Synthesis of 2-Oxindoles from Substituted Indoles by Hypervalent-Iodine Oxidation

Article abstract of DOI:10.1002/ejoc.201701807

A practical conversion of indoles into the corresponding 2-oxindoles is achieved efficiently using a hypervalent iodine reagent. This oxidation is amenable to different substituted indoles, and allows the synthesis of a wide range of synthetically valuable substituted 2-oxindoles in up to 90 % yield. Furthermore, Ropinirole, a drug used to alleviate the symptoms of Parkinson's disease, was synthesized in three steps in an overall yield of 44 % using this method.

Full text of DOI:10.1002/ejoc.201701807

A Journal of
Accepted Article
Title: Synthesis of 2-oxindoles from substituted indoles by hypervalent
iodine oxidation
Authors: Xinpeng Jiang, Cong Zheng, Lijun Lei, Kai Lin, and
Chuanming Yu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701807
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10.1002/ejoc.201701807
European Journal of Organic Chemistry
Full Paper
Synthesis of 2-oxindoles from substituted indoles by hypervalent
iodine oxidation
Xinpeng Jiang,[a] Cong Zheng,[a] Lijun Lei,[a] Kai Lin,[a] and Chuanming Yu*[a,b]
to be controlled under a low level and within a narrow range.
Thus syringe pump technology assisted [10], visible light-driven[11]
or gas diffusion electrode (GDE)[12] controlled in situ generation
system of hydrogen peroxide has to be applied to maintain
desirable enzyme activity (Scheme 2-c); 4) synthetic
metalloporphyrin complex like meso-tetraphenylporphyriniron(III)
Abstract: A practical conversion of indoles into corresponding 2-
oxindoles achieved efficiently with hypervalent iodine. This oxidation
is amenable to different substituted indoles and allowing the
synthesis of a wide range of synthetically valuable substituted 2-
oxindoles in up to 90% yields. Furthermore, Ropinirole, a drug used
to alleviate the symptoms of Parkinson’s disease, was synthesized
in three steps with 44% combined yield by using this method.
chloride (TPP)
catalyzed
oxidation
of
indole with
peroxomonosulphate or sodium perborate in aqueous
acetonitrile/acetic acid medium[13] (Scheme 2-d); 5) oxidation of
indoles to 2-oxindoles in the presence of potentially dangerous
-
[14]
peroxides, such as HSO5
and m-chloroperbenzoic acid (m-
CPBA)[15] (Scheme 2-e); 6) oxidation with pyridinium bromide
perbromide (PBPB) in acetic acid, followed by reductive
dehalogenation (Scheme 2-f)[16]
.
Nonetheless, above-mentioned oxidative methods still suffer
from some limitations. For instance, these methods are often
hampered by restricted substrate scopes, especially requiring 3-
or 5- substituted indoles to prevent undesired substitution, other
drawbacks including involvement of tedious technique,
expensive or even dangerous reagents. Therefore, it is still of
quite interest to develop a versatile and efficient methodology for
the preparation of 2-oxindoles directly from indoles with wide
substrate scope.
Introduction
Oxindole framework is a privileged heterocyclic motif of a
large family of bioactive alkaloids and
a
series of
pharmaceutically active compounds[1]
， which act as anti-
inflammatory agents[2], kinase inhibitor[3], receptor antagonists[4],
and protease inhibitors[5] (Scheme 1).
Scheme 2. Different protocols for the oxidation of indoles to 2-
oxindoles.
Ten years ago, Togni’s research group reported
a
conceptually new family of electrophilic atom transfer reagents
based on a cyclic hypervalent iodine(III) core[17]. During the
preparation of the Togni reagent,1-chloro-1,2-benziodoxol-3-
(1H)-one L1 was usually used as a stable and promising
chlorine transfer reagent[18]. The cyclic structure confers to these
Scheme 1. Bioactive 2-oxindole derivatives
While many methods exist for the construction of oxindoles
from nonindole precursors[6], the development of a general and
efficient method for directly converting indoles into
corresponding 2-oxindoles is still a big challenge[7]. The most
notable methods that prepare 2-oxindoles directly from indoles
are as follows: 1) oxidation of 3-substituted indoles with DMSO
under strong acidic conditions, by which only limited functional
groups could be tolerated[8] (Scheme 2-a); 2) bromination of
indoles by using N-Bromosuccinimide (NBS), followed by
hydrolysis with hydrochloric acid at high temperature[9] (Scheme
2-b); 3) chloroperoxidase (CPO) catalyzed oxidation of indoles
with hydrogen peroxide, by which the concentration of H2O2 has
benziodoxole-derived reagents an exceptional stability[19]
.
Besides simple electron-transfer, the use of these hypervalent
iodine derivatives for oxidative reaction is also emerging as a
promising area. A large number of methodologies have been
developed in recent years using these hypervalent iodine
reagents in organofluorine chemistry and homogeneous
catalysis[20]. Herein, we proposed to use 1-halo-1,2-benziodoxol-
3-(1H)-one as efficient oxidants to conduct the oxidation of
various vulnerable bioactive alkaloids and reported an
application of these reagents in the oxidation of indoles to 2-
oxindoles.
Results and Discussion
[a] College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, P.R. China
We started the investigation by exploring the reaction of 1-
methylindole 1a with 1-chloro-1,2-benziodoxol-3-(1H)-one L1. To
our delight, when the reaction was conducted at 40 oC in
EA/H2O = 1/1, the desired product 1-methylindolin-2-one 2a was
obtained in 14% yield. The structure of 2a was confirmed by
[b] Collaborative Innovation Center of Yangtze River Delta Region Green
Pharmaceuticals, Zhejiang University of Technology, Hangzhou, P.R. China
* Corresponding author. Fax: (+86)571-88320867, E-mail: ycm@zjut.edu.cn
Supporting information for this article is given via a link at the end of the
document.
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10.1002/ejoc.201701807
European Journal of Organic Chemistry
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1HNMR and 13CNMR analysis. Inspired by this result, we started
to optimize the reaction conditions by screening a series of
solvent combinations, including acetone/H2O, MeCN/H2O,
THF/H2O, and 1,4-dioxane/H2O (Table 1, entries1–5). We
observed that 1,4-dioxane/H2O = 1/1 turned out to be superior,
providing 2a in 36% yield (Table 1, entry 5). Running the
reaction at higher temperature gave 2a in much better yield
(Table 1, entry 6). To increasing the solubility of L1 in reaction
system, the ratio of 1,4-dioxane/H2O was then changed from 1:1
to 1:10, the yield of 2a was raised up to 65% (Table 1, entries 6-
8). However, further improvement of the yield turned out to be
very difficult for the undesired chlorination of indole at 3-position.
We reasoned that it might be due to the strong nucleophilic
attack ability of chlorine in the reaction system. Therefore, we
started to optimize the reaction condition by replacing the
chloride in L1 to other anions. Among these oxidants, 1-fluoro-
1,2-benziodoxol-3-(1H)-one L3 shows relatively better result,
providing 2a in 41% yield (Table 1, entry 10), without any in
corporationly fluorine into the final products[21]. Other hypervalent
iodine reagents like 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one
L2, 2-Iodoxybenzoic acid L4 or Dess-Martin periodinane L5
afforded no desired product under the same reaction conditions
(Table 1, entries 9, 11, and 12). It’s envisioned that the yield of
the reaction with L3 could be further improved due to the large
amount of starting material recovery (Table 1, entry 10).
Subsequently, the reaction was conducted under reflux for 5 h,
and the yields were increased from 41% to 90% (Table 1,
entries10 and 13). Further examination showed that when the
loading of L3 was changed to 1.5 eq. and 0.8 eq. the yields of 2a
were decreased to 75% and 81% respectively (Table 1, entries
14 and 15). Finally, the optimized reaction conditions were
defined as follows: the mixture of 2a and 1.1 equivalents of L3
in1,4-dioxane/H2O = 1:5 was heated at reflux for 5 h.
due to the lower electron density in nitrogen atom and thus
poorer nucleophilic ability of indole to hypervalent iodine reagent.
Table 2. Substrate scope of reaction
Table 1. Optimization of reaction conditions
The effect of different substituents on the indole ring was
then examined. To our delight, after replacing L1 to L3 undesired
substitution on 3- or 5- position of indole ring had been mostly
avoided. Therefore, indoles possessing various substitutions
underwent oxidation more selective and in higher yields. A
methyl group on different positions of indole ring were found to
be tolerated, gave 2g-2i in 62-87% yields. Substrate with
electron-rich group provided the corresponding 2-oxindoles 2j in
74% yields. Substrates bearing strong electron-withdrawing
groups (NO2, CN) were also effective towards transformation
and provided oxidation products 2k and 2l in 68% and 89%
yields respectively. Brominated indole could also afford the
corresponding product 2m in good yield under the identical
Entry
L
Solvent
Temp Time Yield
(°C)
40
40
40
40
40
80
(h)
24
24
24
24
24
5
(%)b
14
1
2
3
4
5
6
7
8
9
10
11
12
13
14c
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L3
L3
EA/H2O (1:1)
acetone/H2O (1:1)
MeCN/H2O (1:1)
THF/H2O (1:1)
26
27
27
36
1,4-dioxane/H2O (1:1)
1,4-dioxane/H2O (1:1)
1,4-dioxane/H2O (1:5)
1,4-dioxane/H2O (1:10)
1,4-dioxane/H2O (1:5)
1,4-dioxane/H2O (1:5)
1,4-dioxane/H2O (1:5)
1,4-dioxane/H2O (1:5)
1,4-dioxane/H2O (1:5)
1,4-dioxane/H2O (1:5)
58
80
5
65
80
5
56
80
80
5
5
ND
41
reaction
conditions,
offering
possibilities
for
further
functionalization. In addition, the reactivity of N-free indoles with
either electron-donating 2n or withdrawing substituents 2o-2r
were applicable to provide corresponding products in 63-81%
yields. However, the introduction of 2-hydroxyethyl and 2-
aminoethyl group at 3-position of indole gave corresponding
products 2s and 2t in low yields, which were probably due to the
80
80
reflux
5
5
5
ND
ND
91
reflux
5
80
[a] Reagents and conditions: 1a (0.6mmol), L (1.1 equiv, 0.66mmol) in solvent
at reflux for 5 to 24 h. [b] Yield of isolated product 2a. [c] 0.8 eq of L3 was used.
existence of vulnerable functional groups[22]
.
With the optimized conditions in hand, we next examined the
scope of indoles for this reaction (Table 2). The substituents on
nitrogen were first examined. Simple aliphatic groups on indole’s
nitrogen were found to be tolerated, giving 2a and 2c in 90%
and 76% yield respectively, but a benzyl group seemed to be
less efficient and resulted in lower yield of 2f (55%). The
reaction of 1H-indole proceeded smoothly to give 2b in 81%
yield. N-aryl substituted indole afforded product 2d in moderate
yield. The N-acetyl indole, on the other hand, resulted in
complicated mixture under the same conditions, which might be
To further demonstrate the utility of this new method, we
applied it to the synthesis of Ropinirole, which has been
approved for alleviating symptoms related to Parkinson’s
disease[7]. As a start, 1H-indole-4-carbaldehyde 3 was treated
with MeNO2 in the presence of AcONH4. The Knoevenagel
reaction product was then reduced with LiAlH4 to form related
amine 4, which was dipropylated to afford N-(2-(1H-indol-4-yl)
ethyl)-N-propylpropan-1-amine
5
in 85% yield. Finally,
intermediate 5 was oxidized with L3 under standard conditions to
give Ropinirole in 76% yield. Thus, by using this high efficient
oxidation methodology, the synthesis of Ropinirole was reduced
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10.1002/ejoc.201701807
European Journal of Organic Chemistry
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to three steps with 44% combined yield from 1H-indole-4-
carbaldehyde 3.
according to literature procedures. Unless otherwise noted, all reagents
were obtained from commercial sources, and were used without further
purification. 1H NMR and 13C NMR were obtained from varian mercury-
plus 400MHz (AVANCE Ⅲ 500MHz or AVANCE Ⅲ 600MHz) and 100
(125 MHz or 150 MHz) MHz. Chemical shifts are reported downfield from
TMS (δ = 0) or CDCl3 (δ = 7.26) or DMSO-d6 (δ = 2.50) for 1H NMR. For
13C NMR, chemical shifts are reported in the scale relative to CDCl3 (δ =
77.0) or DMSO-d6 (δ = 39.5). Mass spectra were measured with a thermo
finnigan LCQ advantage instrument using ESI ionization.
Preparation of 1-Fluoro-1,2-benziodoxol-3-(1H)-one (L3)[23]: Spray-
dried KF (2.18 g, 37.6mmol, 5 eq) was flame dried under high vacuum
and reacted with 1-chloro-1,2-benziodoxol-3-(1H)-one (2.00 g, 7.5 mmol,
1 eq) in dry MeCN (250 mL) under argon at 75oC for 3.5h. After carefully
canula-filtered under Ar, the filtrate was then concentrated under reduced
pressure to afford L3 as a white solid (1.96g, 98%). M.p.: 212-213℃. 1H
NMR (600 MHz, DMSO-d6) δ 7.98 (dd, J = 7.9, 1.2 Hz, 1H), 7.71 (dd, J =
7.6, 1.7 Hz, 1H), 7.46 (td, J = 7.5, 1.2 Hz, 1H), 7.22 (td, J = 7.6, 1.7 Hz,
1H); 13C NMR (150 MHz, DMSO-d6) δ 168.1, 140.5, 136.9, 132.5, 130.1,
128.2, 94.1; 19F NMR (565 MHz, DMSO-d6) δ -148.23. Anal. Cacld for:
C7H4FIO2 (%) C, 31.61; H, 1.52; F, 7.14. Found: C, 31.82; H, 1.70; F,
7.20.
Scheme 3. A concise synthesis of Ropinirole
To gain insight of the mechanism, radical scavenger 2,6-di-
tert-butyl-4-methylphenol (BHT) was added to the reaction
mixtures. Similar and slightly lower yield ruled out the possibility
of radical mechanism (Scheme 3a). Based on the above results
and the fact that quantitative amount of 2-iodobenzoic acid could
be isolated after the reaction, a plausible mechanism has been
proposed in Scheme 3b. Initially, intermediate II is generated via
the nucleophilic attack of I towards hypervalent iodine reagent L3.
The water attacks C3 position of iodonium salt II to afford
intermediate III, which then undergoes β-H elimination and
isomerization to give final product 2-oxindole IV. According to
this mechanism, when L1 was applied as an oxidant,
intermediate II might be attacked by Cl- to form chlorinated by
product. While using L3 instead of L1, the formation of fluorinated
indoles was avoided due to the week nucleophilicity of F-, as a
General Procedure for the Preparation of Compounds 2a–2t: To a
solution of L3 (175.5 mg, 0.66 mmol) in 1,4-dioxane/H2O (1:5) (0.4 mL/2
mL) was added 1-methylindole 2a (78 mg, 0.6 mmol). The mixture was
then heated in 140 °C oil bath and refluxed for 5-6 h until the starting
materials were completely consumed. The reaction then quenched with
sat. NaHCO3, and diluted with ethyl acetate and H2O. The organic phase
was dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography on silica
gel (n-hexane/ethyl acetate = 6/1).
result,
the
yield
of
product
was
increased.
1-Methyl-1,3-dihydro-indole-2-one (2a).
Yellow solid (72 mg, 90% yield), m. p. = 82-83 °C. Analytical data for 2a
was consistent with that previously reported[24] 1H NMR (400 MHz,
.
CDCl3) δ = 7.29 – 7.20 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 7.8
Hz, 1H), 3.51 (s, 2H), 3.20 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ =
175.0, 145.1, 127.8, 124.4, 124.2, 122.3, 108.0, 35.7, 26.1 ppm. MS
(ESI) m/z 148.1 [M+H] +.
1-H-1,3-dihydro-indole-2-one (2b).
Brown solid (65 mg, 81% yield), m. p. = 126-127 °C. Analytical data for
2b was consistent with that previously reported[25] 1H NMR (600 MHz,
.
CDCl3) δ = 9.04 (br, 1H), 7.21 (t, J = 8.0 Hz, 2H), 7.01 (t, J = 7.5 Hz, 1H),
6.90 (d, J = 7.7 Hz, 1H), 3.55 (s, 2H)ppm; 13C NMR (150 MHz, CDCl3) δ
= 177. 6, 142.4, 127.9, 125.2, 124.6, 122.3, 109.7, 36.2 ppm. MS (ESI)
m/z 134.1 [M+H] +.
1-Ethyl-1,3-dihydro-indole-2-one (2c).
Colorless solid (73mg, 76% yield), m. p. = 92-93°C. Analytical data for 2c
was consistent with that previously reported[26] 1H NMR (600 MHz,
.
CDCL3) δ = 7.29 – 7.24 (m, 2H), 7.03 (d, J = 0.9 Hz, 1H), 6.84 (d, J = 7.8
Hz, 1H), 3.77 (q, J = 7.2 Hz, 2H), 3.51 (s, 2H), 1.27 (t, J = 7.3 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ = 174.7, 144.2, 127.8, 124.7, 124.4, 122.1,
108.1, 35.8, 34.6, 12.6 ppm. MS (ESI) m/z 162.1 [M+H] +.
Scheme 4. Control experiment and proposed mechanism of
indoles leading to 2-oxindoles
Conclusions
1-Phenyl-1,3-dihydro-indol-2-one (2d).
Colorless solid (76 mg, 61% yield), m. p. = 120-121°C. Analytical data for
2d was consistent with that previously reported[26] 1H NMR (500 MHz,
.
In conclusion, we have developed a convenient method for
the synthesis of 2-oxindoles directly from indoles with
hypervalent iodine under neutral conditions. A broad range of
functional groups were well tolerated, giving ideal 2-oxindoles in
moderate to excellent yields. It is clear that the electronic
properties of indoles play important roles in this transformation.
By using this method, Ropinirole, a drug used to alleviate the
symptoms of Parkinson’s disease, could be synthesized in three
steps with 44% combined yield. The application of this reagent
in other transformations is actively underway in our laboratory.
CDCl3) δ = 7.56 – 7.50 (m, 2H), 7.43 – 7.39 (m, 3H), 7.31 (d, J = 7.3 Hz,
1H), 7.20 (t, J = 7.8 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 7.9 Hz,
1H), 3.72 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ = 174.5, 145.3,
134.5, 129.7, 128.1, 127.8, 126.7, 124.6, 124.3, 122.8, 109.4, 36.1 ppm.
MS (ESI) m/z 210.2 [M+H] +.
1-Bn-1,3-dihydro-indol-2-one (2f).
Colorless solid (73 mg, 55% yield), m. p. = 67-68°C. Analytical data for 2f
was consistent with that previously reported[26] 1H NMR (500 MHz,
.
CDCl3) δ = 7.31 (d, J = 4.4 Hz, 4H), 7.25 (d, J = 7.4 Hz, 2H), 7.16 (t, J =
7.8 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 4.92 (s, 2H),
3.62 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ = 175.1, 144.3, 135.9,
128.8, 127.8, 127.6, 127.4, 124.5, 124.4, 122.4, 109.1, 43.7, 35.8 ppm.
MS (ESI) m/z 224.3 [M+H] +.
Experimental Section
1,3-dimethylindolin-2-one (2g).
General Methods: Solvents were distilled under argon atmosphere
[18b]
[18b]
from calcium hydride (MeCN). The L1
and L2
were prepared
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10.1002/ejoc.201701807
European Journal of Organic Chemistry
Full Paper
.
was consistent with that previously reported[27] 1H NMR (500 MHz,
White solid (84 mg, 87% yield), m. p. = 54-55°C. Analytical data for 2g
176.0, 142.6, 128.0, 127.2, 125.1, 124.5, 110.3, 35.8 ppm. MS (ESI) m/z
168.2 [M+H] +.
CDCl3) δ = 7.30 – 7.22 (m, 2H), 7.06 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 7.8
Hz, 1H), 3.43 (q, J = 7.6 Hz, 1H), 3.21 (s, 3H), 1.48 (d, J = 7.7 Hz, 3H)
ppm; 13C NMR (150 MHz, CDCl3) δ = 178.7, 144.0, 130.7, 127.9, 123.5,
122.4, 107.9, 40.6, 26.2, 15.4 ppm. MS (ESI) m/z 184.2 [M+Na] +.
5-Nitro-1,3-dihydro-indol-2-one (2q).
Pink solid (86 mg, 81% yield), m. p. = 239-240°C. Analytical data for 2q
was consistent with that previously reported[32] 1H NMR (500 MHz,
.
DMSO-d6) δ = 11.04 (br, 1H), 8.15 (dd, J = 8.6, 2.4 Hz, 1H), 8.12 – 8.06
(m, 1H), 6.98 (d, J = 8.6 Hz, 1H), 3.63 (s, 2H) ppm; 13C NMR (125 MHz,
DMSO-d6) δ = 176.6, 150.3, 141.7, 127.0, 124.9, 120.0, 108.9, 35.6 ppm.
MS (ESI) m/z 177.0 [M-H] -.
1-Methyl-5- Methyl -1,3-dihydro-indol-2-one (2h).
Tan solid (62 mg, 64% yield), m. p. = 101-102°C. Analytical data for 2h
was consistent with that previously reported[24] 1H NMR (500 MHz,
.
CDCl3) δ = 7.08 (d, J = 8.3 Hz, 2H), 6.70 (d, J = 7.7 Hz, 1H), 3.48 (s, 2H),
3.19 (s, 3H), 2.33 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ = 175.1,
142.8, 131.8, 128.00, 125.2, 124.5, 107.7, 35.8, 26.2, 21.0 ppm. MS (ESI)
m/z 162.1 [M+H] +.
4-Nitro-1,3-dihydro-indol-2-one (2r).
Yellow solid (85 mg, 79% yield), m. p. = 119-120 °C. Analytical data for
2r was consistent with that previously reported[33]. 1H NMR (600 MHz,
DMSO-d6) δ = 10.84 (br, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 8.1 Hz,
1H), 7.21 (d, J = 7.7 Hz, 1H), 3.90 (s, 2H) ppm; 13C NMR (150 MHz,
DMSO-d6) δ = 175.4, 146.0, 143.9, 129.1, 122.5, 115.7, 114.9, 37.1 ppm.
MS (ESI) m/z 177.2 [M-H] -.
1-Methyl-6-Methyl-1,3-dihydro-indol-2-one (2i).
Yellow solid (67 mg, 71% yield), m. p. = 84-85 °C. Analytical data for 2i
was consistent with that previously reported[28] 1H NMR (600 MHz,
.
CDCl3) δ = 7.10 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.64 (s, 1H),
3.46 (s, 2H), 3.18 (s, 3H), 2.38 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3)
δ = 175.4, 145.2, 137.9, 123.9, 122.7, 121.3, 109.0, 35.4, 26.0, 21.7 ppm.
MS (ESI) m/z 162.2 [M+H] +.
3-(2-hydroxyethyl) indolin-2-one (2s).
Yellow solid (52 mg, 49% yield), m. p. = 110-111 °C. Analytical data for
2s was consistent with that previously reported[34] 1H NMR (600 MHz,
.
DMSO-d6) δ 10.32 (br, 1H), 7.25 (d, J = 7.4 Hz, 1H), 7.16 (t, J = 7.7 Hz,
1H), 6.93 (t, J = 8.0 Hz, 1H), 6.85 – 6.76 (m, 1H), 4.63 (s, 1H), 3.54 (s,
2H), 3.46 (s, 1H), 1.99 (s, 1H), 1.83 (s, 1H) ppm; 13C NMR (150 MHz,
DMSO-d6) δ 179.2, 142.6, 129.8, 127.5, 124.1, 121.2, 109.1, 57.9, 42.3,
33.4 ppm. IR (KBr) v = 3450-3000, 1704, 1619, 1473, 1381, 908, 734 cm-
1. MS (ESI) m/z 178.1 [M+H] +.
1-Methyl-5-Methoxy-1,3-dihydro-indol-2-one (2j).
Atrovirens solid (78 mg, 74% yield), m. p. = 97-98°C. Analytical data for
2j was consistent with that previously reported[27] 1H NMR (400 MHz,
.
CDCl3) δ = 6.86 (s, 1H), 6.79 (dd, J = 8.5, 2.3 Hz, 1H), 6.70 (d, J = 8.4 Hz,
1H), 3.78 (s, 3H), 3.50 (s, 2H), 3.18 (s, 3H) ppm; 13C NMR (125 MHz,
CDCl3) δ = 174.7, 155.8, 138.8, 125.8, 112.1, 111.9, 108.2, 55.8, 36.1,
26.2 ppm. MS (ESI) m/z 178.2 [M+H] +.
3-(2-aminoethyl) indolin-2-one (2t).
Yellow solid (46 mg, 43% yield), m. p. = 100-101 °C. 1H NMR (600 MHz,
DMSO-d6) δ 10.33 (br, 1H), 7.25 (d, J = 7.4 Hz, 1H), 7.16 (t, J = 8.1 Hz,
1H), 6.93 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 3.65 – 3.49 (m, 2H),
3.46 (t, J = 6.6 Hz, 1H), 2.01 (dq, J = 13.5, 6.5 Hz, 1H), 1.82 (dq, J = 13.5,
7.1 Hz, 1H) ppm; 13C NMR (150 MHz, DMSO-d6) δ 179.2, 142.6, 129.8,
127.5, 124.1, 121.2, 109.1, 57.9, 42.3, 33.4 ppm. IR (KBr) v = 3650-3400,
1686, 1637, 1473, 1388, 1139 cm-1. MS (ESI) m/z 178.1 [M+H] +.
1-Methyl-5-Nitro-1,3-dihydro-indol-2-one (2k).
Tan solid (78 mg, 68% yield), m. p. = 195-196°C. Analytical data for 2k
was consistent with that previously reported[29] 1H NMR (500 MHz,
.
DMSO-d6) δ = 8.27 (d, J = 11.1 Hz, 1H), 8.15 (s, 1H), 7.20 (d, J = 8.7 Hz,
1H), 3.72 (s, 2H), 3.19 (s, 3H) ppm; 13C NMR (125 MHz, DMSO-d6) δ =
174.9, 151.2, 142.1, 126.0, 124.9, 119.6, 108.2, 35.0, 26.3 ppm. MS
(ESI) m/z 191.2 [M-H] -.
Preparation of 2-(1H-indol-4-yl) ethan-1-amine (4).
1-Methyl-5-Cyan-1,3-dihydro-indol-2-one (2l).
Ammonium acetate (220 mg, 1.1 mmol) was added to a solution of 4-
indolcarboxaldehyde (440 mg, 3.0 mmoI) in nitromethane (5 mL). Atfer
refluxed for 3.5 h, the reaction mixture was diluted with AcOEt and
washed with brine. The organic layer was dried and concentrated to
dryness. The resultant residue was then washed with cyclohexane and
dried under vacuum to obtain 4-(2-nitrovinyl) indole (415 mg), which was
used in the next step without further purification.
White solid (92 mg, 89% yield), m. p. = 200-201 °C. Analytical data for 2l
was consistent with that previously reported[28] 1H NMR (600 MHz,
.
DMSO-d6) δ = 7.75 (d, J = 9.7 Hz, 1H), 7.66 (s, 1H), 7.13 (d, J = 8.2 Hz,
1H), 3.61 (s, 2H), 3.14 (s, 3H) ppm; 13C NMR (150 MHz, DMSO-d6) δ =
174.4, 149.1, 133.1, 127.2, 126.1, 119.5, 109.0, 103.6, 34.7, 26.1 ppm.
MS (ESI) m/z 173.2 [M+H] +.
A solution of 4-(2-nitrovinyl) indole (302 mg, 1.6 mmoI) in THF (30 mL)
was added to a suspension of LiAlH4 (305 mg, 8.0 mmol) in THF (20 mL)
at 0°C under N2 protection. The reaction mixture slowly warmed to room
temperature before heated to reflux and then stirred for another 3 hours.
After low down the reaction temperature back to 0°C, ice water was
added to quench the reaction. The resulting mixture was filtered,
concentrated, and extracted with AcOEt (30 mL × 3). The organic layer
was dried, filtered and concentrated to obtain 4 as a yellow solid (236 mg,
68% yield). 1H NMR (600 MHz, DMSO- d6) δ 11.10 (s, 1H), 7.30 (s, 1H),
7.23 (d, J = 8.1 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 7.0 Hz, 1H),
6.48 (s, 1H), 2.93 – 2.89 (m, 2H), 2.88 – 2.84 (m, 2H) ppm; 13C NMR
(150 MHz, DMSO-d6) δ 135.8, 131.4, 127.3, 124.6, 120.9, 118.4, 109.4,
99.4, 42.6, 37.3 ppm.
1-Methyl-5-Bromo-1,3-dihydro-indol-2-one (2m).
Light pink solid (124 mg, 91% yield). m. p. = 171-172 °C. Analytical data
for 2m was consistent with that previously reported[27]. 1H NMR (600 MHz,
CDCl3) δ = 7.36 (d, J = 9.3 Hz, 1H), 7.31 (s, 1H), 6.65 (d, J = 8.3 Hz, 1H),
3.47 (s, 2H), 3.15 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ = 174.2,
144.1, 130.6, 127.3, 126.3, 114.8, 109.3, 35.4, 26.1 ppm. MS (ESI) m/z
244.9[M+NH4] +.
3-Methyl-1,3-dihydro-indol-2-one (2n).
White solid (68 mg, 77% yield), m. p. = 119-120 °C. Analytical data for 2n
was consistent with that previously reported[30]. 1H NMR (600 MHz, CDCl3)
δ = 9.59 (br, 1H), 7.17-7.24 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.94 (d, J =
7.6 Hz, 1H), 3.48 (q, J = 7.7 Hz, 1H), 1.51 (d, J = 7.7 Hz, 3H) ppm; 13C
NMR (150 MHz, CDCl3) δ = 182.0, 141.4, 131.2, 127.8, 123.6, 122.2,
109.9, 41.1, 15.2 ppm. MS (ESI) m/z 148.2 [M+H] +.
Preparation of N-(2-(1H-indol-4-yl)ethyl)-N-propylpropan-1-amine (5).
A
mixture of 4-[(2-amino) ethyl] indole (236 mg, 1.48 mmoI), 1-
iodopropane (1300 mg, 7.5 mmol), NaHCO3 (380 mg, 4.5mmol) in
toluene (15 mL) was stirred at reflux temperature for 21h. NaHCO3 (210
mg, 2.5 mmol) in water (5 mL) and 1-iodopropane (425 mg, 2.5 mmoI)
were added to the resultant mixture sequentially, the resulting mixture
was stirred at the same temperature for 6h, and then filtered and
separated after it cooled down to room temperature. The organic layer
was washed with water (15mL), dried, filtered, and evaporated to obtain
5 as a yellow liquid (277 mg, 85% yield). 1H NMR (600 MHz, DMSO-d6) δ
11.06 (s, 1H), 7.30 (s, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.00 – 6.95 (m, 1H),
6.79 (d, J = 7.0 Hz, 1H), 6.41 (s, 1H), 2.98 – 2.87 (m, 2H), 2.85 – 2.65 (m,
2H), 2.54 – 2.48 (m, 1H), 2.45 – 2.42 (m, 3H), 1.38 – 1.46 (m, 4H), 0.86
(t, J = 7.4 Hz, 6H) ppm; 13C NMR (150 MHz, DMSO-d6) δ 135.7, 131.9,
127.1, 124.6, 120.9, 118.5, 109.2, 99.1, 55.4, 54.6, 30.6, 20.2, 11.8 ppm.
6-Fluoro-1,3-dihydro-indol-2-one (2o).
Whitish solid (57 mg, 63% yield), m. p. = 131-132 °C. Analytical data for
2o was consistent with that previously reported[31]. 1H NMR (600 MHz,
DMSO-d6) δ = 10.49 (br, 1H), 7.22 – 7.14 (m, 1H), 6.75 – 6.67 (m, 1H),
6.61 (dd, J = 9.3, 2.2 Hz, 1H), 3.43 (s, 2H) ppm; 13C NMR (150 MHz,
DMSO-d6) δ = 176.8, 161.8 (d, J = 239.1 Hz, 1C), 145.1 (d, J = 12.1 Hz,
1C), 125.4 (d, J = 9.8 Hz, 1C), 121.5 (d, J = 2.7 Hz, 1C), 107.0 (d, J =
22.0 Hz, 1C), 97.3 (d, J = 26.7 Hz, 1C), 35.1 ppm; 19F NMR (565 MHz,
DMSO-d6) δ = -114.1 ppm. MS (ESI) m/z 152.2 [M+H] +.
5-chloro-1,3-dihydro-indol-2-one (2p).
Deep yellow solid (66 mg, 66% yield), m. p. = 194-195 °C. Analytical data
for 2p was consistent with that previously reported[25]. 1H NMR (600 MHz,
DMSO-d6) δ = 10.46 (br, 1H), 7.25 (s, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.80
(d, J = 8.3 Hz, 1H), 3.49 (s, 2H) ppm; 13C NMR (150 MHz, DMSO-d6) δ =
Preparation of 4-(2-(dipropylamino) ethyl) indolin-2-one (Ropinirole).
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10.1002/ejoc.201701807
European Journal of Organic Chemistry
Full Paper
Following the general procedure, Ropinirole was isolated as a brown
liquid (61 mg, 76% yield). Analytical data for Ropinirole was consistent
with previously reported[35]. 1H NMR (600 MHz, CDCl3) δ 9.35 (s, 1H),
7.14 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H),
3.48 (s, 2H), 2.66 – 2.74 (m, 4H), 2.58 – 2.45 (m, 4H), 1.46-1.54 (m, 4H),
0.89 (t, J = 7.4 Hz, 6H) ppm; 13C NMR (150 MHz, CDCl3) δ 177.8, 142.5,
136.8, 128.0, 124.0, 122.7, 107.6, 55.9, 54.0, 35.1, 30.5, 20.0, 11.9 ppm.
IR (KBr) v = 3195, 2961, 2920, 2812, 1708, 1616, 1461, 1381, 1042, 910,
742 cm-1. MS (ESI) m/z 261.2 [M+H] +.
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Keywords: 2-oxindoles • hypervalent iodine reagent • indoles •
oxidation
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10.1002/ejoc.201701807
European Journal of Organic Chemistry
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Entry for the Table of Contents
Full Paper
Fluorine chemistry
Xinpeng Jiang, Cong Zheng, Lijun Lei,
Kai Lin, and Chuanming Yu*
Page No. – Page No.
Synthesis of 2-oxindoles from
substituted indoles by hypervalent
iodine oxidation
By use of hypervalent iodine, the practical and efficient conversion of indoles
into corresponding 2-oxindoles is achieved under neutral conditions. This
oxidation is amenable to different substituted indoles.
* 2-oxindoles • hypervalent iodine reagent • indoles • oxidation
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