Rapid Oxidation Indoles into 2-Oxindoles Mediated by PIFA in Combination with n-Bu4NCl ? H2O

Article abstract of DOI:10.1002/adsc.202100234

We report the development of a rapid approach for directly converting indoles into 2-oxindoles promoted by HOCl formed in situ from the combination of (bis(trifluoroacetoxy) iodo)benzene (PIFA) and n-Bu₄NCl ? H₂O. The procedure is widely functional group tolerant and provides 2-oxindoles in up to 95% yield within 5 min. The potential applications of the developed methodology are demonstrated by the gram-scale preparation of 3-methyl-2-oxindole (11 a), the one-pot two-step syntheses of spiro-oxindoles 26 a and 26 b, and the formal synthesis of (-)-folicanthine (2). (Figure presented.).

Full text of DOI:10.1002/adsc.202100234

Title: Rapid Oxidation Indoles into 2-Oxindoles Mediated by PIFA in
Combination with n-Bu4NCl·H2O
Authors: Peng Liang, Hang Zhao, Tingting Zhou, Kaiyun Zeng, Wei
Jiao, Yang Pan, Yazhou Liu, Dong-Mei Fang, Xiaofeng Ma,
and Huawu Shao
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202100234
Link to VoR: https://doi.org/10.1002/adsc.202100234

10.1002/adsc.202100234
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Rapid Oxidation Indoles into 2-Oxindoles Mediated by PIFA in
Combination with n-Bu4NCl·H2O
Peng Liang [a, b], Hang Zhao[b], Tingting Zhou[b], Kaiyun Zeng[b], Wei Jiao[a], Yang
Pan[a], Yazhou Liu[a], Dongmei Fang[a], Xiaofeng Ma*[a] and Huawu Shao*[a]
a
Natural Products Research Centre, Chengdu Institute of Biology, Chinese Academy of Sciences, 610041 Chengdu,
People’s Republic of China.
Fax: +028-82890288
E-mail: shaohw@cib.ac.cn; maxf@cib.ac.cn
School of Chemical Engineering, Institute of Pharmaceutical Engineering Technology and Application, Key
b
Laboratory of Green Chemistry of Sichuan Institutes of Higher Education, Sichuan University of Science &
Engineering, Xueyuan Street 180, Huixing Road, Zigong, Sichuan 643000, People’s Republic of China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. We report the development of a rapid approach for
directly converting indoles into 2-oxindoles promoted by
HOCl formed in situ from the combination of
(bis(trifluoroacetoxy) iodo)benzene (PIFA) and n-
Bu4NCl·H2O. The procedure is widely functional group
tolerant and provides 2-oxindoles in up to 94% yield within 5
min. The potential applications of the developed methodology
are demonstrated by the gram-scale preparation of 3-methyl-
2-oxindole (11a), the one-pot two-step syntheses of spiro-
oxindoles 26a and 26b, and the formal synthesis of (-)-
folicanthine (2).
Keywords: 2-Oxindole; Hypervalent iodine, Halide
species; Spiro-oxindoles
aqueous conditions can also lead to the formation of 2-
oxindoles; however, the amount of NBS needs to be
Introduction
The 3-substituted 2-oxindole motif is a versatile
synthetic building block for the total syntheses of
[1]
biologically active indole-based natural products.
Selected examples include trigolute B (1),[2a] (-)-
folicanthine
(2),[2b]
desoxyeseroline
(3),[2c-2e]
esermethole (4),[2f] (±)-corynoxine (5) (Figure 1).[2g]
This framework is also present in a host of natural
products and pharmaceutical molecules, such as the
p53 inhibitor 6,[3a] SM-130686 (7),[3b] and maremycin
(8).[3c] In this context, the development of a general,
mild, and direct method for the transformation indoles
into oxindoles is highly desired. Indeed, continual
development has led to the development of a wide
range of oxidation strategies (Figure 2A).[4] Among
these, the DMSO/HCl(aq) system reported by Fontana
et al. in 1977 remains a robust and frequently
employed method, despite its inherent shortcomings,
including its narrow functional-group tolerance under
strong acidic conditions.[5] In addition, the treatment of
indoles with N-bromosuccinimide (NBS) under
1
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10.1002/adsc.202100234
Advanced Synthesis & Catalysis
Figure 1. Selected applications and biologically active
compounds containing the 3-substituted 2-oxindole subunit.
Figure 2. Selected examples of direct oxidations of indoles
at their 2-positions and the application of the
PhI(OAc)2/halide combination.
carefully controlled to reduce the formation of 3-
bromo-2-oxindole by-products, while limited scope
and low yields render this method less important.[6] An
elegant synthetic procedure based on the use of cyclic
hypervalent iodine(III) 9 as an activating agent was
developed in 2018 for the oxidation of indoles.[7] The
method generally provides 3-unsubstituted 2-
oxindoles in high yields, while 3-substitued indoles
only afforded the corresponding products in moderate
yields with limited scope (four examples, 43–87%
yields).
Treating hypervalent iodine compounds, such as
PhI(OAc)2 (PIDA), with halides is well-known to
generate diacetoxyiodate(I) anions or acetyl
hypoiodites that can react with double bonds or
activated methylene groups to deliver a range of
unusual C-C, C-O, or C-N bond-forming reactions
(Figure 2B).[9, 10] Considering the above-mentioned
limitations for the construction of 3-substituted 2-
oxindoles and our continued interest in the
development of mild conditions for the
functionalization of heterocyclic compounds,[11] we
believed that an alternative protocol that rapidly
transforms indoles into 2-oxindoles under mild
conditions with broad functional group tolerance
represents a practical advantage. In particular, we
wished to pursue an efficient way of generating HOX
in situ, which would chlorohydroxylate the indole and
then rapidly eliminate HX to generate the 2-oxindole
product. Herein, we report a metal-free and efficient
approach that converts indoles into 3-substituted 2-
oxindoles, which involves forming HOCl in situ by
A breakthrough was very recently reported by the
4a]
Tong’s group,[2d,
in which different types of
oxidized indole were prepared in a mild and green
manner that included converting the indole into the 2-
[2d, 4a]
oxindole,
oxidative rearrangement[2d, 4a] and
[4a]
Witkop oxidation[2d] using oxone[2d] or H2O2 as the
terminal oxidant. Although often effective, this
process suffers from limited benzene-ring functional-
group tolerance (only Me, Br, and MeO substituents
were investigated) and long reaction times (up to 4 h).
Very recently, Argade et al. used SiO2/H2SO4 to
oxidize indole;[8] however, this reaction is limited only
to indoles devoid of substituents on the nitrogen atom
and with an amide substituent at the 3-position, with
yields ranging from 63% to 82% after stirring at room
temperature for 12–24 h.
combining
(bis(trifluoroacetoxy)
iodo)benzene
(PIFA) and n-Bu4NCl•H2O (Figure 2C).
Results and Discussion
Preliminary screening was performed using 3-
methyl-1H-indole (10a), PIDA, and n-Bu4NI in
CH2Cl2 at room temperature (Table 1, Entry 1).
Although 10a was entirely consumed, the reaction
gave a complex mixture. Surprisingly, the desired 2-
2
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10.1002/adsc.202100234
Advanced Synthesis & Catalysis
oxindole 11a was isolated in 25% yield using PIFA
instead of PIDA (Entry 2). The reaction conditions
were further optimized by examining different halogen
sources, which revealed that n-Bu4NCl•H2O was most
efficient among NaI, NaCl, n-Bu4NF•6H2O, n-
Bu4NCl•H2O, and n-Bu4NBr (Entries 3–7). After a
Table 1. Screening the reaction conditions.[a]
Yield
Entry Oxidant
Additive
Solvent
(%)[b]
1
2
3
4
5
PIDA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
n-Bu4NI
n-Bu4NI
NaI
CH2Cl2 Complex
CH2Cl2
CH2Cl2
CH2Cl2
25
32
60
NaCl
n-Bu4NF•6H2O CH2Cl2 Complex
n-Bu4NCl•H2O CH2Cl2
n-Bu4NBr
n-Bu4NCl•H2O
n-Bu4NCl•H2O CH3CN
n-Bu4NCl•H2O THF
n-Bu4NCl•H2O toluene
n-Bu4NCl•H2O CH2Cl2
6
94
48
90
61
37
83
94
7[c]
8
CH2Cl2
DCE
9
10
11
12[d]
[a]
Reaction conditions: 10a (0.2 mmol), oxidant (0.22
mmol), H2O (0.22 mmol), and additive (0.22 mmol) in 1.0
mL solvent (H2O ≤ 500 ppm) at room temperature for 5 min.
[b] Isolated yield.
[c] Standard conditions, with 0.42 mmol of H2O.
[d] Without the addition of H2O.
series of trials, 11a was isolated in 94% yield when the
reaction was carried out with 1.1 equiv. of both PIFA
and n-Bu4NCl•H2O in CH2Cl2 at room temperature
(entry 12).
[a] Standard conditions except that 80 °C was used instead of
25 °C and DCM was replaced with DCE.
[b] Standard conditions except that −40 °C was used instead
of 25 °C.
With the optimal conditions in hand, we next
examined the scope of the substituents on the benzene
ring and the nitrogen atom of the indole, the results of
which are summarized in Table 2. Substrates 10b–10f,
in which benzyl, aryl, methyl, allyl and propargyl
groups were installed on the nitrogen atom, provided
the corresponding oxindole products 11b–11f in yields
of 64–93% in only 5 min. We then examined the
reactivities of 3-methyl-1H-indoles with various
substituents on the benzene ring. Oxidation proceeded
effectively when electron-rich substituents, such as
methyl or methoxy, were used, to afford the
corresponding 2-oxindoles 11g–11k in excellent
yields in only 5 min. Substrates with electron-
withdrawing groups, such as CN and NO2, on the
benzene ring provided products in very short times and
with little variation in yield (76% and 71%,
respectively). In addition, the reaction was found to be
insensitive to the position of the substituent of the on
the benzene ring, with all reactions complete in less
than 5 min (11l–11r). A current limitation of the
procedure is that the indoles with an electron
withdrawing group on nitrogen atom did not provide
the oxidative products as evidenced by substrates 11s-
11u.
Table 2. Substituent scope on the benzene ring and
the nitrogen atom of indole.[a]
To further expand the scope of this transformation,
we subjected a wide range of 3-substituted indoles to
3
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10.1002/adsc.202100234
Advanced Synthesis & Catalysis
the standard the reaction conditions. As shown in
Table 3, each examined indole substrate was
such as [3,3'-biindoline]-2,2'-dione (13s) and 3-chloro-
4-(2-hydroxyethyl)indolin-2-one (13t) were also
efficiently prepared using our methodology.
Table 3. Scope of the indole 3-substituent.[a]
Interestingly, when indole was subjected to the
standard reaction conditions in table 3, we detected a
complex reaction mixture, with the isolation of 3-
chlorinated 2-oxindole 13n in about 50% yield,
however, a slight change of the reaction conditions by
adding 2.2 equiv of both PIFA and n-Bu4NCl•H2O led
to the formation of 13n directly from indole in 83%
yield. The new conditions were thus used to convert
some other indoles without a substituted group at 3-
position into corresponding 3-chloro-2-oxindoles,
(15a-15c), which were obtained in 61-78% yield
(Table 4).
Table 4. Scope of chlorination-oxidation indoles into
3-Cl-2-oxindoles. [a]
[a] Reaction conditions: 14 (0.2 mmol), PIFA (0.44 mmol),
and n-Bu4NCl•H2O (0.44 mmol) in 1.0 mL CH2Cl2 (H2O ≤
500 ppm) at room temperature for 5 min.
[b] Run at −40 °C.
A series of control experiments was carried out to
gain additional information on the mechanism of our
oxidation process (Table 5). Only trace amounts of
product 11a or no 2-oxindole product was formed
when PIFA was replaced with PIDA or in the absence
of PIFA (entries 2 and 3). The yield of 11a was
dramatically lower (approximately 30%) in the
absence of n-Bu4NCl•H2O or with only 20 mol% n-
Bu4NCl•H2O (entries 4 and 5). The 2-oxindole product
was also produced, albeit in very low yield (18%),
when n-Bu4NHSO4 was used (entry 6). Thus, we
conclude that the n-Bu4NCl•H2O/PIFA combination is
required to successfully transform an indole into the
[a]
Standard condition except that −40 °C was used instead
of 25 °C.
[b] Standard condition except that 80 °C was used instead of
25 °C and DCM was replaced with DCE.
effectively converted into the corresponding oxindole
within 5 min. Long-chain and sterically demanding
alkyl groups were found to be suitable substrates for
this transformation and afforded oxindoles 13a–13f in
moderate-to-good yields. Furthermore, various
functional groups, including benzyl, cyano, ester, and
azido groups, are well tolerated in this oxidation
reaction (13g–13k). It is worth noting that substrates
with hydroxyl groups and double bonds were smoothly
transformed into the corresponding 2-oxindoles 13l
and 13m. In addition, 3-Ar-, 3-OAc-, and 3-Cl-
substituted 2-oxindoles 13n–13r were obtained in
yields of 80–82% from the corresponding 3-
substituted indoles. Lastly, more complex products,
Table 5. Control experiments.
Variations from standard
conditions
Yield
of 11a
Entry
1
2
none
94%
PIDA instead of PIFA, 12 h
< 10%
4
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10.1002/adsc.202100234
Advanced Synthesis & Catalysis
3
4
5
6
without PIFA
0%
29%
without n-Bu4NCl•H2O,
H2O (110 mol%) was added,
12 h
n-Bu4NCl•H2O (20 mol%) +
H2O (100 mol%), 12 h
n-Bu4NHSO4 (110 mol%) +
H2O (110 mol%) instead of n-
Bu4NCl•H2O, 5 min
PIFA + n-Bu4NCl, 5 min,
in glovebox
32%
18%
7
8
9
decomposed
PIFA + n-Bu4NCl + H218O,
5 min, in glovebox
BHT (100 mol%) was added,
5 min
11a + 11a-
18O 90%
91%
corresponding
2-oxindole.
Furthermore,
10a
decomposed rapidly when it was stirred in a glovebox
with PIFA and n-Bu4NCl under the optimized
conditions, and product 11a was not detected by
HRMS (entry 7). However, the introduction of 1.2
Figure 3. Confirming the structure of the intermediate.
18
equiv. of H2 O under the identified conditions in a
glovebox led to the formation of 18O-labeled TFA in
the reaction mixture, as confirmed by HRMS, along
with oxindole products 11a and 11a-18O (Table 5,
entry 8). Therefore, H2O appears to play a pivotal role
in this reaction. We believe that a radical process is not
involved because the 2-oxindole product was isolated
in similar yield (91%) when 2,6-di-tert-butyl-4-
methylphenol (BHT, a radical inhibitor) was added to
the reaction mixture under the identified conditions
(Table 5, entry 9).
We attempted to prepare the ammonium-complexed
halogen(I) species following the procedure reported by
Toth,[10a] but a UV-absorbing yellow solid was
obtained; its structure is proposed to be 16 or its
polymer (Figure 3A) based on NMR spectroscopy,
forms Cl-OH after reductive elimination.[12] The
indole then nucleophilically attacks 16 or Cl-OH to
produce intermediate 21, which then adds hydroxide
(Path A) or trifluoroacetate anion (Path B) to form
hemiacetal 22 or 23, respectively (we assume that
hydrolysis of 23 can also form 22).[13] Subsequent
elimination of HCl from 22 or HCl and TFA from 23
provides indole 24. Finally, keto-enol tautomerism
affords the desired product 11a. We prefer this
proposed mechanism even though intermediate 22 or
chloronium-intermediate 21’ can also be produced
directly by the reaction of intermediate 16 or Cl-OH
with the C=C of indole, followed by reaction with
HRMS, and its ability to chlorinate
a
monoterpenoid[10o] (Figure 3B) and indole (Figure 3C,
left). When PIFA and n-Bu4NCl•H2O were replaced
with 16, oxindole product 11a was produced in 73%
yield under otherwise standard conditions (Figure 3C,
right).
Based on the above observations, we propose a
plausible mechanism for our transformation, as shown
in Figure 4. Initially, n-Bu4NCl•H2O reacts with PIFA
to generate highly active intermediate 16, which then
Figure 4. A plausible reaction mechanism for the PIFA-
mediated oxidation of indole.
5
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10.1002/adsc.202100234
Advanced Synthesis & Catalysis
hydroxide or trifluoroacetate to generate 22 or 23,
respectively; however, this alternative cannot be ruled
out at this stage.
conditions afforded 28 as a crude mixture, which was
then transformed into 29 through double substitution
in 42% yield over two steps. It is noteworthy that many
compounds obtained by this methodology, including
11d, 13i, 13l, and 26, are key intermediates in the total
syntheses of complex indole alkaloids, including those
shown in Figure 1.
A key feature of this transformation is its high
efficiency; all examined reactions were complete in
less than 5 min with good-to-excellent yields of the
corresponding products, which means that it can be
used when needed. To examine the potential
application of our method, we oxidized 10a on the
gram scale (13.1 g, 100 mmol) under the standard
reaction conditions with stirring for only 10 min, from
which we obtained 13.4 g (91% yield) of 11a (Figure
5A). Moreover, the reaction is always very clean, with
no work-up necessary; once PIFA has been completely
added, the solvent is simply removed and the crude
reaction mixture is purified by chromatography or can
be used in the next step without further purification.
For example, spiro-oxindoles 26a and 26b were
prepared in yields of 84% and 45%, respectively, using
one-pot two-step processes from 3-substituted indoles
25a and 25b (Figure 5B). Alternatively, if necessary,
following oxidation, a simple work-up provides the
crude mixture, which can be also used in the next step.
As shown in Figure 5C, treatment of 27 under standard
Conclusion
We developed a mild and rapid protocol for the
synthesis of 3-substituted 2-oxindoles from indoles
that is promoted by the combination of PIFA and n-
Bu4NCl•H2O. The method has a number of advantages,
including the use of inexpensive reagents, broad
substrate scope, very short reaction times (less than 5
min), and good isolated yields. Mechanistic studies
revealed that oxidation may take place through an in-
situ-generated HOCl species. The applications of our
protocol were demonstrated by the preparation of 11a
on a 13.4 g scale and the one-pot two-step syntheses of
spirooxindoles 26a and 26b, and the formal synthesis
of (-)-folicanthine (2).
Experimental Section
General Procedure for the Oxidation Indoles into 2-
Oxindoles:
PhI(OTFA)2 (0.22 mmol, 110 mol%) was added dropwise
to a solution of the indole (0.2 mmol, 100 mol%) and n-
Bu4NCl•H2O (0.22 mmol, 110 mol%) in CH2Cl2 (1.0 mL)
with stirring at open air listed in Tables 1–3 (between -40
and 80 °C). The resulting solution was stirred for further
1–5 min. Water (30 mL) was added to the reaction mixture
once the starting material had been completely consumed as
determined by TLC, and the aqueous layer was extracted
with CH2Cl2 (3 x 5 mL). The organic layer was washed with
brine, dried over Na2SO4, and concentrated in vacuo. The
crude product was purified by flash column chromatography
to afford the oxindole.
General Procedure for the Chlorination-Oxidation
Indoles into 3-Cl-2-Oxindoles：
PhI(OTFA)2 (0.44 mmol, 220 mol%) was added dropwise
to a solution of the indole (0.2 mmol, 100 mol%) and n-
Bu4NCl•H2O (0.44 mmol, 220 mol%) in DCM (1 mL) at
°
-40 C or at room temperature. The resulting solution was
stirred for further 1–5 min. Water (30 mL) was added to the
reaction mixture once the starting material had been
completely consumed as determined by TLC, and the
aqueous layer was extracted with CH2Cl2 (3 x 5 mL). The
organic layer was washed with brine, dried over Na2SO4,
and concentrated in vacuo. The crude product was purified
by flash column chromatography to afford the oxindole.
CCDC-1867773
contains
the
supplementary
Figure 5. Applications of the PIFA mediated indole
oxidation.
crystallographic data for compound 11b. These data can be
obtained
free
of
charge
via
www.ccdc.cam.ac.uk/data_request/cif.
6
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10.1002/adsc.202100234
Advanced Synthesis & Catalysis
Acknowledgements
[6] a) T. Cohen, R. M. Moran, G. Sowinski, J. Org. Chem.
1961, 26, 1, 263-264; b) S. P. Breazzano, D. L. Boger, J.
Am. Chem. Soc. 2011, 133, 18495-18502.
We thank Chinese Academy of Sciences (the Hundred Talents
Program, the Biological Resources Programme (KFJ-BRP-008)),
the National Science Foundation of China (21772192 and
22001246), the Thousand Talents Program of Sichuan Province
and Key Project of the Science and Technology Department of
Zigong (2020YGJC11), Sichuan Province, for the financial
support.
[7] X. P. Jiang, C. Zheng, L. J. Lei, K. Lin, C. M. Yu, Eur.
J. Org. Chem. 2018, 1437-1442.
[8] S. V. Shelar, N. P. Argade, Org. Biomol. Chem. 2019,
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Zhdankin, P. J. Stang, Chem. Rev. 2002, 102, 2523-2584;
b) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2008, 108,
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10.1002/adsc.202100234
Advanced Synthesis & Catalysis
FULL PAPER
Rapid Oxidation Indoles into 2-Oxindoles
Mediated by PIFA in Combination with n-
Bu4NCl·H2O
Adv. Synth. Catal. Year, Volume, Page – Page
Peng Liang, Hang Zhao, Tingting Zhou, Kaiyun
Zeng, Wei Jiao, Yang Pan, Yazhou Liu, Dongmei
Fang, Xiaofeng Ma,* Huawu Shao*
8
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