Sodium Iodide/Hydrogen Peroxide-Mediated Oxidation/Lactonization for the Construction of Spirocyclic Oxindole-Lactones

Article abstract of DOI:10.1002/adsc.201600441

The sodium iodide/hydrogen peroxide-mediated oxidation/lactonization of indolepropionic acids was achieved, affording the corresponding spirocyclic oxindole-lactones in moderate to high yields. This metal-free procedure features mild reaction conditions, non-toxicity and easy handling, with hydrogen peroxide (H₂O₂) as a clean oxidant. (Figure presented.).

Full text of DOI:10.1002/adsc.201600441

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DOI: 10.1002/adsc.201600441
Sodium Iodide/Hydrogen Peroxide-Mediated Oxidation/Lactoni-
zation for the Construction of Spirocyclic Oxindole-Lactones
Guofeng Li,b Liwu Huang,a Jiecheng Xu,a Wangsheng Sun,b,* Junqiu Xie,a
Liang Hong,a,* and Rui Wanga,b,*
a
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Peopleꢀs Republic of China
E-mail: hongliang@sysu.edu.cn
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou 730000, Peopleꢀs
b
Republic of China
E-mail: sunws@lzu.edu.cn or wangrui@lzu.edu.cn
Received: April 25, 2016; Revised: June 11, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600441.
Abstract: The sodium iodide/hydrogen peroxide-
mediated oxidation/lactonization of indolepropionic
acids was achieved, affording the corresponding spi-
rocyclic oxindole-lactones in moderate to high
yields. This metal-free procedure features mild reac-
tion conditions, non-toxicity and easy handling, with
hydrogen peroxide (H2O2) as a clean oxidant.
and the use of environmentally harmful metals like
Hg, Tl, strong acids or non-ideal solvents, which
hinder their practical application. Therefore, we
aimed to realize a mild and metal-free strategy for
the direct synthesis of spirocyclic lactones.
Recently, a simple catalytic system combining the
use of an iodide salt or iodine with a terminal oxidant
has been found effective in various oxidative coupling
reactions.[7,8] The exploration of efficient transforma-
Keywords: hydrogen peroxide; indolepropionic
acids; oxidation; sodium iodide; spirocyclic oxin-
dole-lactones
3,3-Disubstituted oxindoles are frequently found in
many natural products, pharmaceuticals, and biologi-
cally active compounds. Thus the synthesis of these
compounds has been intensely pursued by synthetic
chemists and pharmaceutical chemists.[1] Among
them, spirocyclic oxindole-lactones are a family of
common oxindole motifs with interesting biological
activities and act as useful synthons for the synthesis
of 3-hydroxyoxindole derivatives.[2] Previously report-
ed methods mainly focused on (i) the annulations of
isatins with enals or propionic acid,[3] (ii) Michael/cyc-
lization of 3-hydroxyoxindoles,[4] and (iii) intramolecu-
lar lactonization of 3-hydroxyoxindole esters.[5] All
these methods need the use of the pre-prepared isa-
tins and 3-hydroxyoxindoles (Scheme1). Thus the de-
velopment of general and direct methods for the
preparation of spirocyclic oxindole-lactones from
simple substrates like indoles is of great importance.
Oxidization/lactonization of indolepropionic acids
is a direct approach for the synthesis of spirocyclic ox-
indole-lactones.[6] However, most of the existing
Scheme 1. Synthesis and transformation of spirocyclic oxin-
methods typically require the multistep procedures dole-lactones.
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tions by this strategy is still attractive and promising. then examined other oxidants such as PIDA and
With the continuing interest in the synthesis of spi- TBHP, but neither of them could lead to formation of
rooxindoles,[9] we herein communicate our progress in the desired product (Table 1, entries 7 and 8). Fur-
the NaI/H2O2-mediated oxidization/lactonization of 3- thermore, when increasing the amount of H2O2 to 4.0
indolepropionic acids for the synthesis of spirocyclic and 6.0 equiv., 90% and 99% conversions, respective-
oxindole-lactones in moderate to good yields. This ly, were obtained in a greatly reduced reaction time
method has several advantages, including being of 2 h (Table 1, entries 9 and 10). At last, other sol-
metal-free, mild reaction conditions and avoiding vents such as CH2Cl2, EtOAc, toluene, THF, MeOH
toxic by-products derived from the oxidant.
were screened, but none of them gave better conver-
We started our study by using 3-indolepropionic sion than CH3CN (Table 1, entries 11–15). Thus, the
acid 1a as a model substrate at room temperature in optimal reaction reactions were 10 mol% of NaI and
CH3CN for 12 h. To our delight, when treated with 6.0 equiv. of H2O2 as the oxidant in CH3CN at room
iodine (10 mol%) in the presence of H2O2 temperature for 2 h (Table 1, entry 10).
(2.2 equiv.), the corresponding spirocyclic oxindole-
With the optimized conditions in hand, we subse-
lactone 2a could be obtained in a promising conver- quently examined the scope of this reaction by using
sion of 70% (Table 1, entry 1). Encouraged by this various substituted indolepropionic acids. As shown
result, further screening of other iodide sources like in Table 2, all substrates containing either electron-
NaI, CuI, TBAI, NIS and KI was carried out (Table 1, donating or electron-withdrawing groups ran smooth-
entries 2–6). The conversion could be increased to ly to afford the corresponding spirocyclic oxindole-
93% when using NaI (Table 1, entry 2), while TBAI lactones in moderate to good yields. Substrates with
and KI gave 80% and 85% conversion, respectively electron-donating methyl substituent on different sites
(Table 1, entries 4 and 6). When applying CuI and worked well to afford the corresponding oxindole-lac-
NIS as iodide source, complex mixtures were ob- tones 2b, 2c, 2d and 2e in 82–94% yields. Compared
served instead of the spirocyclic oxindole-lactone. We with the methyl substituent, the methoxy or benzylox-
yl substituent gave the products (2f–2j) in a slightly
lower yield. Electron-withdrawing, halogen-containing
Table 1. Optimization of the reaction conditions.[a]
indolepropionic acids were tolerated well and gave
the desired products (2k–2q) in moderate yields. In
addition, the N-protected indoles like 1-methyl-3-in-
dolepropionic acid and 1-benzyl-3-indolepropionic
acids could also furnish the oxindole-lactones 2r and
2s in 95% and 74% yields, respectively.[10] We have
also tried 3-indolebutanoic acid and 2-methyl-3-in-
AHCTUNGTREGdNNUN olepropionic acid. Unfortunately, the reaction did
Entry Catalyst Oxidant[b]
(equiv.)
Solvent
t
Conv.[c]
[h] [%]
not proceed when 3-indolebutanoic acid was used,
while 2-methyl-3-indolepropionic acid gave a complex
mixture.
1
2
3
4
5
6
7
8
I2
H2O2 (2.2)
H2O2 (2.2)
H2O2 (2.2)
H2O2 (2.2)
H2O2 (2.2)
H2O2 (2.2)
PIAD (2.2)
TBHP (2.2)
H2O2 (4.0)
H2O2 (6.0)
H2O2 (6.0)
H2O2 (6.0)
H2O2 (6.0)
H2O2 (6.0)
H2O2 (6.0)
CH3CN 12 70
CH3CN 12 93
CH3CN 12
CH3CN 12 80
CH3CN 12
CH3CN 12 85
CH3CN 12
CH3CN 12
CH3CN 2
CH3CN 2
CH2Cl2
EtOAc
toluene
THF
In order to demonstrate the synthetic utility of this
methodology, we next prepared 3-hydroxy-2-oxindole
derivatives 3 and 4 from the oxindole-lactones 2r
(Scheme 2). In the presence of ammonium hydroxide
in methanol, the lactone 2r underwent aminolysis to
afford amide 3, which could be used for the synthesis
of a 5-HT6 antagonist.[11] When treated with LiAlH4
in THF followed by acetic anhydride, hexahydropyri-
do[2,3-b]indole 4, a core structure found in chaetomi-
nine,[12] could be formed in 42% overall yield from 2r
by sequential reduction/cyclization/acetylation.
The addition of TEMPO did not hamper the reac-
tion, showing that the reaction may not involve the
radical pathway. Based on this result and the sugges-
tion of a reviewer, we propose a plausible stepwise
mechanism as shown in Scheme 3. Firstly, hypervalent
iodine species [IO]À/[IO2]À was likely to be generated
by the reaction of IÀ with H2O2.[13] The hypervalent
iodine species would then react with 1a to form 2-
iodo-3-indolepropionic acid 5, which could be easily
NaI
CuI
TBAI
NIS
KI
–
–
–
–
–
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
9
90
99
50
95
80
10
40
10
11
12
13
14
15
2
2
2
2
2
MeOH
[a]
All reactions were performed with 1a (0.10 mmol) and
catalyst (10 mol%) in 1.0 mL of the solvent at room tem-
perature.
[b]
[c]
H2O2 is a 30% aqueous solution, TBHP is a 70% aque-
ous solution.
1
Determined by H NMR spectroscopy of the crude mix-
ture.
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Table 2. Scope of the reaction.[a]
[a]
Unless otherwise noted, all reactions were performed with 1 (0.10 mmol), NaI (10 mol%) and H2O2 (6.0 equiv.) in 1.0 mL
of CH3CN at room temperature for 2 h. The isolated yield is given in each case.
This reaction was conducted at 608C.
[b]
[c]
A scale-up experiment to 1 mmol was performed.
Scheme 3. Proposed mechanism.
In summary, we have developed an environmentally
and economic transformation mediated by NaI/H2O2
for the synthesis of spirocyclic oxindole-lactones in
moderate to high yield. This metal-free method can
Scheme 2. Transformation of 2r.
hydrolyzed to the oxindole 6.[14] Then, oxidation of provide an efficient approach to afford 3-hydroxyox-
oxindole 6 would afford the final product spirolactone indole derivatives, which possess potential biologically
2a.[7a]
activity. Further study on the enantioselective genera-
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Typical Procedure
To a solution of 3-indolepropionic acids 1 (0.10 mmol) in
CH3CN(1.0 mL) was added NaI (10 mol%) followed by
30% H2O2 (6 equiv.). The reaction mixture was stirred at
room temperature until completion of the reaction. After
this time, the solvent was removed under vacuum and the
residue was purified by flash column chromatography (pe-
troleum ether/AcOEt) to give the pure desired product 2.
Acknowledgements
We gratefully acknowledge financial support from the NSFC
(21432003, 21572278 and 21502079) and the Program for
Chang-Jiang Scholars and Innovative Research Team in Uni-
versity (IRT 15R27).
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6 Sodium Iodide/Hydrogen Peroxide-Mediated Oxidation/
Lactonization for the Construction of Spirocyclic Oxindole-
Lactones
Adv. Synth. Catal. 2016, 358, 1 – 6
Guofeng Li, Liwu Huang, Jiecheng Xu, Wangsheng Sun,*
Junqiu Xie, Liang Hong,* Rui Wang*
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