Catalyst-free aldol condensation of ketones and isatins under mild reaction conditions in DMF with molecular sieves 4 A as additive

Article abstract of DOI:10.1039/b906684e

In the presence of molecular sieve (MS) 4 A in DMF, a catalyst-free aldol condensation of a variety of aromatic and aliphatic ketones with isatins under mild reaction conditions has been developed. This approach may provide access to a wide range of 3-sub

Full text of DOI:10.1039/b906684e

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Catalyst-free aldol condensation of ketones and isatins under mild reaction
˚
conditions in DMF with molecular sieves 4 A as additive†
Wen-Bing Chen,a,b Yu-Hua Liao,a,b Xi-Lin Du,c Xiao-Mei Zhanga and Wei-Cheng Yuan*a
Received 3rd April 2009, Accepted 19th June 2009
First published as an Advance Article on the web 14th July 2009
DOI: 10.1039/b906684e
˚
In the presence of molecular sieve (MS) 4 A in DMF, a catalyst-free aldol condensation of a
variety of aromatic and aliphatic ketones with isatins under mild reaction conditions has been
developed. This approach may provide access to a wide range of 3-substituted-
3-hydroxyindolin-2-ones in good to excellent yields.
this kind of compounds.4 Through careful examination of the
Introduction
existing literature procedures, we noted that nearly all existing
methods for the aldol reaction of ketones with isatins inevitably
required a base, a metal complex or an organic molecule serving
as catalyst.3d,3i,4,5 However, due to the fact that the highly reactive
b-carbonyl group of isatin derivatives is susceptible to nu-
cleophilic attack,6 we envisioned that the aldol condensation
between isatin derivatives and ketones might readily proceed
catalyst-free under certain appropriate reaction conditions.
In view of the 12 Principles of Green Chemistry,7 catalyst-free
reactions have been attracting more and more attention from
organic synthesis chemists.8 We recently have been trying to
develop approaches to carry out reactions without any catalyst.
Fortunately, we discovered that the aldol condensations of a
variety of aromatic or aliphatic ketones with isatins proceeded
smoothly at room temperature in DMF under catalyst-free
conditions, and this approach may provide access to a wide range
of 3-substituted-3-hydroxyindolin-2-ones derivatives in high
yields. To the best of our knowledge, there are not any precedent
protocols of this work for the preparation 3-substituted-3-
hydroxyindolin-2-ones through the aldol condensation of isatins
and ketones under catalyst free condition. Herein, we wish to
describe our preliminary results about this work.
The indole nucleus, a common and important structural func-
tionality of a variety of both natural and unnatural products,
is probably the most well-known heterocycle.1 In particular, the
3-substituted-3-hydroxyindolin-2-ones, one class of compounds
bearing the indole skeletal structure, are found in several bio-
logically active alkaloids and pharmacological agents2 (Fig. 1).
Owing to the significance of this structural motif, numerous
elegant methodologies have been developed and continue to be
explored for the construction of this structure.3 Among them,
the aldol addition of appropriate ketones to isatins should be
one of the most concise and straightforward approaches to
Results and discussion
To begin with, the addition of acetophenone 1a to free isatin
2a was examined to screen the optimal reaction conditions
(Table 1). The desired adduct 3a was obtained in very trace
amount using THF as solvent at room temperature for 24 h
(Table 1, entry 1). A variety of dry solvents, such as dioxane,
CH3CN, CH2Cl2, toluene, CHCl3, DMSO and ethyl ether,
were also tested respectively, but the results were disappointing
(Table 1, entry 2). The desired product was not even obtained
in the neat reaction using acetophenone 1a as both solvent and
substrate (Table 1, entry 3). Treatment of the model reaction in
dry DMF at room temperature gave 3a in 30% yield (Table 1,
entry 4),9 although the yield was low, we were encouraged to
examine the reaction in detail to increase the yield. Fortunately,
a noticeable increase in the reaction rate and the 88% yield of 3a
Fig. 1 Examples of biologically active 3-substituted-3-hydroxyindole-
2-ones.
aKey Laboratory for Asymmetric Synthesis & Chirotechnology of
Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu, 610041, P. R. of China.
E-mail: yuanwc@cioc.ac.cn; Fax: +86 (28) 85229250
bGraduate School of Chinese Academy of Sciences, Beijing, 100049, P. R.
of China
cDepartment of General Surgery, TangDu Hospital, The Fourth Military
Medical University, Xi’an, 710038, P. R. of China
˚
† Electronic supplementary information (ESI) available: 1H NMR and
13C NMR spectra. See DOI: 10.1039/b906684e
was obtained by adding 10 mg molecular sieves (MS) 4 A to the
reaction system as additive (Table 1, entry 4 vs. 5).10 We supposed
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Table 1 Optimization of the reaction conditionsa
in 80% and 90% yield, respectively, (Table 2, entries 14–15).
Gratifying results were achieved in the examination of isatin
derivatives bearing electron-withdrawing (2b, 2d and 2e) or
electron-donating substituents (2c) at the phenyl ring (Table 2). It
was found that all the isatin substrates worked well with aromatic
ketones under the standard reaction conditions and afforded the
desired aldol adducts in general over 70% yield (Table 2, entries
16–19).
Entry Solvent
Additive Time/h Yield (%)b
As a logical extension, we next studied the reactions of
N-1 protected isatins 2f and 2g with ketones 1a, 1k and 1i,
respectively (Table 2, entries 20–25). It was found that in all
cases the reactions proceeded smoothly and provided their
corresponding products with good yields ranging from 80% to
95%. It was noteworthy that the N-benzyl adduct 3x could be
effectively achieved with 95% isolated yield in only 3 h at room
temperature (Table 2, entry 23) and the N-methyl product 3w
could also be obtained with 89% isolated yield in 2.5 h (Table 2,
entry 22). Further investigation on the scope of aromatic ketones
was conducted by increasing the size of the alkyl substituent in
acetophenone. As shown in Table 2, the substrates 1q, 1r and 1s
also worked well for the aldol condensation with free isatin 1a
(Table 2, entries 26–28). Generally, the aldol reaction tolerated
a variety of different aromatic ketones and isatins and showed
high reactivity in DMF with catalyst-free.
1
2
THF
Dioxane (CH3CN,
CH2Cl2, toluene, CHCl3,
DMSO, ethyl ether)
neat
DMF
DMF
DMF
DMF
—
—
24
24
trace
—
3
4
5
6
7
8
9
—
—
MS 4 A
˚
MS 3 A
MS 5 A
˚
MS 4 A
MS 4 A
24
24
12
16
16
12
72
—
30
88
87
87
87c
24
˚
˚
DMF
NMPd
˚
a All reactions were performed using isatin (1.0 mmol) and acetophenone
(2.0 mmol) with 10 mg MS at room temperature. b Isolated yields
of purified products. Using 90 mg MS 4 A as additive. d NMP is
c
˚
N-methyl-2-pyrrolidone.
that the molecular sieves might absorb the small amount of water
present in the reaction system. Similar results were obtained at
Encouraged by the above results, we hoped to further
investigate the scope and limitations of this methodology, and
so explored a series of aliphatic ketones as the aldol donors
under the optimized reaction conditions. As shown in Table 3,
the acyclic aliphatic ketones 1u, 1v and 1w all reacted well with
free isatin 2a (Table 3, entries 1–3). However, in the case 1v as
substrate, the reaction only gave the adduct 3e¢ with very high
regioselectivity in 64% yield (Table 3, entries 2).11 While using
pentan-3-one 1w as aldol donor, the product was obtained in
75% yield and 4.3 : 1 diasteroselectivity (Table 3, entries 2).
On the other hand, the aldol reaction between cyclic aliphatic
ketones 1x and 1y with free isatin 2a also proceeded well under
the optimized reaction conditions with as high as 87% yields,
but the relatively poor diastereoselectivities of 2.6 : 1 and 1.1 : 1
were slightly imperfect (Table 3, entries 4–5). The success of the
developed method prompted us to try conducting the reaction
of acetone (1u) and 4,6-dibromoisatin (2d) under the optimal
conditions to synthesise convolutamydine A (Table 3, entry 6),
which was firstly isolated from the marine bryozoan species
Amathia convolute by Kamano and co-workers in 1995, and
its (R)-(+)-enantiomer was identified as an anti-leukemia agent
(Table 3, entry 6).12 The corresponding product 3i¢ was smoothly
obtained in 66% chemical yield under the optimized reaction
conditions (Table 3, entry 6).
˚
˚
same reaction conditions when adding 10 mg MS 3 A or MS 5 A
to the reaction system, respectively (Table 1, entries 6 and 7).
We hoped to further increase the yield by adding 90 mg MS
˚
4 A, but found no significant improvement in the yield. Further
examining NMP as solvent, the product 3a was obtained only
in 24% yield for 72 h (Table 1. entry 9). It is interesting that
this reaction proceeded very well in DMF but worked poorly
in other solvents. The exact reason for this is not clear, but we
suppose that the DMF solvent acts like a poor base, which may
have efficiently promoted this reaction with activated molecular
sieves as additive under catalyst-free conditions. Accordingly, we
˚
chose dry DMF (solvent), 10 mg MS 4 A (additive) and room
temperature as the optimal reaction conditions.
With a set of optimized reaction conditions at hand, we
firstly explored the scope of the reaction by using various
aromatic ketones 1a–s and isatin derivatives 2a–g. The results
are summarized in Table 2. It was found that all the reactions
proceeded smoothly and afforded the desired adducts under the
optimized reaction conditions. A wide range of acetophenone
derivatives bearing electron-withdrawing (1b–h) and electron-
donating (1i–k) groups on the phenyl ring could be employed in
the aldol addition with free isatin (2a) and were nicely converted
into corresponding products (3b–k) in moderate to good yields
ranging from 66% to 94% (Table 2, entries 1–10). Strikingly,
the reaction of 1h addition to 2a even completed in 3 h and
provided the aldol adduct 3h in as high as 95% isolated yield
(Table 2, entry 7). The hetero-aromatic ketones, such as 2-thienyl
(1l), 2-furanyl (1m) and 2-pyridyl ketones (1n) underwent the
aldol reaction with free isatin (2a) to afford the products 3l,
3m and 3n in 90%, 88% and 91% yield, respectively (Table 2,
entries 11–13). Similar good results were observed in the cases
of 1-acetonaphthone (1o) and 6-methoxy-1-acetonaphthone
(1p) as substrates and the products were smoothly obtained
Conclusion
In conclusion, we have developed an efficient aldol reaction of a
variety of aromatic and aliphatic ketones with isatins using DMF
as solvent at room temperature under catalyst-free. Various
desired products, 3-substituted-3-hydroxyindolin-2-ones, were
smoothly obtained with good to excellent chemical yields.
This approach has the following prominent advantages: (1)
catalyst free, (2) very mild reaction condition, (3) high efficiency,
(4) very wide-scope of substrate. Further investigation to develop
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Table 2 Aldol condensation of aromatic acetones and isatins with catalyst-freea
Entry
1
Ketones 1
Isatins 2
Products 3
Time/h
48
Yield (%)b
88
1b
2a
3b
2
3
1c
1d
2a
2a
3c
48
9
80
87
3d
4
5
6
1e
1f
2a
2a
2a
3e
48
16
10
80
80
87
3f
1g
3g
7
8
1h
1i
2a
2a
3h
3
94
66
3i
16
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Table 2 (Contd.)
Entry
9
Ketones 1
Isatins 2
Products 3
Time/h
18
Yield (%)b
87
1j
2a
3j
10
11
12
13
14
15
1k
1l
2a
2a
2a
2a
2a
2a
3k
48
24
20
12
42
24
89
90
88
91
80
90
3l
1m
1n
1o
1p
3m
3n
3o
3p
16
17
1a
1a
2b
2d
3q
3r
20
24
80
82
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Table 2 (Contd.)
Entry
18
Ketones 1
Isatins 2
Products 3
Time/h
36
Yield (%)b
70
1i
2e
3s
19
1i
2c
3t
16
84
20
21
1a
1k
2f
2f
3u
12
24
90
87
3v
22
23
24
25
1i
2f
3w
2.5
3
89
95
80
90
1a
1k
1i
2g
2g
2g
3x
3y
24
5
3z
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Table 2 (Contd.)
Entry
26
Ketones 1
Isatins 2
Products 3
Time/h
24
Yield (%)b
91c
1q
2a
3a¢
3b¢
27
28
1r
1s
2a
2a
9
80d
63e
3c¢
36
All reactions were performed using isatins (1.0 mmol) and aromatic ketones (2.0 mmol) with 10 mg MS 4 A in DMF at room temperature. b Isolated
yields of purified products. c The diastereoselectivity was determined by 1H NMR and erythro : threo = 3.4 : 1. d The diastereoselectivity was
determined by 1H NMR and erythro : threo = 3.4 : 1. e The diastereoselectivity was determined by 1H NMR and erythro : threo = 8.1 : 1.
a
˚
more efficient and convenient reactions from a green chemistry
viewpoint is under way in our laboratory.
General procedure for the aldol condensation reaction of ketones
and isatins with catalyst-free
To a solution of isatins 2 (0.5 mmol) in freshly distilled DMF
(1.5 mL) was added ketones 1 (1.0 mmol) in the presence of
sufficiently activated MS 4A (10 mg). The reaction mixture
was stirred at room temperature for several hours and was
monitored by TLC. When the isatins 2 fully disappeared, then
the solvent was removed under reduced pressure to obtain the
crude products. The crude products were purified by silica gel
chromatography using ethyl acetate : petroleum ether = 1 : 3 to
1 : 1 as eluent to give the corresponding products 3.
Experimental
˚
General information
1H NMR spectra were recorded on Bruker NMR spectrometers
at 300 MHz. 13C NMR spectra were recorded on Bruker NMR
spectrometers at 75 MHz. IR spectra were recorded in KBr
or neat on a Nicolet (MX-1E FT-IR) spectrometer. HRMS
spectra were recorded on Bruker ESI-Q-TOF mass spectrom-
eter, microTOF Q II. All melting points were uncorrected.
All the reagents were purchased from commercial sources.
Solvents used in this work are reagent grade and were purified
by distillation prior to use. DMF solvent must be sufficiently
refluxed in calcium hydride for 5 h and distilled from calcium
3-Hydroxy-3-(2-oxo-2-◦phenylethyl)indolin-2-one13 (3a). White
1
solid, mp 196.6–197.8 C; H NMR (300 MHz, (CD3)2SO) d
10.25 (brs, 1H), 7.88–7.86 (m, 2H), 7.60 (d, J = 7.2 Hz, 1H),
7.51–7.46 (m, 2H), 7.26 (d, J = 7.2 Hz, 1H), 7.18–7.12 (m, 1H),
6.87–6.79 (m, 2H), 6.05 (br s, 1H), 4.05 (d, J = 17.4 Hz, 1H),
3.56 (d, J = 17.4 Hz, 1H);13C NMR (75 MHz, (CD3)2SO) d 45.8,
˚
hydride before use. MS 4 A must be activated sufficiently before
use.
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Table 3 Aldol condensation of aliphatic acetones and isatins with catalyst-freea
Entry
1
Ketones 1
Products 3
Time/h
18
d.r. (erythro/threo)b
—
yield (%)c
70
1u
3d¢
2
3
4
1v
3e¢
14
18
14
—
64
75
87
1w
3f¢
4.3 : 1
2.6 : 1
1x
3g¢
5
6
a
1y
1u
3h¢
12
20
1.1 : 1
87
66
3i¢
—
All reaction were performed using isatin (1.0 mmol) and ketones (2.0 mmol) with 10 mg MS 4 A at room temperature. b The diastereoselectivity was
determined with 1H NMR. c Isolated yields of purified products.
˚
73.0, 109.4, 121.1, 123.6, 127.9, 128.7, 128.9, 131.7, 133.4, 136.2,
142.9, 178.4, 196.5; IR (KBr) 3401.3, 3258.1, 3072.0, 2908.2,
1716.5, 1683.1, 1619.7, 1471.1, 1354.9, 753.7, 690.8 cm-1. HRMS
(ESI): Calculated for C16H13NNaO3 ([M + Na]+): 290.0788,
found: 290.0794.
J = 17.4 Hz, 1H), 3.55 (d, J = 17.4 Hz, 1H); 13C NMR
(75 MHz, (CD3)2SO) d 45.8, 73.1, 109.5, 121.3, 123.7, 126.7,
127.6, 128.8, 129.9, 130.8, 131.6, 133.1, 138.0, 142.9, 178.3,
195.6; IR (KBr) 3372.4, 3193.5, 3057.0, 2899.5, 1695.5, 1681.1,
1584.3, 1486.2, 1210.1, 747.8 cm-1. HRMS (ESI): Calculated for
C16H12ClNNaO3 ([M + Na]+): 324.0398, found: 324.0393.
3-Hydroxy-3-(2-oxo-2-(4-chlorophenyl)ethyl)indolin-2-one (3b).
White solid, mp 196–197.4 ◦C;1H NMR (300 MHz, (CD3)2SO) d
10.28 (brs, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H),
7.27 (d, J = 7.2 Hz, 1H), 7.16 (m, 1H), 6.88–6.80 (m, 2H), 6.09
(brs, 1H), 4.03 (d, J = 17.4 Hz, 1H), 3.57 (d, J = 17.4 Hz, 1H);
13C NMR (75 MHz, (CD3)2SO) d 45.8, 73.0, 109.4, 121.2, 123.7,
128.8, 129.2, 129.8, 131.6, 134.9, 138.4,. 142.9, 178.3, 195.6; IR
(KBr) 3373.7, 3191.9, 3056.4, 3035.6, 2898.8, 1699.3, 1680.6,
1622.2, 1468.0, 1209.8, 747.7 cm-1. HRMS (ESI): Calculated for
C16H12ClNNaO3 ([M + Na]+): 324.0398, found: 324.0393.
3-Hydroxy-3-(2-oxo-2-(2-chlorophenyl)ethyl)indolin-2-one
◦
1
(3d). White solid, mp 189.5–190.5 C; H NMR (300 MHz,
(CD3)2SO) d 10.31 (brs, 1H), 7.49–7.39 (m, 4H), 7.31 (d, J =
7.5 Hz, 1H), 7.21–7.16 (m, 1H), 6.91–6.83 (m, 1H), 6.82 (d, J =
7.5 Hz, 1H), 6.14 (brs, 1H), 3.89 (d, J = 16.8 Hz, 1H), 3.53 (d, J =
16.8 Hz, 1H); 13C NMR (75 MHz, (CD3)2SO) d 49.6, 73.1, 109.5,
121.3, 123.9, 127.3, 129.1, 129.3, 129.7, 130.4, 131.1, 132.5,
138.0, 142.8, 177.9, 198.7; IR (KBr) 3341.1, 3201.4, 3058.5,
2885.1, 1698.0, 1682.2, 1620.6, 1647.8, 753.5 cm-1. HRMS (ESI):
Calculated for C16H12ClNNaO3 ([M + Na]+): 324.0398, found:
324.0393.
3-Hydroxy-3-(2-oxo-2-(3-chlorophenyl)ethyl)indolin-2-one (3c).
White solid, mp 197.8–198.9 ◦C; 1H NMR (300 MHz,
(CD3)2SO) d 10.26 (brs, 1H), 7.88 (d, J = 8.7 Hz, 2H), 7.55
(d, J = 8.7 Hz, 2H), 7.26 (d, J = 7.2 Hz, 1H), 7.14 (d,
J = 7.8 Hz, 1H), 6.87–6.78 (m, 2H), 6.07 (brs, 1H), 4.03 (d,
3-Hydroxy-3-(2-oxo-2-(4-nitrophenyl)ethyl)indolin-2-one (3e).
White solid, mp 190.2–190.3 ◦C; 1H NMR (300 MHz,
(CD3)2SO) d 10.32 (brs, 1H), 8.28–8.12 (m, 4H), 7.29–6.84 (m,
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4H), 6.15 (brs, 1H), 4.10 (d, J = 15.3, 1H), 3.64 (d, J = 15.3, 1H);
13C NMR (75 MHz, (CD3)2SO) d 46.3, 73.1, 109.5, 121.2, 123.8,
129.1, 129.4, 131.4, 140.7, 142.8, 149.9, 178.1, 195.9; IR (KBr)
3379.0, 3189.3, 3065.3, 2895.0, 1730.6, 1695.9, 1625.9, 1343.0,
1205.9, 746.4 cm-1. HRMS (ESI): Calculated for C16H12N2NaO5
([M + Na]+): 335.0638, found: 335.0639.
123.6, 128.0, 128.9, 129.2, 131.8, 133.8, 142.9, 143.8, 178.4,
195.9; IR (KBr) 3372.2, 3205.0, 3055.7, 2896.6, 1721.8, 1700.7,
1675.2, 1619.8, 1176.8, 754.9 cm-1. HRMS (ESI): Calculated for
C17H15NNaO3 ([M + Na]+): 304.0944, found: 304.0951.
3-Hydroxy-3-(2-oxo-2-(4-methoxy◦phenyl)ethyl)indolin-2-one
1
(3k). White solid, mp 181.2–183.7 C; H NMR (300 MHz,
3-Hydroxy-3-(2-oxo-2-(4-fluorophenyl)ethyl)indolin-2-one (3f).
White solid, mp 198.9–199.3 ◦C; 1H NMR (300 MHz,
(CD3)2SO) d 10.26 (brs, 1H), 7.97 (dd, J = 5.4, 8.7 Hz, 2H),
7.33–7.26 (m, 4H), 6.84 (dd, J = 7.8, 8.4 Hz, 2H), 6.06 (brs,
1H), 4.04 (d, J = 17.7 Hz, 1H), 3.56 (d, J = 17.7 Hz, 1H);
13C NMR (75 MHz, (CD3)2SO) d 45.7, 73.0, 109.4, 115.8,
121.1, 123.6, 128.9, 130.9, 133.0, 142.9, 163.4, 166.8, 178.3,
195.1; IR (KBr) 3379.3, 3196.1, 3059.6, 2898.5, 1699.9, 1679.1,
1619.1, 1468.6, 1229.5, 755.0 cm-1. HRMS (ESI): Calculated for
C16H12FNNaO3 ([M + Na]+): 308.0693, found: 308.0701.
(CD3)2SO) d 10.25 (brs, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.25 (d,
J = 7.2 Hz, 1H), 7.18–7.12 (m, 1H), 7.00 (d, J = 8.7 Hz, 2H),
6.87–6.79 (m, 2H), 6.03 (brs, 1H), 4.01 (d, J = 17.4 Hz, 1H),
3.81 (s, 3H), 3.53 (d, J = 17.4 Hz, 1H); 13C NMR (75 MHz,
(CD3)2SO) d 45.4, 55.5, 73.1, 109.4, 113.8, 121.1, 123.6, 128.9,
129.2, 130.3, 131.9, 142.9, 163.3, 178.4, 194.8; IR (KBr) 3381.4,
3194.4, 3053.9, 2901.4, 1722.1, 1697.4, 1668.4, 1600.5, 1468.9,
1256.6, 1166.8, 990.9, 579.9 cm-1. HRMS (ESI): Calculated for
C17H15NNaO4 ([M + Na]+): 320.0893, found: 320.0897.
3-Hydroxy-3-(2-oxo-2-(thiophen-2-yl)ethyl)indolin-2-one (3l).
White solid, mp 180.8–181.5 ◦C; 1H NMR (300 MHz,
(CD3)2SO) d 10.27 (brs, 1H), 7.97 (d, J = 12.0 Hz, 2H), 7.29–
7.15 (m, 3H), 6.82 (dd, J = 7.2, 16.2 Hz, 2H), 6.12 (brs, 1H),
3.96 (d, J = 16.2 Hz, 1H), 3.48 (d, J = 16.2 Hz, 1H); 13C NMR
(75 MHz, (CD3)2SO) d 45.9, 73.0, 109.5, 121.2, 123.8, 128.8,
129.0, 131.4, 133.9, 135.2, 142.8, 143.5, 178.2, 189.3, IR (KBr)
3374.5, 3302.2, 3055.7, 2900.5, 1701.5, 1653.8, 1617.0, 1413.0,
1225.9, 725.1 cm-1. HRMS (ESI): Calculated for C14H11NNaO3S
([M + Na]+): 296.0352, found: 296.0362.
3-Hydroxy-3-(2-oxo-2-(3-bromoro◦phenyl)ethyl)indolin-2-one
1
(3g). White solid, mp 191.8–192.8 C; H NMR (300 MHz,
(CD3)2SO) d 10.29 (brs, 1H), 7.99 (s, 1H), 7.89 (d, J = 5.7 Hz,
1H), 7.90 (d, J = 6.3 Hz, 1H), 7.45–7.44 (m, 1H), 7.28 (d,
J = 5.4 Hz, 1H), 7.18–7.17 (m, 1H), 6.86–6.83 (m, 2H), 6.09
(brs, 1H), 4.08 (d, J = 17.2 Hz, 1H), 3.57 (d, J = 17.2 Hz,
1H); 13C NMR (75 MHz, (CD3)2SO) d 45.9, 73.0, 109.4, 121.2,
122.1, 123.8, 127.0, 129.0, 130.5, 130.9,131.5, 135.9, 138.2, 142.8,
178.2, 195.5; IR (KBr) 3395.6, 3342.3, 3281.5, 3061.2, 2901.1,
1726.0, 1680.0, 1620.7, 1471.5, 1206.9, 777.9 cm-1. HRMS (ESI):
Calculated for C16H12BrNNaO3 ([M + Na]+): 367.9893, found:
367.9884.
3-(2-(Furan-2-yl)-2-oxoethyl)-3-hydroxyindolin-2-one (3m).
White solid, mp 195.7–196.2 ◦C; 1H NMR (300 MHz,
(CD3)2SO) d 10.26 (brs, 1H), 7.92 (s, 1H), 7.46 (d, J = 3.6 Hz,
1H), 7.26 (d, J = 7.2 Hz, 1H), 7.13 (dd, J = 6.6, 7.5 Hz, 1H),
6.86–6.67 (m, 2H), 6.66 (d, J = 1.5 Hz, 1H), 6.11 (brs, 1H),
3.78 (d, J = 16.2 Hz, 1H), 3.30 (d, J = 16.2 Hz, 1H); 13C
NMR (75 MHz, (CD3)2SO) d 45.2, 73.0, 109.4, 112.5, 119.1,
121.2, 123.9, 129.0, 131.1, 142.6, 147.9, 151.6, 178.0, 184.3; IR
(KBr) 3342.7, 3297.2, 3096.2, 2917.8, 1723.4, 1657.1, 1617.8,
1461.9, 760.6 cm-1. HRMS (ESI): Calculated for C14H11NNaO4
([M + Na]+): 280.0580, found: 280.0579.
3-Hydroxy-3-(2-oxo-2-(4-bromophenyl)ethyl)indolin-2-one
◦
1
(3h). White solid, mp 194.1–194.7 C; H NMR (300 MHz,
(CD3)2SO) d 10.28 (brs, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.69 (d,
J = 8.1 Hz, 2H), 7.27 (d, J = 6.9 Hz, 1H), 7.15 (d, J = 7.5, 1H),
6.88–6. 80 (m, 2H), 6.09 (brs, 1H), 4.05 (d, J = 17.4 Hz, 1H),
3.55 (d, J = 17.4, 1H); 13C NMR (75 MHz, (CD3)2SO) d 45.7,
73.0, 109.4, 121.2, 123.7, 127.6, 128.9, 129.9, 131.6, 131.8, 135.2,
142.9, 178.2, 195.8; IR (KBr) 3369.2, 3198.7, 3059.8, 2899.6,
1703.6, 1687.4, 1621.8, 1467.6, 1208.4, 987.8, 749.0 cm-1. HRMS
(ESI): Calculated for C16H12BrNNaO3 ([M + Na]+): 367.9893,
found: 367.9884.
3-Hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one (3n).
White solid, mp 154.1–155.3 ◦C; 1H NMR (300 MHz,
(CD3)2SO) d 10.29 (brs, 1H), 8.74–7.92 (m, 1H), 7.94–7.91 (m,
1H), 7.74 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.22 (d,
J = 7.2 Hz, 1H), 7.15–7.14 (m, 1H), 6.85–6.80 (m, 2H), 6.13 (brs,
3-Hydroxy-3-(2-oxo-2-(2-hydroxyphenyl)ethyl)indolin-2-one
◦
1
(3i). White solid, mp 197.2–197.8 C; H NMR (300 MHz,
(CD3)2SO) d 11.34 (brs, 1H), 10.29 (brs, 1H), 7.81–7.79 (m, 1H),
7.47–7.45 (m, 1H), 7.27 (d, J = 7.2 Hz, 2H), 7.19–7.15 (m, 1H),
6.93–6.81 (m, 4H), 6.10 (brs, 1H), 4.10 (d, J = 17.7 Hz, 1H),
3.66 (d, J = 17.7 Hz, 1H); 13C NMR (75 MHz, (CD3)2SO) d
47.3, 72.9, 109.5, 117.6, 119.2, 120.8, 121.2, 123.6, 129.0, 130.7,
131.6, 136.0, 142.8, 160.1, 178.3, 201.4; IR (KBr) 3370.7, 3262.6,
3041.6, 2906.3, 1711.7, 1636.9, 1615.8, 1466.4, 1278.0, 1063.0,
751.2, 582.7 cm1. HRMS (ESI): Calculated for C16H13NNaO4
([M + Na]+): 306.0737, found: 306.0747.
1H), 4.28 (d, J = 17.7 Hz, 1H), 3.65 (d, J = 17.7 Hz, 1H); 13
C
NMR (75 MHz, (CD3)2SO) d 44.9, 73.0, 109.4, 121.1, 121.2,
123.6, 127.9, 128.9, 131.6, 137.6, 142.9, 149.2, 152.2, 178.3,
197.7; IR (KBr) 3441.3, 3303.8, 3263.6, 3083.9, 1715.9, 1697.1,
1618.0, 1470.3, 996.0, 768.8 cm-1. HRMS (ESI): Calculated for
C15H12N2NaO3 ([M + Na]+): 291.0740, found: 291.0738.
3-Hydroxy-3-(2-(naphthalen-1-yl)◦-2-oxoethyl)indolin-2-one
1
(3o). White solid, mp 170.5–172.3 C; H NMR (300 MHz,
(CD3)2SO) d 10.32 (brs, 1H), 8.09 (d, J = 7.5 Hz, 2H), 8.02 (d,
J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 7.6 Hz,
1H), 7.52–7.46 (m, 2H), 7.34 (d, J = 7.2 Hz, 1H), 7.17 (d, J =
1.2 Hz, 1H), 6.86–6.80 (m, 2H), 6.14 (brs, 1H), 4.07 (d, J =
16.8 Hz, 1H), 3.73 (d, J = 16.8 Hz, 1H); 13C NMR (75 MHz,
(CD3)2SO) d 49.1, 73.4, 109.5, 121.2, 123.8, 124.7, 124.9, 126.3,.
127.5, 128.1, 128.3, 128.9, 129.1, 131.5, 132.5, 133.3, 135.1,
3-Hydroxy-3-(2-oxo-2-p-tolylethyl)indolin-2-one (3j). White
◦
1
solid, mp 191.5–192.3 C; H NMR (300 MHz, (CD3)2SO) d
10.25 (brs, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.30–7.13 (m, 3H),
7.15 (m, 1H), 6.83 (dd, J = 7.2, 16.2 Hz, 2H), 6.04 (brs, 1H), 4.03
(d, J = 17.5 Hz, 1H), 3.54 (d, J = 17.5 Hz, 1H), 2.35 (s, 3H); 13
C
NMR (75 MHz, (CD3)2SO) d 21.1, 45.6, 73.0, 109.4, 121.1,
1472 | Green Chem., 2009, 11, 1465–1476
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142.8, 178.2, 200.7; IR (KBr) 3378.6, 3212.9, 3058.1, 2881.8,
1697.6, 1671.8, 1471.8, 777.2 cm-1. HRMS (ESI): Calculated for
C20H15NNaO3 ([M + Na]+): 340.0944, found: 340.0961.
1-Methyl-3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one (3u).
White solid, mp 176.5–178.0 ◦C; 1H NMR (300 MHz,
(CD3)2SO) d 7.88 (d, J = 7.2 Hz, 2H), 7.86–7.61 (m, 1H), 7.51–
7.46 (m, 2H), 7.35–7.33 (m, 1H), 7.27–7.24 (m, 1H), 6.99–6.94
(m, 2H), 6.16 (brs, 1H), 4.15 (d, J = 17.7 Hz, 1H), 3.66 (d, J =
17.7 Hz, 1H), 3.15 (s, 3H); 13C NMR (75 MHz, (CD3)2SO) d 25.9,
46.1, 72.7, 108.2, 121.8, 123.2, 127.9, 128.7, 129.1, 131.1, 133.5,
136.0, 144.4, 176.7, 196.5; IR (KBr) 338434, 3308.3, 3059.5,
2936.0, 1710, 1615.8, 1469.0, 1352.7, 767.4 cm-1. HRMS (ESI):
Calculated for C17H15NNaO3 ([M + Na]+): 304.0944, found:
304.0949.
3-Hydroxy-3-(2-(6-methoxynaphthalen-1-yl)-2-oxoethyl)indo-
lin-2-one (3p). White solid, mp 205.6–207.3 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 10.27 (brs, 1H), 8.60 (s, 1H), 8.05 (d,
J = 9.0 Hz, 1H), 8.02–7.79 (m, 2H), 7.37 (d, J = 2.4 Hz, 1H),
7.30–7.23 (m, 2H), 7.15 (d, J = 1.1 Hz, 1H), 6.86–6.80 (m, 2H),
6.09 (brs, 1H), 4.18 (d, J = 17.4 Hz, 1H), 3.90 (s, 3H), 3.66 (d,
J = 17.4 Hz, 1H); 13C NMR (75 MHz, (CD3)2SO) d 45.5, 55.3,
73.1, 106.1, 109.3, 119.4, 120.9, 123.5, 123.8, 126.9, 127.3, 128.8,
131.0, 131.2, 131.5, 131.7, 136.9, 142.9, 159.4, 178.3, 195.9; IR
(KBr) 3380.7, 3349.7, 3057.6, 2957.4, 2894.7, 1721.1, 1673.2,
1620.1, 1482.8, 1175.4, 748.8 cm-1. HRMS (ESI): Calculated
for C21H17NNaO4 ([M + Na]+): 370.1050, found: 370.1037.
1-Methyl-3-hydroxy-3-(2-oxo-2-(4-methoxyphenyl)ethyl)-
indolin-2-one (3v). White solid, mp 192.3–193.8 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 7.85 (d, J = 7.5 Hz, 2H), 7.33–7.26 (m,
2H), 7.00–6.98 (m, 4H), 6.11 (brs, 1H), 4.08 (d, J = 17.7 Hz,
1H), 3.81 (s, 3H), 3.57 (d, J = 17.7 Hz, 1H), 3.15 (s, 3H); 13C
NMR (75 MHz, (CD3)2SO) d 25.9, 45.7, 55.5, 72.7, 108.2, 113.8,
121.8, 123.1, 129.0, 130.3, 131.2, 144.4, 163.3, 176.8, 194.7; IR
(KBr) 3362.3, 3089.5, 2952.5, 1689.8, 1672.0, 1599.4, 1265.2,
1169.2, 756.5 cm-1. HRMS (ESI): Calculated for C18H17NNaO4
([M + Na]+): 334.1050, found: 334.1060.
5-Bromo-3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one (3q).
White solid, mp 213.8–216.8 ◦C; 1H NMR (300 MHz,
(CD3)2SO) d 10.42 (brs, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.87–
7.61 (m, 1H), 7.53–7.48 (m, 3H), 7.34 (dd, J = 6.3, 8.1 Hz, 1H),
6.78 (d, J = 8.1 Hz, 1H), 6.20 (brs, 1H), 4.16 (d, J = 17.8 Hz, 1H),
3.63 (d, J = 17.8 Hz, 1H); 13C NMR (75 MHz, (CD3)2SO) d 45.7,
73.0, 111.4, 112.9, 126.7, 127.9, 128.7, 131.5, 133.5, 134.4, 135.9,
142.3, 177.9, 196.6; IR (KBr) 3219.5, 2892.9, 1698.2, 1618.7,
1218.6, 827.0 cm-1. HRMS (ESI): C16H12BrNNaO3 ([M + Na]+):
367.9893, found: 367.9889.
1-Methyl-3-hydroxy-3-(2-oxo-2-(4-bromophenyl)ethyl)-
indolin-2-one (3w). White solid, mp 165.0–166.2 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 7.80 (d, J = 8.4 Hz, 2H), 7.67 (d,
J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.29–7.27 (m, 1H),
6.99–6.93 (m, 2H), 6.20 (brs, 1H), 4.13 (d, J = 17.4 Hz, 1H),
3.65 (d, J = 17.4 Hz, 1H), 3.16 (s, 3H); 13C NMR (75 MHz,
(CD3)2SO) d 25.99, 46.0, 72.7, 108.3, 121.9, 123.3, 127.7, 129.2,
129.9, 130.9, 131.8, 135.0, 144.3, 176.6, 195.8; IR (KBr) 3340.8,
3060.7, 2930.5, 2902.4, 1687.5, 1617.6, 1588.8, 1470.9, 1071.0,
753.4 cm-1. HRMS (ESI): Calculated for C17H14BrNNaO3
([M + Na]+): 382.0049, found: 382.0073.
4,6-Dibromo-3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one
◦
1
(3r). White solid, mp 187.0–188.2 C; H NMR (300 MHz,
(CD3)2SO) d 10.73 (brs, 1H), 7.91 (d, J = 7.5 Hz, 2H), 7.63–
7.47 (m, 3H), 7.23 (s, 1H), 7.01 (s, 1H), 6.39 (brs, 1H), 4.46
(d, J = 18.3 Hz, 1H), 3.69 (d, J = 18.3 Hz, 1H);13C NMR
(75 MHz, (CD3)2SO) d 44.2, 74.3, 111.9, 118.9, 122.4, 126.7,
127.8, 128.91, 128.97, 133.8, 135.5, 146.7, 177.4, 196.5; IR
(KBr) 3369.1, 3305.2, 3083.0, 3033.5, 1712.1, 1686.7, 1676.7,
1611.0, 1349.3, 1218.2, 689.6 cm-1. HRMS (ESI): Calculated for
C16H11Br2NNaO3 ([M + Na]+): 445.9003, found: 445.9027.
1-Benzyl-3-hydroxy-3-(2-oxo-2-(4-bromophenyl)ethyl)indolin-
2-one (3x). White solid, mp 189.9–191.4 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 7.93 (d, J = 6.9 Hz, 2H), 7.61 (d,
J = 6.6 Hz, 1H), 7.50–6.91 (m, 10H), 6.79 (d, J = 7.2 Hz, 1H),
6.37 (brs, 1H), 4.95 (s, 2H), 4.25 (d, J = 17.7 Hz, 1H), 3.78 (d,
J = 17.7 Hz, 1H); 13C NMR (75 MHz, (CD3)2SO) d 42.8, 46.0,
72.9, 108.9, 122.0, 123.4, 127.3, 128.0, 128.5, 128.8, 129.0, 131.2,
133.6, 136.0, 136.5, 143.5, 176.9, 196.6; IR (KBr) 3401.0, 3321.2,
3261.2, 3074.3, 3031.6, 2908.2, 1715.0, 1696.9, 1681.5, 1349.8,
1215.8, 767.0 cm-1. HRMS (ESI): Calculated for C23H19NNaO3
([M + Na]+): 380.1257, found: 380.1249.
5,7-Dibromo-3-hydroxy-3-(2-oxo-2-(4-bromophenyl)ethyl)-
indolin-2-one (3s). White solid, mp 142.7–145.8 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 10.81 (brs, 1H), 7.82 (d, J = 8.1 Hz, 2H),
7.72 (d, J = 8.1 Hz, 2H), 7.61 (s, 1H), 7.55 (s, 1H), 6.41 (brs, 1H),
4.20 (d, J = 18.3 Hz, 1H), 3.67 (d, J = 18.3 Hz, 1H); 13C NMR
(75 MHz, (CD3)2SO) d 45.9, 73.8, 102.6, 113.5, 125.9, 127.9,
130.1, 131.8, 133.5, 134.7, 135.6, 142.0, 177.8, 196.0; IR (KBr)
3241.5, 2956.4, 2904.3, 1736.1, 1682.8, 1616.5, 1584.9, 1460.3,
1215.8, 1161.6, 1071.3, 567.6 cm-1. HRMS (ESI): Calculated for
C16H10Br3NNaO3 [M + Na]+): 523.8103, found: 523.8084.
1-Benzyl-3-hydroxy-3-(2-oxo-2-(4-methoxyphenyl)ethyl)-
indolin-2-one (3y). White solid, mp 161.0–162.9 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 7.91 (d, J = 8.4 Hz, 2H), 7.49 (d, J =
7.5 Hz, 2H), 7.38–7.33 (m, 3H), 7.29 (d, J = 7.5 Hz, 1H), 7.18–
7.13 (m, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.94–6.89 (m, 1H), 6.76
(d, J = 7.8 Hz, 1H), 6.31 (brs, 1H), 4.93 (s, 2H), 4.16 (d, J =
17.4 Hz, 1H), 3.81 (s, 3H), 3.70 (d, J = 17.4 Hz, 1H); 13C NMR
(75 MHz, (CD3)2SO) d 42.8, 45.7, 55.6, 72.9, 108.9, 113.9, 121.9,
123.4, 127.3, 128.5, 128.9, 129.1, 130.4, 131.3, 136.5, 143.5,
163.4, 177.0, 194.8; IR (KBr) 3042.3, 3084.9, 3029.8, 2927.1,
1694.5, 1673.9, 1602.3, 1245.8, 1172.0, 772.5 cm-1. HRMS (ESI):
Calculated for C24H21NNaO4 ([M + Na]+): 410.1363, found:
410.1365.
6,7-Dimethyl-3-hydroxy-3-(2-oxo-2-(4-bromophenyl)ethyl)-
◦
1
indolin-2-one (3t). White solid, mp 179.8–181.2 C H NMR
(300 MHz, (CD3)2SO) d 10.27 (brs, 1H), 7.82 (d, J = 7.8 Hz,
2H), 7.68 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 7.2 Hz, 1H), 6.67
(d, J = 7.2 Hz, 1H), 5.80 (brs, 1H), 3.99 (d, J = 17.4 Hz,
1H), 3.54 (d, J = 17.4 Hz, 1H), 2.16 (s, 3H), 2.13 (s, 3H);
13C NMR (75 MHz, (CD3)2SO) d 13.1, 19.7, 45.8, 73.4, 117.4,
120.7, 122. 4, 127.6, 129.0, 130.0, 131.8, 135.3, 137.4, 141.5,
179.0, 195.8; IR (KBr) 3262.4, 2985.3, 2919.7, 1715.6, 1697.0,
1681.9, 1585.1, 1399.0, 1211.4 cm-1. HRMS (ESI): Calculated
for C18H16BrNNaO3 ([M + Na]+): 396.0206, found: 396.0226.
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1-Benzyl-3-hydroxy-3-(2-oxo-2-(4-bromophenyl)ethyl)indolin-
2-one (3z). White solid, mp 184.5–184.9 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 7.84 (d, J = 8.1 Hz, 2H), 7.70 (d,
J = 8.1 Hz, 2H), 7.47 (d, J = 7.2 Hz, 2H), 7.35–7.25 (m, 4H),
7.19–7.13 (m, 1H), 6.95–6.90 (m, 1H), 6.77 (d, J = 7.5 Hz,
1H), 6.35 (brs, 1H), 4.92 (s, 2H), 4.19 (d, J = 17.4 Hz, 1H),
3.73 (d, J = 17.4 Hz, 1H); 13C NMR (75 MHz, (CD3)2SO)
d 42.8, 45.9, 72.8, 109.0, 122.0, 123.5, 127.3, 127.8, 128.5,.
129.1, 130.1, 131.0, 131.8, 135.0, 136.4, 143.4, 176.8, 195.8; IR
(KBr) 3326.7, 3085.4, 3060.4, 2924.8, 1704.3, 1686.9, 1614.6,
1467.6, 1654.5, 1347.3, 750.2 cm-1. HRMS (ESI): Calculated for
C23H18BrNNaO3 ([M + Na]+): 458.0362, found: 458.0374.
(ESI): Calculated for C18H15NNaO3 ([M + Na]+): 316.0944,
found: 316.0955.
Minor isomer: white solid, mp 213.8–214.6 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 10.29 (brs, 1H), 7.63 (d, J = 7.2 Hz,
1H), 7.54–6.78 (m, 7H), 6.00 (brs, 1H), 3.37–3.31 (m, 1H), 3.10–
3.08 (m, 2H), 2.76–2.72 (m, 1H), 2.29–2.22 (m, 1H); 13C NMR
(75 MHz, (CD3)2SO) d 23.9, 28.8, 54.1, 74.4, 109.4, 121.2,
123.2, 126.3, 128.6, 128.9, 130.3, 131.8, 132.5, 133.6, 142.7,
144.4, 177.8, 197.6; IR (KBr) 3276.4, 3060.3, 3022.0, 2927.5,
1727.0, 1674.4, 1473.4, 750.4 cm-1. HRMS (ESI): Calculated for
C18H15NNaO3 ([M + Na]+): 316.0944, found: 316.0955.
3-Hydroxy-3-(2-oxopropyl)indolin-2-one (3d¢). White solid,
◦
1
3-Hydroxy-3-(1-oxo-1-phenylpropan-2-yl)indolin-2-one (3a¢).
Major isomer: white solid, mp 140.4–142.7 ◦C; 1H NMR
(300 MHz, (CD3)2SO,) d 10.31 (brs, 1H), 7.99–6.10 (m, 9H),
6.10 (brs, 1H), 4.29 (q, J = 6.9 Hz, 1H), 1.04 (d, J = 6.9 Hz, 3H);
13C NMR (75 MHz, (CD3)2SO) d 12.09, 46.2, 47.7, 76.0, 109.4,
121.2, 125.1, 128.5, 128.72, 129.2, 130.4, 133.2, 137.4, 142.5,
178.1, 201.5; IR (KBr) 3315.5, 3215.3, 3061.2, 2990.4, 2936.4,
1700.8, 1678.0, 1624.5, 1475.2, 1185.5, 754.3 cm1. HRMS (ESI):
Calculated for C17H15NNaO3 ([M + Na]+): 304.0944, found:
304.0964.
mp 171.9–172.8 C; H NMR (300 MHz, (CD3)2SO) d 10.23
(brs, 1H), 7.24 (d, J = 6.9 Hz, 1H), 7.20–7.15 (m, 1H), 6.93–6.77
(m, 2H), 6.00 (brs, 1H), 3.28 (d, J = 16.5 Hz, 1H), 3.03 (d, J =
16.5 Hz, 1H), 2.00 (s, 3H); 13C NMR (75 MHz, (CD3)2SO) d
30.6, 50.3, 72.7, 109.5, 121.3, 123.8, 129.1, 131.6, 142.6, 178.3,
205.3; IR (KBr) 3365.8, 3316.8, 3064.4, 2896.6, 1720.5, 1621.8,
1470.8, 1182.4, 1088.9, 760.8 cm-1. HRMS (ESI): Calculated for
C11H11NNaO3 ([M + Na]+): 228.0631, found: 228.0639.
3-Hydroxy-3-(2-oxobutyl)indolin-2-one (3e¢). White solid,
◦
1
Minor isomer: white solid, mp 140.4–142.7 ◦C; 1H NMR
(300 MHz, (CD3)2SO,) d 10.19 (brs, 1H), 7.99–6.10 (m, 9H),
6.09 (brs, 1H), 4.18 (q, J = 7.2 Hz, 1H), 1.40 (d, J = 7.2 Hz,
3H); 13C NMR (75 MHz, (CD3)2SO) d 12.5, 47.7, 75.8, 109.6,
121.2, 125.0, 128.3, 128.7, 129.2, 131.1, 136.3, 137.4, 142.6,
178.6, 200.8; IR (KBr) 3315.5, 3215.3, 3061.2, 2990.4, 2936.4,
1700.8, 1678.0, 1624.5, 1475.2, 1185.5, 754.3 cm-1. HRMS (ESI):
Calculated for C17H15NNaO3 ([M + Na]+): 304.0944, found:
304.0964.
mp 119.2–120.3 C; H NMR (300 MHz, (CD3)2SO) d 10.19
(brs, 1H), 7.24–7.14 (m, 2H), 6.90 (dd, J = 7.5, 0.6 Hz, 1H),
6.77 (d, J = 7.5 Hz, 1H), 5.95 (brs, 1H), 3.25 (d, J = 16.5 Hz,
1H), 2.97 (d, J = 16.5 Hz, 1H), 2.39–2.33 (m, 2H), 0.76 (t, J =
7.2 Hz, 3H); 13C NMR (75 MHz, (CD3)2SO) d 7.3, 35.7, 49.1,
72.7, 109.4, 121.2, 123.7, 128.9, 131.5, 142.5, 178.2, 207.4; IR
(KBr) 3349.2, 2979.6, 2941.8, 1723.8, 1622.3, 1473.5, 1181.2,
776.5, 641.0 cm-1. HRMS (ESI): Calculated for C12H12NNaO3
([M + Na]+): 242.0788, found: 242.0798.
3-Hydroxy-3-(3-oxopentan-2-yl)indolin-2-one (3f¢). Major
isomer: white solid, mp 95.7–99.6 ◦C; 1H NMR (300 MHz,
(CD3)2SO) d 10.31 (brs, 1H), 7.26–7.10 (m, 2H), 6.95–6.90 (m,
1H), 6.77 (d, J = 7.5 Hz, 1H), 6.17 (brs, 1H), 3.22 (q, J = 7.2 Hz,
1H), 2.77–2.50 (m, 2H), 0.89 (d, J = 7.2 Hz, 3H), 0.90–0.71
(m, 3H); 13C NMR (75 MHz, (CD3)2SO) d 7.6, 10.9, 37.6, 50.0,
76.5, 109.5, 121.4, 125.3, 129.2, 129.4, 142.3, 177.9, 211.9; IR
(KBr) 3291.1, 2978.1, 2938.5, 1978.1, 2938.5, 1713.3, 1621.6,
1472.0, 755.9 cm-1. HRMS (ESI): Calculated for C13H15NNaO3
([M + Na]+): 256.0944, found: 256.0949.
3-Hydroxy-3-(1-oxo-2,3-dihydro-1H-inden-2-yl)◦indolin-2-one
(3b¢). Major isomer: white solid, mp 183.1–185.2 C; 1H NMR
(300 MHz, (CD3)2SO) d 10.38 (brs, 1H), 7.64–6.29 (m, 8H), 6.29
(brs, 1H), 3.63–3.09 (m, 3H); 13C NMR (75 MHz, (CD3)2SO)
d 28.3, 53.1, 75.3, 109.5, 121.6, 122.9, 124.1, 126.6, 127.2,
129.2, 130.4, 134.8, 136.4, 142.5, 153.9, 177.9, 203.5; IR (KBr)
3272.7, 3058.6, 2910.1, 1734.9, 1699.9, 1621.8, 1472.8, 1287.5,
1204.7, 755.0 cm-1. HRMS (ESI): Calculated for C17H13NNaO3
([M + Na]+): 302.0788, found: 302.0788.
Minor isomer: white solid, mp 183.1–185.2 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 10.31 (brs, 1H), 7.64–6.29 (m, 8H), 6.23
(brs, 1H), 3.63–3.09 (m, 3H); 13C NMR (75 MHz, (CD3)2SO)
d 28.4, 52.4, 75.2, 109.6, 121.1, 122.8, 124.0, 126.7, 127.2,
129.1,130.4, 134.8, 136.8, 142.1, 153.3, 177.2, 203.7; IR (KBr)
3272.7, 3058.6, 2910.1, 1734.9, 1699.9, 1621.8, 1472.8, 1287.5,
1204.7, 755.0 cm-1. HRMS (ESI): Calculated for C17H13NNaO3
([M + Na]+): 302.0788, found: 302.0788.
Minor isomer: white solid, mp 95.7–99.6 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 10.23 (brs, 1H), 7.26–7.10 (m, 2H),
6.95–6.90 (m, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.17 (brs, 1H), 3.21
(q, J = 7.2 Hz, 1H), 2.77–2.50 (m, 2H), 1.16 (d, J = 7.2 Hz,
3H), 0.90–0.71 (m, 3H); 13C NMR (75 MHz, (CD3)2SO) d 7.6,
10.7, 34.6, 52.4, 75.7, 109.6, 121.3, 124.6, 128.9, 130.9, 142.3,
178.4, 210.6; IR (KBr) 3291.1, 2978.1, 2938.5, 1978.1, 2938.5,
1713.3, 1621.6, 1472.0, 755.9 cm-1. HRMS (ESI): Calculated for
C13H15NNaO3 ([M + Na]+): 256.0944, found: 256.0949.
3-Hydroxy-3-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)indolin-
2-one (3c¢). Major isomer: white solid, mp 213.8–214.6 ◦C;
1H NMR (300 MHz, (CD3)2SO) d 10.29 (brs, 1H), 7.63 (d,
J = 7.2 Hz, 1H), 7.54–6.78 (m, 7H), 6.08 (brs, 1H), 3.37–3.31
(m, 1H), 3.10–3.08 (m, 2H), 2.76–2.72 (m, 1H), 2.29–2.22 (m,
1H); 13C NMR (75 MHz, (CD3)2SO) d 23.4, 29.1, 54.9, 74.4,
109.5, 120.9, 124.5, 126.6, 128.6, 129.0, 130.3, 131.8, 132.2,
133.7, 143.7, 144.5, 178.8, 196.3; IR (KBr) 3276.4, 3060.3,
3022.0, 2927.5, 1727.0, 1674.4, 1473.4, 750.4 cm-1. HRMS
3-Hydroxy-3-(2-oxocyclopentyl)indolin-2-one (3g¢). Major
◦
1
isomer: white solid, mp 138.2–140.0 C; H NMR (300 MHz,
(CD3)2SO) d 10.28 (brs, 1H), 7.33 (d, J = 7.2 Hz, 2H), 7.17–6.84
(m, 1H), 6.77–6.72 (m, 1H), 5.97 (brs, 1H), 2.85 (t, J = 10.2 Hz,
1H), 2.22–1.74 (m, 6H); 13C NMR (75 MHz, (CD3)2SO) d 20.2,
24.7, 40.3, 54.9, 75.1, 109.6, 121.3, 124.7, 129.3, 131.0, 142.9,
178.4, 216.5; IR (KBr) 3380.3, 2949.0, 2980.2, 2883.6, 1733.4,
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1709.0, 1621.0, 1470.7, 770.2 cm-1. HRMS (ESI): Calculated for
C13H13NNaO3 ([M + Na]+): 254.0788, found: 254.0774.
Minor isomer: white solid, mp 138.2–140.0 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 10.28 (brs, 1H), 7.33 (d, J = 7.2 Hz,
2H), 7.17–6.84 (m, 1H), 6.77–6.72 (m, 1H), 5.92 (brs, 1H), 2.85
(t, J = 10.2 Hz, 1H), 2.22–1.74 (m, 6H); 13C-NMR (75 MHz,
(CD3)2SO) d 19.7, 25.1, 40.3, 53.8, 75.1, 109.6, 121.8, 124.3,
129.2, 130.0, 142.4, 177.8, 216.8; IR (KBr) 3380.3, 2949.0,
2980.2, 2883.6, 1733.4, 1709.0, 1621.0, 1470.7, 770.2 cm-1.
HRMS (ESI): C13H13NNaO3 ([M + Na]+): 254.0788, found:
254.0774.
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3-Hydroxy-3-(2-oxocyclohexyl)indolin-2-one (3h¢). Major
◦
1
isomer: white solid, mp 175.0–177.0 C; H NMR (300 MHz,
(CD3)2SO) d 10.18 (brs, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.17–7.11
(m, 1H), 6.87–6.76 (m, 1H), (d, J = 7.5 Hz, 1H), 5.80 (brs, 1H),
3.23 (dd, J = 5.1 Hz, 7.8 Hz, 1H), 2.56–2.48 (m, 1H), 2.32–2.30
(m, 1H), 2.08–1.48 (m, 6H); 13C NMR (75 MHz, (CD3)2SO)
d 24.5, 26.8, 27.8, 41.6, 57.5, 73.9, 109.5, 120.9, 124.9, 128.7,
130.9, 143.5, 178.8, 209.2, IR (KBr) 3334.7, 3235.6, 3059.6,
2937.7, 1718.3, 1702.6, 1618.2, 1470.3, 1175.4, 745.8 cm-1.
HRMS (ESI): Calculated for C14H15NNaO3 ([M + Na]+):
268.0944, found: 268.0951.
Minor isomer: white solid, mp 175.0–177.0 ◦C; 1H NMR
(300 MHz, (CD3)2SO) d 10.13 (brs, 1H), 7.22–7.14 (m, 2H),
6.88–6.77 (m, 2H), 5.72 (brs, 1H), 3.24 (dd, J = 5.1, 7.8 Hz,
1H), 2.37–2.26 (m, 2H), 2.08–2.01 (m, 2H), 1.83–1.47 (m,
4H); 13C NMR (75 MHz, (CD3)2SO) d 24.7, 26.8, 27.8, 27.82,
42.3, 57.5, 73.7, 109.2, 121.1, 123.8, 128.7, 130.9, 143.5, 178.1,
209.9; IR (KBr) 3334.7, 3235.6, 3059.6, 2937.7, 1718.3, 1702.6,
1618.2, 1470.3, 1175.4, 745.8 cm-1. HRMS (ESI): Calculated for
C14H15NNaO3 ([M + Na]+): 268.0944, found: 268.0951.
4 For selected examples, see: (a) G. Luppi, M. Monari, R. J. Correˆa,
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Chem. Soc., 1933, 55, 325; (b) E. M. Beccalli, A. Marchesini and T.
Pilati, J. Chem. Soc., Perkin Trans. 1, 1994, 579; (c) S. J. Garden,
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4,6-Dibromo-3-hydroxy-3-(2-oxopropyl)indolin-2-one
(3i¢).
White solid, mp 211.3–212.5 ◦C; 1H NMR (300 MHz,
(CD3)2SO) d 10.64 (brs, 1H), 7.28 (s, 1H), 6.94 (s, 1H), 6.24 (brs,
1H), 3.73 (d, J = 17.7 Hz, 1H), 3.15 (d, J = 17.7 Hz, 1H), 2.02
(s, 3H); 13C NMR (75 MHz, (CD3)2SO) d 30.1, 48.4, 73.8, 111.9,
119.0, 122.5, 126.8, 128.8, 146.5, 177.4, 205.4; IR (KBr) 3392.6,
3169.2, 3032.0, 2903.3, 1716.4, 1609.7, 1434.9, 1362.0, 1327.2,
684.4 cm-1. HRMS (ESI): Calculated for C11H9Br2NNaO3
([M + Na]+): 383.8841 found: 383.8847.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (NO. 20802074).
6 (a) J. F. M. da Silva, S. J. Garden and A. C. Pinto, J. Braz. Chem.
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Notes and References
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9 The solvents investigated in this work were all carefully dried in
advance. DMF used in this work must be sufficiently refluxed in
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calcium hydride for 5 h and distilled from calcium hydride before
use.
10 The powdered molecular sieves 4 A were activated by placing
the powder under vacuum and heating with the flame of spirit
lamp.
11 In this case, the reaction took place preferentially at the C1 position
of butan-2-one 1v and gave 3e¢ as the major regioisomer while the
other regioisomeric product of C3 addition to isatin could hardly be
determined by 1H NMR.
12 Y. Kamano, H. P. Zhang, Y. Ichihara, H. Kizu, K. Komiyama and
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˚
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©