 3.17 (s, 3H),
3.85 (brs, 1H), 6.80 (d, 1H, J = 7.8 Hz), 7.07 (dt, 1H, J = 0.9,
7.6 Hz), 7.29–7.36 (m, 2H); 13C NMR (CDCl3, 100 MHz) d 24.3,
26.2, 56.2, 62.2, 74.2, 108.1, 122.9, 124.0, 129.6, 130.5, 143.8,
178.5; ESI-HRMS(m/z): [M + Na]+ calc. for C14H18N2O2Na,
269.1266, found 269.1260.
3-((tert-Butylamino)methyl)-3-hydroxy-1-methylindolin-2-one
[6(a)(iii)]. Pale yellow solid, m.p. = 94–95 ◦C; 1H NMR
(CDCl3, 400 MHz) d 1.29 (s, 9H), 2.81 (d, 1H, J = 12.4 Hz),
3.20 (s, 3H), 3.51 (t, 1H, J = 12.2 Hz), 6.86 (d, 1H, J =
7.8 Hz), 7.14 (t, 1H, J = 7.5 Hz), 7.36 (t, 1H, J = 7.7 Hz),
7.52 (d, 1H, J = 7.3 Hz); 13C NMR (CDCl3, 100 MHz) d 26.1,
27.0, 46.7, 53.9, 71.7, 108.7, 123.7, 124.2, 129.4, 130.1, 143.0,
177.5; ESI-HRMS(m/z): [M + Na]+ calc. for C14H20N2O2Na,
271.1422, found 271.1417.
3-Hydroxy-1-methyl-3-(piperidin-1-ylmethyl)indolin-2-one
[6(a)(x)]. Pale yellow solid, m.p. = 112–114 ◦C; 1H NMR
(CDCl3, 400 MHz) d 1.42–1.45 (m, 2H), 1.57–1.63 (m, 4H),
2.54–2.59 (m, 3H), 2.76–2.81 (m, 3H), 3.16 (s, 3H), 5.33 (brs,
1H), 6.79 (d, 1H, J = 7.5 Hz), 7.07 (dt, 1H, J = 0.9, 7.7 Hz),
7.26–7.32 (m, 2H); 13C NMR (CDCl3, 100 MHz) d 23.8, 26.1,
26.4, 56.4, 64.3, 73.6, 108.1, 122.9, 123.9, 129.5, 130.8, 143.8,
174.4; ESI-HRMS(m/z): [M + Na]+ calc. for C15H20N2O2Na,
283.1422, found 283.1417.
3-((Benzylamino)methyl)-3-hydroxy-1-methylindolin-2-one
1
[6(a)(iv)]. Colourless liquid; H NMR (CDCl3, 400 MHz) d
2.91 (q, 2H, J = 12.2, 24.8 Hz), 3.17 (s, 3H), 3.89 (dd, 2H,
J = 13.0, 18.0 Hz), 6.82 (d, 1H, J = 7.6 Hz), 7.09 (t, 1H, J =
7.5 Hz), 7.27–7.38 (m, 7H); 13C NMR (CDCl3, 100 MHz) d
26.1, 53.7, 54.5, 73.8, 108.4, 123.1, 123.9, 127.2, 128.1, 128.5,
129.0, 129.9, 139.6, 143.8, 178.2; ESI-HRMS(m/z): [M + Na]+
calc. for C17H18N2O2Na, 305.1266, found 305.1260.
3 - Hydroxy - 1 - methyl - 3 - (morpholino◦methyl ) indolin - 2 - one
[6(a)(xi)]. White solid, m.p. = 163–164 C; 1H NMR (CDCl3,
400 MHz) d 2.52–2.57 (m, 2H), 2.73–2.84 (m, 4H), 3.17 (s, 3H),
3.65 (t, 4H, J = 4.3 Hz), 4.60 (brs, 1H), 6.81 (d, 1H, J = 7.7 Hz),
7.08 (t, 1H, J = 7.4 Hz), 7.30–7.35 (m, 2H); 13C NMR (CDCl3,
100 MHz) d 26.2, 55.1, 64.2, 67.3, 74.3, 108.3, 123.0, 124.0,
129.8, 129.9, 143.9, 178.3; ESI-HRMS(m/z): [M + Na]+ calc.
for C14H18N2O3Na, 285.1215, found 285.1210.
3-((Cyclohexylamino)methyl)-3-hydroxy-1-methylindolin-2-
one [6(a)(v)]. Colourless semisolid; 1H NMR (CDCl3,
400 MHz) d 1.06–1.27 (m, 6H), 1.57–1.61 (m, 1H), 1.69–1.76
(m, 2H), 1.85–1.88 (m, 1H), 1.92–1.95 (m, 1H), 2.42–2.47 (m,
1H), 2.81 (d, 1H, J = 12.1 Hz), 2.98 (d, 1H, J = 12.2 Hz), 3.15
(s, 3H), 6.80 (d, 1H, J = 7.8 Hz), 7.06–7.09 (m, 1H), 7.29–7.34
(m, 2H); 13C NMR (CDCl3, 100 MHz) d 24.9, 25.0, 26.0, 33.7,
33.9, 73.4, 108.3, 123.0, 123.8, 129.5, 129.7, 143.8, 178.5; ESI-
HRMS(m/z): [M + Na]+ calc. for C16H22N2O2Na, 297.1579,
found 297.1573.
3-Hydroxy-1-methyl-3-((phenylamino)methyl)indolin-2-one
[8(a)(i)]. Pale yellow solid, m.p. = 125–126 ◦C; 1H NMR
(CDCl3, 400 MHz) d 3.18 (s, 3H), 3.34 (dd, 1H, J = 1.7, 12.8 Hz),
3.70 (dd, 1H, J = 10.0, 12.8 Hz), 3.77 (brs, 1H), 4.45 (d, 1H, J =
8.3 Hz), 6.70 (dd, 2H, J = 0.8, 8.4 Hz), 6.76 (t, 1H, J = 7.4 Hz),
6.86 (d, 1H, J = 7.8 Hz), 7.11–7.19 (m, 3H), 7.37 (dt, 1H, J =
1.2, 7.8 Hz), 7.47 (dd, 1H, J = 0.8, 7.4 Hz); 13C NMR (CDCl3,
100 MHz) d 26.2, 50.9, 74.5, 108.7, 114.0, 118.7, 123.4, 124.2,
128.4, 129.3, 130.3, 143.6, 147.7, 177.5; ESI-HRMS(m/z): [M +
Na]+ calc. for C16H16N2O2Na, 291.1109, found 291.1104.
3-((Dimethylamino)methyl)-3-hydroxy-1-methylindolin-2-one
[6(a)(vi)]. Off white solid, m.p. = 134–136 ◦C; 1H NMR
(CDCl3, 400 MHz) d 2.43 (s, 6H), 2.76 (s, 2H), 3.18 (s, 3H),
4.55 (brs, 1H), 6.81 (d, 1H, J = 7.8 Hz), 7.08 (dt, 1H, J = 0.8,
7.6 Hz), 7.30–7.36 (m, 2H); 13C NMR (CDCl3, 100 MHz) d
26.2, 47.8, 65.2, 74.2, 108.2, 122.9, 124.0, 129.7, 130.3, 143.9,
178.5; ESI-HRMS(m/z): [M + Na]+ calc. for C12H16N2O2Na,
243.1109, found 243.1104.
3-Hydroxy-1-methyl-3-((p-tolylamino)methyl)indolin-2-one
◦
1
3-Hydroxy-1-methyl-3-((methyl(phenyl)amino)methyl) indo-
[8(a)(ii)]. White solid, m.p. = 99–101 C; H NMR (CDCl3,
400 MHz) d 2.24 (s, 3H), 3.19 (s, 3H), 3.31 (d, 1H, J = 12.8 Hz),
lin-2-one [6(a)(vii)]. White solid, m.p. = 118–120 ◦C; 1H NMR
2556 | Green Chem., 2011, 13, 2553–2560
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3.66 (t, 1H, J = 9.6 Hz), 3.78 (brs, 1H), 4.34 (brs, 1H), 6.64
(d, 2H, J = 7.2 Hz), 6.86 (d, 1H, J = 7.8 Hz), 6.99 (d, 2H,
J = 7.7 Hz), 7.13 (t, 1H, J = 7.5 Hz), 7.37 (t, 1H, J = 7.7 Hz),
7.47 (d, 1H, J = 7.4 Hz); 13C NMR (CDCl3, 100 MHz) d 20.4,
26.2, 51.3, 74.3, 108.6, 114.3, 123.3, 124.1, 128.1, 128.4, 129.7,
130.2, 143.7, 145.3, 177.6; ESI-HRMS(m/z): [M + Na]+ calc.
for C17H18N2O2Na, 305.1266, found 305.1260.
138.9, 142.0, 144.9, 152.8, 166.0, 179.3; ESI-HRMS(m/z): [M +
Na]+ calc. for C16H15N3O5Na, 352.0909, found 352.0904.
3-Hydroxy-1-methyl-3-((3-nitrophenylamino)methyl)indolin-
◦
1
2-one [8(a)(viii)]. Yellow solid, m.p. = 142–144 C; H NMR
(CDCl3, 400 MHz) d 3.19 (s, 3H), 3.43 (dd, 1H, J = 3.4, 13.0 Hz),
3.72–3.77 (m, 2H), 4.88 (dd, 1H, J = 2.8, 8.8 Hz), 6.88 (d, 1H, J =
7.8 Hz), 6.93–6.96 (m, 1H), 7.14 (dt, 1H, J = 0.8, 7.7 Hz), 7.25
(t, 1H, J = 8.1 Hz), 7.38 (dt, 1H, J = 1.2, 7.8 Hz), 7.42 (t, 1H, J =
2.3 Hz), 7.48 (dd, 1H, J = 0.7, 7.4 Hz), 7.52–7.54 (m, 1H); 13C
NMR (CDCl3, 100 MHz) d 26.3, 50.4, 74.7, 107.1, 108.9, 112.9,
119.6, 123.6, 124.2, 128.2, 129.7, 130.5, 143.3, 148.7, 149.3,
177.2; ESI-HRMS(m/z): [M + Na]+ calc. for C16H15N3O4Na,
336.0960, found 336.0955.
3-((4-Fluorophenylamino)methyl)-3-hydroxy-1-methylindolin-
2-one [8(a)(iii)]. Pale yellow solid, m.p. = 127–129 ◦C; 1H
NMR (CDCl3, 400 MHz) d 3.17 (s, 3H), 3.34 (d, 1H, J =
12.8 Hz), 3.63 (d, 1H, J = 12.8 Hz), 3.87 (brs, 2H), 6.62–6.66 (m,
2H), 6.85–6.90 (m, 3H), 7.14 (dt, 1H, J = 0.8, 8.2 Hz), 7.38 (dt,
1H, J = 1.2, 7.8 Hz), 7.47 (dd, 1H, J = 0.7, 7.4 Hz); 13C NMR
(CDCl3, 100 MHz) d 26.2, 51.7, 74.6, 108.7, 115.0, 115.1, 115.5,
115.7, 123.4, 124.2, 128.4, 130.3, 143.5, 143.9, 155.3, 157.6,
177.5; ESI-HRMS(m/z): [M + Na]+ calc. for C16H15FN2O2Na,
309.1015, found 309.1010.
5-Fluoro-3-hydroxy-1-methyl-3-((phenylamino)methyl)in-
dolin-2-one [8(b)(i)]. Pale yellow solid, m.p. = 104–106 ◦C; 1H
NMR (CDCl3, 400 MHz) d 3.18 (s, 3H), 3.35 (d, 1H, J =
13.0 Hz), 3.66 (t, 1H, J = 12.1 Hz), 3.84 (brs, 1H), 4.45 (d, 1H, J =
9.2 Hz), 6.71 (d, 2H, J = 8.0 Hz), 6.76-6.81 (m, 2H), 7.08 (t, 1H,
J = 8.8 Hz), 7.17–7.26 (m, 3H); 13C NMR (CDCl3, 100 MHz) d
26.4, 50.9, 74.8, 109.2, 109.3, 112.5, 112.7, 114.0, 116.3, 116.5,
118.9, 129.3, 130.0, 130.1, 139.4, 147.5, 158.4, 160.8, 177.3; ESI-
HRMS(m/z): [M + Na]+ calc. for C16H15FN2O2Na, 309.1015,
found 309.1010.
3-((4-Chlorophenylamino)methyl)-3-hydroxy-1-methylindolin-
2-one [8(a)(iv)]. White solid, m.p. = 144–147 ◦C; 1H NMR
(CDCl3, 400 MHz) d 3.14 (s, 3H), 3.36 (d, 1H, J = 13.0 Hz), 3.63
(d, 1H, J = 13.0 Hz), 4.29 (brs, 2H), 6.56 (d, 2H, J = 8.6 Hz),
6.85 (d, 1H, J = 7.8 Hz), 7.07 (d, 2H, J = 8.6 Hz), 7.12 (t, 1H,
J = 7.6 Hz), 7.37 (dt, 1H, J = 1.0, 7.8 Hz), 7.46 (dd, 1H, J = 0.8,
7.3 Hz); 13C NMR (CDCl3, 100 MHz) d 26.2, 50.9, 74.8, 108.7,
114.8, 122.9, 123.4, 124.2, 128.5, 129.0, 130.2, 143.4, 146.4,
177.5; ESI-HRMS(m/z): [M + Na]+ calc. for C16H15ClN2O2Na,
325.0720, found 325.0714.
5-Fluoro-3-hydroxy-1-methyl-3-((p-tolylamin◦o)methyl)in-
dolin-2-one [8(b)(ii)]. White solid, m.p. = 148–149 C; 1H NMR
(CDCl3, 400 MHz) d 2.24 (s, 3H), 3.17 (s, 3H), 3.32 (d, 1H, J =
12.8 Hz), 3.61 (t, 1H, J = 11.5 Hz), 3.86 (brs, 1H), 4.31 (d,
1H, J = 9.3 Hz), 6.64 (d, 2H, J = 7.3 Hz), 6.77–6.80 (m, 1H),
7.00 (d, 2H, J = 7.6 Hz), 7.07 (t, 1H, J = 8.9 Hz), 7.23 (d,
1H, J = 7.5 Hz); 13C NMR (CDCl3, 100 MHz) d 20.4, 26.4, 51.3,
74.6, 109.2, 109.3, 112.4, 112.7, 114.3, 116.3, 116.5, 128.4, 129.8,
130.0, 130.0, 139.5, 145.1, 158.4, 160.8, 177.3; ESI-HRMS(m/z):
[M + Na]+ calc. for C17H17FN2O2Na, 323.1172, found 323.1166.
3-((4-Bromophenylamino)methyl)-3-hydroxy-1-methylindolin-
2-one [8(a)(v)]. White solid, m.p. = 153–154 ◦C; 1H NMR
(CDCl3, 400 MHz) d 3.19 (s, 3H), 3.32 (d, 1H, J = 12.9 Hz),
3.54 (brs, 1H), 3.65 (t, 1H, J = 11.8 Hz), 4.52 (d, 1H, J =
9.6 Hz), 6.57 (d, 2H, J = 7.8 Hz), 6.88 (d, 1H, J = 7.8 Hz), 7.14
(t, 1H, J = 7.6 Hz), 7.25 (d, 2H, J = 9.3 Hz), 7.39 (t, 1H, J =
7.7 Hz), 7.46 (d, 1H, J = 7.3 Hz); 13C NMR(CDCl3, 100 MHz)
d 26.3, 50.8, 74.6, 108.8, 110.2, 115.4, 123.4, 124.2, 128.3, 130.3,
131.9, 143.5, 146.7, 177.4; ESI-HRMS(m/z): [M + Na]+ calc.
for C16H15BrN2O2Na, 369.0215, found 369.0209.
5-Fluoro-3-((4-fluorophenylamino)methyl)-3-hydroxy-1-meth-
ylindolin-2-one [8(b)(iii)]. Pale brown solid, m.p. = 149–151 ◦C;
1H NMR (CDCl3, 400 MHz) d 3.18 (s, 3H), 3.33 (d, 1H, J =
12.8 Hz), 3.58 (t, 1H, J = 11.6 Hz), 3.82 (brs, 1H), 4.36 (d,
1H, J = 8.9 Hz), 6.63–6.67 (m, 2H), 6.78–6.82 (m, 1H), 6.89
(t, 2H, J = 8.6 Hz), 7.08 (t, 1H, J = 8.8 Hz), 7.23 (d, 1H, J =
7.4 Hz); 13C NMR (CDCl3, 100 MHz) d 26.4, 51.7, 74.6, 109.3,
109.4, 112.4, 112.7, 115.1, 115.2, 115.6, 115.8, 116.4, 116.6,
129.9, 129.9, 139.5, 143.7, 155.4, 157.8, 158.4, 160.8, 177.2; ESI-
HRMS(m/z): [M + Na]+ calc. for C16H14F2N2O2Na, 327.0921,
found 327.0916.
3-((2-Chloro-4-fluorophenylamino)methyl)-3-hydroxy-1-meth-
◦
1
ylindolin-2-one [8(a)(vi)]. White solid, m.p. = 131–133 C; H
NMR (CDCl3, 400 MHz) d 3.20 (s, 3H), 3.46 (dd, 1H, J = 3.5,
12.8 Hz), 3.58 (brs, 1H), 3.66 (dd, 1H, J = 9.4, 12.8 Hz), 4.82 (dd,
1H, J = 2.8, 9.2 Hz), 6.66 (dd, 1H, J = 5.0, 9.0 Hz), 6.82–6.89
(m, 2H), 7.03 (dd, 1H, J = 2.9, 8.2 Hz), 7.14 (dt, 1H, J = 0.8,
7.7 Hz), 7.37–7.41 (m, 1H), 7.48 (dd, 1H, J = 0.8, 7.3 Hz); 13C
NMR (CDCl3, 100 MHz) d 26.3, 50.9, 74.9, 108.8, 112.5, 112.6,
114.1, 114.4, 116.3, 116.6, 120.0, 120.1, 123.4, 124.2, 128.2,
130.4, 140.3, 143.5, 153.7, 156.1, 177.1; ESI-HRMS(m/z): [M +
Na]+ calc. for C16H14ClFN2O2Na, 343.0626, found 343.0620.
3-((4-Chlorophenylamino)methyl)-5-fluoro-3-hydroxy-1-meth-
◦
1
ylindolin-2-one [8(b)(iv)]. White solid, m.p. = 155–156 C; H
NMR (CDCl3, 400 MHz) d 3.17 (s, 3H), 3.33 (d, 1H, J =
13.0 Hz), 3.58–3.66 (m, 2H), 4.45 (d, 1H, J = 9.1 Hz), 6.60–6.62
(m, 2H), 6.78–6.80 (m, 1H), 7.05–7.13 (m, 3H), 7.20–7.26 (m,
1H); 13C NMR (CDCl3, 100 MHz) d 26.4, 51.0, 74.8, 109.3,
109.4, 112.4, 112.7, 115.0, 116.4, 116.6, 123.4, 129.1, 129.9,
139.4, 146.1, 158.4, 160.8, 177.2; ESI-HRMS(m/z): [M + Na]+
calc. for C16H14ClFN2O2Na, 343.0626, found 343.0620.
3-Hydroxy-3-((2-hydroxy-5-nitrophenylamino)methyl)-1-me-
thylindolin-2-one [8(a)(vii)]. Brick red solid, m.p. = 177–180 ◦C;
1H NMR (CD3OD, 400 MHz) d 3.16 (s, 3H), 3.64 (d, 1H, J =
13.2 Hz), 3.71 (d, 1H, J = 13.0 Hz), 5.48 (brs, 1H), 6.67 (d, 1H, J =
8.5 Hz), 6.98 (d, 1H, J = 7.6 Hz), 7.10 (t, 1H, J = 6.8 Hz), 7.31–
7.35 (m, 2H), 7.44–7.49 (m, 2H); 13C NMR (CD3OD, 100 MHz)
d 26.4, 50.9, 77.0, 106.1, 109.9, 113.1, 115.1, 124.2, 125.3, 131.0,
3-((4-Bromophenylamino)methyl)-5-fluoro-3-hydroxy-1-meth-
◦
1
ylindolin-2-one [8(b)(v)]. White solid, m.p. = 159–162 C; H
NMR (CDCl3, 400 MHz) d 3.16 (s, 3H), 3.34 (d, 1H, J =
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13.0 Hz), 3.61 (t, 1H, J = 11.7 Hz), 3.83 (d, 1H, J = 4.9 Hz), 4.46
(d, 1H, J = 8.9 Hz), 6.56 (d, 2H, 7.4 Hz), 6.79–6.81 (m, 1H),
7.08 (t, 1H, J = 8.8 Hz), 7.21–7.25 (m, 3H); 13C NMR (CDCl3,
100 MHz) d 26.4, 50.8, 74.8, 109.4, 110.4, 112.5, 112.7, 115.4,
116.4, 116.6, 132.0, 139.3, 146.6, 177.1; ESI-HRMS(m/z): [M +
Na]+ calc. for C16H14BrFN2O2Na, 387.0120, found 387.0115.
HRMS(m/z): [M + Na]+ calc. for C17H17ClN2O2Na, 339.0876,
found 339.0871.
5-Chloro-3-((4-fluorophenylamino)methyl)-3-hydroxy-1-meth-
ylindolin-2-one [8(c)(iii)]. White solid, m.p. = 88–90 ◦C; 1H
NMR (CDCl3, 400 MHz) d 3.15 (s, 3H), 3.33 (d, 1H, J =
12.9 Hz), 3.60 (d, 1H, J = 12.9 Hz), 3.96 (brs, 2H), 6.64 (m,
2H), 6.78 (d, 1H, J = 8.3 Hz), 6.88 (t, 2H, J = 8.6 Hz), 7.34 (dd,
1H, J = 1.8, 8.3 Hz), 7.44 (d, 1H, J = 1.9 Hz); 13C NMR (CDCl3,
100 MHz) d 26.4, 51.7, 74.6, 109.7, 115.2, 115.3, 115.6, 115.8,
124.9, 128.9, 130.0, 130.1, 142.0, 143.5, 155.5, 157.8, 177.1; ESI-
HRMS(m/z): [M + Na]+ calc. for C16H14ClFN2O2Na, 343.0626,
found 343.0620.
3-((2-Chloro-4-fluorophenylamino)methyl)-5-fluoro-3-hydro-
xy-1◦-methylindolin-2-one [8(b)(vi)]. White solid, m.p. = 110–
1
112 C; H NMR (CDCl3, 400 MHz) d 3.18 (s, 3H), 3.47 (dd,
1H, J = 3.3, 13.3 Hz), 3.64 (dd, 1H, J = 9.5, 12.7 Hz), 3.83
(brs, 1H), 4.76 (d, 1H, J = 6.6 Hz), 6.65 (dd, 1H, J = 5.0,
8.9 Hz), 6.79–6.87 (m, 2H), 7.02–7.10 (m, 2H), 7.25 (dd, 1H,
J = 2.2, 7.4 Hz); 13C NMR (CDCl3, 100 MHz) d 26.4, 50.9,
75.2, 109.4, 109.4, 112.5, 112.6, 112.7, 112.8, 114.2, 114.4, 116.4,
116.4, 116.6, 120.1, 120.2, 129.8, 129.9, 139.4, 140.1, 153.8,
156.2, 158.4, 160.8, 177.0; ESI-HRMS(m/z): [M + Na]+ calc.
for C16H13ClF2N2O2Na, 361.0531, found 361.0526.
5-Chloro-3-((4-chlorophenylamino)methyl)-3-hydroxy-1-meth-
ylindolin-2-one [8(c)(iv)]. Pale brown solid, m.p. = 171–173 ◦C;
1H NMR (CDCl3, 400 MHz) d 3.18 (s, 3H), 3.32 (dd, 1H, J =
2.6, 13.0 Hz), 3.60–3.66 (m, 1H), 4.45 (d, 1H, J = 8.2 Hz), 6.63
(d, 2H, J = 8.4 Hz), 6.80 (d, 1H, J = 8.3 Hz), 7.13 (d, 2H, J =
8.4 Hz), 7.36 (d, 1H, J = 8.3 Hz), 7.44 (s, 1H); 13C NMR (CDCl3,
100 MHz) d 26.4, 50.9, 74.6, 109.7, 115.0, 123.5, 124.8, 128.9,
129.1, 129.9, 130.2, 142.0, 146.1, 177.0; ESI-HRMS(m/z): [M +
Na]+ calc. for C16H14Cl2N2O2Na, 359.0330, found 359.0325.
5-Fluoro-3-hydroxy-3-((2-hydroxy-5-nitrophenylamino)me-
thyl)-1-m◦ethylindolin-2-one [8(b)(vii)]. Yellow solid, m.p. =
199–201 C; 1H NMR (CD3OD, 400 MHz) d 3.14 (s, 3H), 3.66
(dd, 2H, J = 13.9, 19.4 Hz), 4.59 (brs, 1H), 6.68 (d, 1H, J =
8.4 Hz), 6.93–6.95 (m, 1H), 7.04–7.08 (m, 1H), 7.25 (d, 1H,
J = 7.4 Hz), 7.39 (s, 1H), 7.44 (d, 1H, J = 8.5 Hz); 13C NMR
(CD3OD, 100 MHz) d 25.2, 49.4, 75.9, 104.9, 109.2, 109.3,
111.7, 111.9, 112.1, 113.4, 115.4, 115.6, 131.6, 137.1, 139.5,
141.0, 150.5, 160.8, 177.5; ESI-HRMS(m/z): [M + Na]+ calc.
for C16H14FN3O5Na, 370.0815, found 370.0810.
3-((4-Bromophenylamino)methyl)-5-chloro-3-hydroxy-1-meth-
◦
1
ylindolin-2-one [8(c)(v)]. White solid, m.p. = 153–155 C; H
NMR (CDCl3, 400 MHz) d 3.15 (s, 3H), 3.32 (dd, 1H, J =
3.3, 13.0 Hz), 3.61 (dd, 1H, J = 10.0, 13.0 Hz), 3.91 (brs,
1H), 4.41 (d, 1H, J = 9.7 Hz), 6.55 (d, 2H, J = 8.8 Hz), 6.78
(d, 1H, J = 8.3 Hz), 7.24 (d, 2H, J = 8.8 Hz), 7.33–7.36 (m,
1H), 7.43 (d, 1H, J = 1.9 Hz); 13C NMR (CDCl3, 100 MHz) d
26.4, 50.8, 74.7, 109.7, 110.5, 115.5, 124.8, 128.9, 130.0, 130.2,
132.0, 142.0, 146.5, 177.0; ESI-HRMS(m/z): [M + Na]+ calc.
for C16H14BrClN2O2Na, 402.9825, found 402.9819.
5-Fluoro-3-hydroxy-1-methyl-3-((3-nitrophenylamino)meth-
yl)indolin-2-one [8(b)(viii)]. Yellow solid, m.p. = 137–139 ◦C;
1H NMR (CDCl3, 400 MHz) d 3.20 (s, 3H), 3.45 (dd, 1H, J =
3.4, 13.1 Hz), 3.73 (dd, 1H, J = 9.3, 13.1 Hz), 3.77 (brs, 1H), 4.86
(dd, 1H, J = 2.8, 9.1 Hz), 6.83 (dd, 1H, J = 4.0, 8.5 Hz), 6.97
(dd, 1H, J = 1.9, 7.8 Hz), 7.10 (dt, 1H, J = 2.6, 8.8 Hz), 7.24–
7.29 (m, 2H), 7.44 (t, 1H, J = 2.2 Hz), 7.56–7.58 (m, 1H); 13C
NMR (CDCl3, 100 MHz) d 26.5, 50.5, 74.8, 107.2, 109.5, 109.6,
112.5, 112.8, 113.1, 116.6, 116.8, 119.7, 129.8, 139.2, 148.5,
149.3, 158.4, 160.9, 176.9; ESI-HRMS(m/z): [M + Na]+ calc.
for C16H14FN3O4Na, 354.0866, found 354.0861.
5-Chloro-3-((2-chloro-4-fluorophenylamino)methyl)-3-hydro-
xy-1◦-methylindolin-2-one [8(c)(vi)]. Off-white solid, m.p. = 99–
1
101 C; H NMR (CDCl3, 400 MHz) d 3.17 (s, 3H), 3.44 (dd,
1H, J = 3.5, 13.0 Hz), 3.59 (brs, 1H), 3.64 (dd, 1H, J = 9.6,
13.0 Hz), 4.80 (dd, 1H, J = 3.1, 9.4 Hz), 6.67 (dd, 1H, J = 5.0,
9.0 Hz), 6.80 (d, 1H, J = 8.3 Hz), 6.86 (dt, 1H, J = 2.9, 8.2 Hz),
7.03 (dd, 1H, J = 2.9, 8.2 Hz), 7.35 (dd, 1H, J = 2.1, 8.3 Hz), 7.46
(d, 1H, J = 2.1 Hz); 13C NMR (CDCl3, 100 MHz) d 26.4, 50.9,
74.8, 109.8, 112.7, 112.7, 114.2, 114.5, 116.4, 116.7, 120.2, 120.3,
124.9, 128.9, 129.7, 130.3, 140.1, 142.1, 153.9, 156.3, 176.7; ESI-
HRMS(m/z): [M + Na]+ calc. for C16H13Cl2FN2O2Na, 377.0236,
found 377.0230.
5 - Chloro - 3 - hydroxy - 1 - methyl - 3 - ((phenylamino)meth-
yl)indolin-2-one [8(c)(i)]. Pale yellow solid, m.p. = 132–133 ◦C;
1H NMR (CDCl3, 400 MHz) d 3.16 (s, 3H), 3.35 (d, 1H, J =
12.8 Hz), 3.67 (t, 1H, J = 11.4 Hz), 3.97 (brs, 1H), 4.39 (d, 1H,
J = 9.2 Hz), 6.69–6.79 (m, 4H), 7.18 (t, 2H, J = 7.2 Hz), 7.34 (d,
1H, J = 8.2 Hz), 7.45 (s, 1H); 13C NMR (CDCl3, 100 MHz) d
26.4, 50.9, 74.6, 109.6, 114.0, 119.0, 124.9, 128.8, 129.3, 130.1,
130.1, 142.1, 147.5, 177.1; ESI-HRMS(m/z): [M + Na]+ calc.
for C16H15ClN2O2Na, 325.0720, found 325.0714.
5-Chloro-3-hydroxy-3-((2-hydroxy-5-nitrophenylamino)me-
thyl)-1-methylindolin-2-one [8(c)(vii)]. Brick red solid, m.p. =
165–167 ◦C; 1H NMR (CD3OD, 400 MHz) d 3.15 (s, 3H),
3.64 (dd, 2H, J = 13.0, 14.7 Hz), 6.64 (d, 1H, J = 8.2 Hz),
6.94 (d, 1H, J = 7.7 Hz), 7.31 (d, 1H, J = 8.1 Hz), 7.37 (s,
1H), 7.46 (s, 2H); 13C NMR (CD3OD, 100 MHz) d 25.1, 49.4,
75.8, 101.8, 102.9, 104.8, 109.6, 112.0, 114.1, 124.5, 129.3, 131.6,
140.1, 144.8, 155.6, 177.8; ESI-HRMS(m/z): [M + Na]+ calc. for
C16H14ClN3O5Na, 386.0520, found 386.0514.
5-Chloro-3-hydroxy-1-methyl-3-((p-tolylamino)methyl)indo-
◦
1
lin-2-one [8(c)(ii)]. White solid, m.p. = 167–168 C; H NMR
(CDCl3, 400 MHz) d 2.24 (s, 3H), 3.17 (s, 3H), 3.31 (d, 1H,
J = 12.5 Hz), 3.63 (t, 1H, J = 8.5 Hz), 3.87 (brs, 1H), 4.29 (brs,
1H), 6.65 (d, 2H, J = 6.5 Hz), 6.78 (d, 1H, J = 6.8 Hz), 7.00
(d, 2H, J = 6.6 Hz), 7.34 (d, 1H, J = 8.1 Hz), 7.44 (s, 1H); 13C
NMR (CDCl3, 100 MHz) d 20.4, 26.3, 51.3, 74.4, 109.6, 114.4,
124.8, 128.4, 128.8, 129.8, 130.0, 130.1, 142.2, 145.1, 177.2; ESI-
5-Chloro-3-hydroxy-1-methyl-3-((3-nitrophenylamino)me-
thyl)indolin-2-one [8(c)(viii)]. Yellow solid, m.p. = 156–158 ◦C;
1H NMR (CDCl3, 400 MHz) d 3.20 (s, 3H), 3.44 (dd, 1H, J =
3.2, 13.1 Hz), 3.46 (brs, 1H), 3.74 (dd, 1H, J = 9.4, 13.0 Hz),
2558 | Green Chem., 2011, 13, 2553–2560
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4.83 (d, 1H, J = 6.9 Hz), 6.83 (d, 1H, J = 8.3 Hz), 6.99 (dd,
1H, J = 1.5, 8.2 Hz), 7.28–7.32 (m, 1H), 7.38 (dd, 1H, J = 2.0,
8.3 Hz), 7.46–7.48 (m, 2H), 7.59 (d, 1H, J = 8.0 Hz); 13C NMR
(CDCl3, 100 MHz) d 26.4, 50.4, 74.6, 107.3, 109.8, 113.3, 119.8,
124.9, 129.1, 129.7, 129.8, 130.4, 141.9, 148.4, 149.2, 176.7; ESI-
HRMS(m/z): [M + Na]+ calc. for C16H14ClN3O4Na, 370.0571,
found 370.0565.
5-Bromo-3-((2-chloro-4-fluorophenylamino)methyl)-3-hydro-
xy-1◦-methylindolin-2-one [8(d)(vi)]. White solid, m.p. = 107–
1
109 C; H NMR (CDCl3, 400 MHz) d 3.17 (s, 3H), 3.44 (dd,
1H, J = 2.8, 12.9 Hz), 3.51 (d, 1H, J = 1.1 Hz), 3.64 (dd,
1H, J = 9.7, 12.4 Hz), 4.78 (d, 1H, J = 8.6 Hz), 6.67 (dd, 1H,
J = 5.0, 8.9 Hz), 6.74 (d, 1H, J = 8.2 Hz), 6.83–6.88 (m, 1H),
7.02–7.05 (m, 1H), 7.49–7.51 (m, 1H), 7.59 (s, 1H); 13C NMR
(CDCl3, 100 MHz) d 26.3, 51.0, 74.7, 110.2, 112.7, 112.8, 114.2,
114.4, 116.1, 116.4, 116.7, 120.3, 127.6, 130.1, 133.2, 140.1,
142.6, 154.5, 156.3, 176.6; ESI-HRMS(m/z): [M + Na]+ calc.
for C16H13BrClFN2O2Na, 420.9731, found 420.9725.
5-Bromo-3-hydroxy-1-methyl-3-((phenylamino)methyl)indo-
◦
1
lin-2-one [8(d)(i)]. Pale brown solid, m.p. = 143–144 C; H
NMR (CDCl3, 400 MHz) d 3.15 (s, 3H), 3.35 (d, 1H, J =
13.0 Hz), 3.67 (d, 1H, J = 13.0 Hz), 4.72 (brs, 2H), 6.69–6.79
(m, 4H), 7.18 (dt, 2H, J = 1.8, 7.4 Hz), 7.49 (dd, 1H, J = 2.0,
8.3 Hz), 7.58 (d, 1H, J = 2.0 Hz); 13C NMR (CDCl3, 100 MHz)
d 26.3, 50.9, 74.6, 110.1, 114.0, 116.0, 118.9, 127.6, 129.3, 130.5,
133.0, 142.6, 147.5, 177.1; ESI-HRMS(m/z): [M + Na]+ calc.
for C16H15BrN2O2Na, 369.0215, found 369.0209.
5-Bromo-3-hydroxy-3-((2-hydroxy-5-nitrophenylamino)meth-
yl)-1-methylindolin-2-one [8(d)(vii)]. Yellow solid, m.p. = 152–
154 ◦C; 1H NMR (CD3OD, 400 MHz) d 3.15 (s, 3H), 3.68 (dd,
2H, J = 13.6, 15.2 Hz), 4.61 (brs, 2H), 6.69 (d, 1H, J = 8.6 Hz),
6.89 (d, 1H, J = 8.3 Hz), 7.38 (d, 1H, J = 2.6 Hz), 7.44–7.47 (m,
2H), 7.58 (d, 1H, J = 2.0 Hz); 13C NMR (CD3OD, 100 MHz) d
26.5, 50.7, 77.2, 106.4, 111.5, 113.1, 114.9, 116.7, 128.8, 133.3,
133.7, 138.5, 142.3, 144.0, 151.9, 178.8; ESI-HRMS(m/z): [M +
Na]+ calc. for C16H14BrN3O5Na, 430.0015, found 430.0009.
5-Bromo-3-hydroxy-1-methyl-3-((p-tolylamino)methyl)indo-
◦
1
lin-2-one [8(d)(ii)]. White solid, m.p. = 161–163 C; H NMR
(CDCl3, 400 MHz) d 2.26 (s, 3H), 3.18 (s, 3H), 3.33 (d, 1H, J =
12.9 Hz), 3.64 (t, 1H, J = 9.6 Hz), 3.87 (brs, 1H), 4.30 (d, 1H, J =
7.6 Hz), 6.66 (d, 2H, J = 8.1 Hz), 6.75 (d, 1H, J = 8.2 Hz), 7.02
5-Bromo-3-hydroxy-1-methyl-3-((3-nitrophenylamino)meth-
yl)indolin-2-one [8(d)(viii)]. Yellow solid, m.p. = 166–168 ◦C;
1H NMR (CDCl3, 400 MHz) d 3.20 (s, 3H), 3.40–3.44 (m, 2H),
3.73 (dd, 1H, J = 9.6, 13.1 Hz), 4.81 (dd, 1H, J = 2.8, 9.3 Hz),
6.77 (d, 1H, J = 8.3 Hz), 6.97–7.00 (m, 1H), 7.29 (t, 1H, J =
8.1 Hz), 7.45 (t, 1H, J = 2.2 Hz), 7.52 (dd, 1H, J = 2.0, 8.1 Hz),
7.57–7.60 (m, 2H); 13C NMR (CDCl3, 100 MHz) d 26.4, 50.4,
74.5, 107.2, 110.3, 113.3, 116.3, 119.8, 127.7, 129.8, 129.9, 133.3,
142.4, 148.4, 149.3, 176.6; ESI-HRMS(m/z): [M + Na]+ calc. for
C16H14BrN3O4Na, 414.0065, found 414.0060.
(d, 2H, J = 8.2 Hz), 7.51 (td, 1H, J = 1.0, 1.9 Hz), 7.59 (s, 1H); 13
C
NMR (CDCl3, 100 MHz) d 20.4, 26.3, 51.3, 74.4, 110.1, 114.4,
116.0, 127.6, 128.4, 129.8, 130.4, 133.0, 142.7, 145.1, 177.1; ESI-
HRMS(m/z): [M + Na]+ calc. for C17H17BrN2O2Na, 383.0371,
found 383.0366.
5-Bromo-3-((4-fluorophenylamino)methyl)-3-hydroxy-1-meth-
◦
1
ylindolin-2-one [8(d)(iii)]. White solid, m.p. = 175–177 C; H
NMR (CDCl3, 400 MHz) d 3.15 (s, 3H), 3.32 (d, 1H, J =
12.8 Hz), 3.59 (t, 1H, J = 10.0 Hz), 4.03 (brs, 1H), 4.29 (d,
1H, J = 9.2 Hz), 6.61–6.65 (m, 2H), 6.73 (d, 1H, J = 8.2 Hz),
6.86–6.90 (m, 2H), 7.48–7.50 (m, 1H), 7.57 (d, 1H, J = 1.8 Hz);
13C NMR (CDCl3, 100 MHz) d 26.3, 51.6, 74.5, 110.2, 115.1,
115.2, 115.6, 115.8, 116.1, 127.6, 130.3, 133.1, 142.6, 143.7,
155.4, 157.8, 177.0; ESI-HRMS(m/z): [M + Na]+ calc. for
C16H14BrFN2O2Na, 387.0120, found 387.0115.
Conclusions
An eco-friendly process in water has been developed for the
aminolysis of 3-oxirane-indolin-2-one derivatives with aliphatic
and aromatic amines. The reactions afford high yields of 3-
hydroxy-3-aminomethylindolin-2-ones with regiospecificity by
opening the oxirane ring from the less-hindered side. The use of
a green solvent, the simplicity of the reaction and the ease of
product isolation make this a suitable method for the synthesis
of these scaffolds.
5-Bromo-3-((4-chlorophenylamino)methyl)-3-hydroxy-1-meth-
◦
1
ylindolin-2-one [8(d)(iv)]. White solid, m.p. = 179–181 C; H
NMR (CDCl3, 400 MHz) d 3.15 (s, 3H), 3.32 (dd, 1H, J =
3.0, 13.0 Hz), 3.62 (dd, 1H, J = 10.1, 13.0 Hz), 3.79 (brs, 1H),
4.42 (d, 1H, J = 7.5 Hz), 6.59–6.63 (m, 2H), 6.74 (d, 1H, J =
8.3 Hz), 7.10–7.13 (m, 2H), 7.50 (dd, 1H, J = 2.0, 8.3 Hz),
7.57 (d, 1H, J = 1.9 Hz); 13C NMR (CDCl3, 100 MHz) d
26.4, 50.9, 74.5, 110.2, 115.0, 116.1, 123.5, 127.6, 129.1, 130.2,
133.1, 142.5, 146.0, 176.9; ESI-HRMS(m/z): [M + Na]+ calc.
for C16H14BrClN2O2Na, 402.9825, found 402.9819.
Acknowledgements
Research funding from the National Institute of Pharmaceutical
Education and Research (NIPER), and the Council of Scientific
and Industrial Research (CSIR), Government of India are
gratefully acknowledged.
5-Bromo-3-((4-bromophenylamino)methyl)-3-hydroxy-1-me-
thylindolin-2-one [8(d)(v)]. Pale brown solid, m.p. = 157–
159 ◦C; 1H NMR (CDCl3, 400 MHz) d 3.16 (s, 3H), 3.32 (d, 1H,
J = 12.9 Hz), 3.62 (t, 1H, J = 11.0 Hz), 3.76 (brs, 1H), 4.43 (d,
1H, J = 9.0 Hz), 6.57 (d, 2H, J = 7.5 Hz), 6.74 (d, 1H, J = 8.0 Hz),
7.25 (d, 2H, J = 7.9 Hz), 7.50 (d, 1H, J = 8.1 Hz), 7.57 (s, 1H);
13C NMR (CDCl3, 100 MHz) d 26.4, 50.8, 74.4, 106.0, 110.2,
112.7, 115.6, 116.1, 127.6, 132.0, 133.2, 146.5, 161.8, 176.8; ESI-
HRMS(m/z): [M + Na]+ calc. for C16H14Br2N2O2Na, 446.9320,
found 446.9314.
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