Oxidative Cleavage of Indoles Mediated by Urea Hydrogen Peroxide or H2O2 in Polar Solvents

Article abstract of DOI:10.1002/adsc.202100214

The oxidative cleavage of indoles (Witkop oxidation) involving the use of H₂O₂ or urea hydrogen peroxide in combination with a polar solvent has been described. Among these solvents, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) stands out as the one affording the corresponding 2-ketoacetanilides generally in higher yields The protocol described has also enabled the oxidation of different pyrroles and furans derivatives. Furthermore, the procedure was implemented in a larger-scale and HFIP was distilled from the reaction mixture and reused (up to 4 cycles) without a significant detriment in the reaction outcome, which remarks its sustainability and applicability. (Figure presented.).

Full text of DOI:10.1002/adsc.202100214

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DOI: 10.1002/adsc.202100214
Oxidative Cleavage of Indoles Mediated by Urea Hydrogen
Peroxide or H2O2 in Polar Solvents
Natalia Llopis,a Patricia Gisbert,a and Alejandro Baezaa,*
a
Departamento de Química Orgánica and Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias, Universidad de Alicante.
Apdo. 99, E-03690 Alicante, Spain
E-mail: alex.baeza@ua.es
Manuscript received: February 16, 2021; Revised manuscript received: May 24, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100214
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
(Scheme 1).[4] In the last decades, concerns about the
safety, sustainability and environment impact of chem-
Abstract: The oxidative cleavage of indoles (Wit-
kop oxidation) involving the use of H2O2 or urea
ical protocols have prompted the development of
hydrogen peroxide in combination with a polar
operationally simple, atom-economy and greener oxi-
solvent has been described. Among these solvents,
dation methodologies.[5] In this sense, the use of
1,1,1,3,3,3-hexafluoroisopropanol (HFIP) stands out
as the one affording the corresponding 2-ketoaceta-
biocatalysts together with H2O2 as oxidant[6] or the
recent findings about the use of photocatalysts[7] or
nilides generally in higher yields The protocol
KCl (cat.)/Oxone system[8,9] (Scheme 1) for the oxida-
described has also enabled the oxidation of different
tive cleavage of indoles represent a great achievement
pyrroles and furans derivatives. Furthermore, the
in this direction.
procedure was implemented in a larger-scale and
HFIP was distilled from the reaction mixture and
On the other hand, our research group has been
working for some years on the use of fluorinated
reused (up to 4 cycles) without a significant detri-
alcohols as solvents and promoters in different organic
ment in the reaction outcome, which remarks its
transformations.[10,11] More concretely, in the last years,
sustainability and applicability.
we became interested in the use of the combination of
1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and H2O2, or
its most stable form UHP (urea-hydrogen peroxide
Keywords: Oxidation; Indoles; HFIP; Hydrogen
adduct), as a green alternative for the oxidation of
Peroxide; Witkop oxidation
organic compounds.[12,13] In this regard, we envisioned
the possibility of testing this system to carry out this
synthetic transformation in a catalyst-free reaction. The
Compounds bearing indole moieties are widely present results of this study are herein disclosed.
in many naturally occurring compounds, mainly alka-
Initially, the search for the optimal reaction con-
loids, with most of them possessing biological ditions was conducted using 2-methylindole (1a) as
activity.[1] Therefore, it is not surprising that several model substrate and H2O2 or UHP indistinctly as
different strategies have been developed for their oxidants in different solvents (Table 1). As can be
further elaboration and transformation.[2] Among them, observed, regardless of the oxidant, the employment of
the oxidative cleavage of C2À C3 double bond of
indoles, known as Witkop oxidation,[3,4] gives access to
a variety of 2-ketoacetanilide derivatives, which are
key intermediates in the synthesis of quinolones and
related bioactive compounds. Traditionally the main
strategies for this reaction involve using transition-
metal based oxidants, hypervalent iodine compounds,
singlet oxygen or ozone and organic peroxides
Scheme 1. Witkop oxidation.
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Table 1. Reaction conditions optimization.[a]
(Table 1, entry 8). It is worth mentioning that lowering
the temperature produced a substantial decrease in the
conversion of 2a in all the cases.
As depicted in Table 1, the optimization study
revealed that there was not a significant difference in
the results achieved when using H2O2 or UHP
(5 equiv.) as oxidants and HFIP as solvent in the model
reaction (Table 1, entries 9 and 17). This situation led
us to evaluate the reaction scope under both conditions.
Additionally, the good results achieved when MeCN in
combination with H2O2 (Table 1, entry 8) prompted us
to explore the reaction under these conditions too. The
best results obtained for each substrate with the
different conditions essayed are shown in Scheme 2.
As already mentioned, good yield was observed for N-
acetylanthranilic acid (2a). The yield was even better
for the N-methylated analogue 2b, with UHP being the
oxidant that provided the best results in HFIP. As
somewhat expected, 5-methoxy-2-methylindole (1c)
produced acid 2c in excellent yield. Similar or slightly
superior results for these substrates were obtained
when the reaction was performed in MeCN. Next, free
NÀ H indoles (indole, 5-methoxyindole, 5-fluoroindole
and 8-ethylindole) lacking a substituent in position 2
or 3 were tested without success. The reaction did not
work or if so, led to the formation of a complex
mixture of oxidation products (isatins among them).
Meanwhile, the N-alkylated analogues, such as N-
methylindole (1d) and N-benzylindole (1e) clearly
reacted toward the formation of the corresponding
isatins (2d and 2e). These were obtained in good
Entry
Oxidant (equiv.)
Solvent
Conv (%)[b]
1
2
3
4
5
6
7
8
H2O2 (2.5)
H2O2 (2.5)
H2O2 (2.5)
H2O2 (2.5)
H2O2 (2.5)
H2O2 (2.5)
H2O2 (2.5)
H2O2 (5)
H2O
<5
<5
35
72
84
i-PrOH
MeOH
TFE
HFIP
MeCN
DMSO
MeCN
HFIP
H2O
i-PrOH
MeOH
TFE
85
81
91 (81)[c]
89 (77)[c]
<5
9
H2O2 (5)
10
11
12
13
14
15
16
17
UHP (2.5)
UHP (2.5)
UHP (2.5)
UHP (2.5)
UHP (2.5)
UHP (2.5)
UHP (2.5)
UHP (5)
<5
30
80
85
HFIP
MeCN
DMSO
HFIP
70
77
92 (79)[c]
[a] Reaction conditions: indole (0.15 mmol), oxidant and solvent
(150 μL), 45 C, 24 h. [b] Conversion toward the formation of
°
[c]
2a determined by GC-MS. Yield of the isolated product
after preparative TLC.
H2O or i-PrOH as solvents did not produce any yields, being H2O2 in HFIP the conditions of choice.
reaction (entries 1, 2, 10 and 11). However, the Next, skatole (1f) was essayed providing the corre-
formation of some desired product was detected when sponding formamide derivative 2f in good yield when
MeOH was used instead (entries 3 and 12). A H2O2 and HFIP were employed. Contrariwise, the
significant change was observed when fluorinated reaction with 1,3-dimethyl-1H-indole (1g) sluggishly
alcohols, 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3- produced, at best, the corresponding oxindole 2g in a
hexafluoroisopropanol (HFIP) were used as solvents. poor 32% yield. This was the major isolated product
The oxidation reaction took place obtaining high amongst other oxidation products (Witkop oxidation
conversion towards the formation of compound 2a among them) regardless of the reaction condition
with both oxidants (entries 4, 5, 13 and 14). Since employed. 2-Benzoylacetanilide (2h) was isolated in
HFIP produced better conversions, a further refinement 75% yield, starting from 3-phenyl-1H-indole (1h) and
of the reaction conditions was conducted with this using H2O2 in HFIP. To our delight, the use of 2-
solvent. Thus, increasing both oxidant equivalents phenyl-1H-indole (1i) gave the pesticide Dianthalexin
(from 2.5 up to 5 equiv.) resulted in an amelioration of B (2i)14 in high yield in a one-step operation procedure
the conversion (Table 1, entries 9 and 17). However, a when UHP in HFIP was employed. Under the same
further increase in the oxidant turned out to be negative conditions, to our surprise, ester 2j was obtained in
for the formation of the desired product. For the sake good yield when the corresponding N-methyl-2-
of comparison, other polar solvents were also studied phenyl-1H-indole (1j) was used. Next, 2,3-dimethyl-
such as MeCN and DMSO. To our surprise, the 1H-indole (1k) and the N-methylated analogue (1l)
reaction worked with both oxidants, being especially were reacted obtaining high yields for acetamides 2k
successful using H2O2 (Table 1, entries 6, 7, 15 and and 2l in both solvents, being UHP the oxidant of
16). Due to its ease of work-up, purification and choice for HFIP. However, lower yields were achieved
cleaner reaction crude, we selected the reaction when 2,3-diphenyl-1H-indole (1m) was tested under
performed with MeCN and H2O2 for a further refine- the same conditions with the better of results being
ment. Thus, as in the previous case, increasing the reached with HFIP as solvent. Disubstituted 3-methyl-
amount of oxidant produced a better yield for 2a 2-phenyl-1H-indoles (1n–1q) bearing different sub-
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aldehyde (1s) produced oxindole (2s) as sole product
in high yields with both oxidants, the regioisomer 3-
formylindole produced a complex mixture of unidenti-
fied oxidation products. This was due to as a
consequential Dakin oxidation.[12b] Finally is worth
mentioning that the reaction with indole-3-carboxylic
acid and ethyl indole-2-carboxylate was also attempted
without success.
With the aim to expand the applicability of the
procedure described, the oxidation of pyrrole and furan
derivatives was also taken into account (Scheme 3). In
this regard, N-methyl and N-benzylpyrrole (3a and
3b) were essayed under the optimized reaction
conditions using HFIP as solvent. In both cases good
yields were obtained for a mixture of N-benzyl and N-
methyl-1,5-dihydro-2H-pyrrol-2-one along with the
corresponding N-alkylmaleimide respectively (4a and
4b), using UHP as oxidant. In contrast, 1H-pyrrole
produced a complex mixture of oxidation products.
Next, 1H-pyrrole-2-carbaldehyde (3c) was also tested,
affording, 3-pyrrolin-2-one (4c) as major oxidation
product in good conversion as a consequence of a
Dakin oxidation and a double bond isomerization.[12b,15]
Furans were eventually evaluated, in which furan
produced an unidentified complex mixture of oxidation
products. 2-Methylfuran (3d) gave rise in moderate
yield to the formation of lactone (4d), and finally, 2,3-
dihydrofuran (3e) produced cyclic hemiacetal 4e in
good yield.
Additionally, it is important to mention that
benzofurans were also considered as substrates for the
a)
Scheme 2. Scope of the oxidative cleavage of indoles.
Reaction conditions: indole (0.15 mmol), oxidant (5 equiv.) and
°
solvent (150 μL), 45 C, 24 h. Yield of the isolated product after
preparative TLC.
stituents at position 5 were also analyzed. As somehow
expected, better yields were obtained when electron-
donating group were present. It is also remarkable that
the higher performance of HFIP in comparison to
MeCN, with the results of the latter being notably
lower. 1,2,3,4-Tetrahydrocarbazole (1r) was next sub-
mitted to the optimized conditions giving rise to
benzocondensed macrocyclic amide 2r in high yields,
especially with the combination UHP/HFIP. Formylin-
doles were also assayed and whereas indole-2-carbox-
a
Scheme 3. Evaluation of pyrroles and furan derivatives.
Reaction conditions: substrate (0.15 mmol), oxidant (5 equiv.)
and HFIP (150 μL), 45 C, 24 h. Yield of the isolated product
after preparative TLC. Products ratio determined by GC-MS
and H NMR. Not purely isolated, conversion determined by
°
b
1
c
d
GC-MS. Product decomposed during purification, estimated
yield by 1H NMR.
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oxidation protocol described. However, the reaction reused up to four times observing only a slight erosion
barely worked even when more forcing conditions on the conversion after each cycle.
(higher temperatures and oxidant amount as well as
In order to gain some insight into the possible
longer reaction time) were employed. On the contrary, reaction mechanism, a couple of control experiments
1,3-diphenylisobenzofuran (5) smoothly reacted to were carried out. Accordingly, oxindoles 2o and 7
afford o-dibenzoylbenzene (6) in excellent yields were submitted to the optimized reaction conditions
especially when UHP was the oxidant of choice with both oxidants and after 24 hours no reaction was
(Scheme 4).
observed (Scheme 5). This result suggest that the
Finally, the methodology herein described was oxidative cleavage does not proceed via the formation
implemented in a larger scale experiment (Figure 1). 2- of the corresponding oxindole and that once such
methylindole (1a) (5.0 mmol) was submitted to the compound is formed the reaction does not evolve
optimal reaction conditions using H2O2, with UHP further. Additionally, a radical-based mechanism was
being implemented as the selected oxidant because it relinquished since the reaction carried out using
allows an easier purification by recrystallization. As a TEMPO as radical scavenger worked practically the
result, the corresponding N-acetylanthranilic acid (2a) same in both solvents (HFIP and MeCN). Based on the
was obtained in 67% yield after recrystallization (n- results, previous experience and the literature
pentane/CH2Cl2 3/1). The high efficiency and low precedents[6,17] a possible reaction mechanism has been
environmental impact of the whole process was clearly proposed (Scheme 5). As depicted, indole would attack
demonstrated by the fact that the E-factor calculated H2O2 which can act as electrophile thanks to the
turned out to be 22.4 which is within the rank for fine activation carried out by HFIP,[18] rendering the hydro-
chemical industry and below the lowest limit for the peroxide A as an intermediate. This can evolve toward
pharmaceutical industry.[16]
the formation of dioxetane B after an intramolecular
In addition, to further demonstrate the sustainability cyclization reaction. This unstable compound would
of the methodology, the recycling of the solvent was rearrange to afford the desired product. Other mecha-
considered in this larger scale reaction. Thus, as nisms proposals leading to the formation of other
depicted in Figure 1, HFIP could be recovered and products described in the article can be found in the
supporting information file.
In summary, we have disclosed herein the develop-
ment of an alternative strategy for the oxidative
cleavage of indoles (Witkop oxidation) using UHP or
H2O2 as oxidants. From the results obtained, the
reaction seems to work well in the presence of highly
polar solvents when indoles bearing a substituent on
position 2 and/or 3 were employed. However, among
all of solvent tested, HFIP usually showed a higher
performance and wider substrate scope, acting as
solvent and reaction promoter. The products were
obtained generally in good yields under smooth
Scheme 4. Oxidative cleavage of isobenzofuran (5).
reaction conditions. Additionally, other heteroaromatic
compounds were also conveniently oxidized. The
success of this protocol relies on the electrophilic
Figure 1. Large-scale reaction, E-factor and recycling of
Scheme 5. Control experiments and proposed reaction mecha-
solvent.
nism.
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[4] M. Mentel, R. Breinbauer, Curr. Org. Chem. 2007, 11,
activation of H2O2 by the fluorinated alcohol. Finally,
the applicability of the procedure was clearly accom-
plished by the implementation of a large-scale experi-
ment and recycling of the HFIP.
159–176.
[5] Green Oxidation in Organic Synthesis, (Eds.: N. Jiao,
S. S. Stahl), John Wiley & Sons Ltd. Chichester, 2019.
[6] a) K.-Q. Ling, L. M. Sayre, Bioorg. Med. Chem. 2005,
13, 3543–3551; b) M. Takemoto, Y. Iwakiri, Y. Suzuki,
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[8] J. Xu, L. Liang, H. Zheng, Y. R. Chi, R. Tong, Nat.
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[9] A green oxidative cleavage of 2-arylindoles for the
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Experimental Section
General Procedure for the Oxidative Cleavage of
Indoles
In
a capped tube, the corresponding indole derivative
(0.15 mmol), HFIP (150 μL) and oxidant (5 equiv.) were added
sequentially in one portion and the mixture was subjected to
°
conventional heating (sand bath) for 24 hours at 45 C. After
cooling down the reaction mixture, it was filtered through
Celite® plug using ethyl acetate as eluent. Then, the solvent was
evaporated under reduced pressure. The corresponding pure
products were obtained after purification by preparative TLC,
using mixtures of hexane and ethyl acetate as eluent.
[10] a) N. Llopis, A. Baeza, Molecules 2020, 25, 3464–3476;
b) J. M. Pérez, C. Maquilón, D. J. Ramón, A. Baeza,
Asian J. Org. Chem. 2017, 6, 1440–1444; c) P. Trillo, A.
Baeza, C. Nájera, J. Org. Chem. 2012, 77, 7344–7354.
[11] For selected reviews about the use of fluorinated alcohols
as promoters in organic transformations, see: a) X.-D.
An, J. Xiao, Chem. Rec. 2019, 19, 142–161; b) I.
Colomer, A. E. R. Chamberlain, M. B. Haughey, T. J.
Donohoe, Nat. Chem. Rev. 2017, 1, 0088; c) J.-P. Bégué,
D. Bonnet-Delpon, B. Crousse, Synlett 2004, 18–20.
[12] a) N. Llopis, P. Gisbert, A. Baeza, J. Org. Chem. 2020,
85, 11072–11079; b) N. Llopis, A. Baeza, J. Org. Chem.
2020, 85, 6159–6164.
Following the general procedure described, the reaction was
carried out at large scale employing 2-methylindole (5.0 mmol,
0.65 g), HFIP (3 mL) and H2O2 (5 equiv., 1 mL), which were
added sequentially in a round-bottom flask. The reaction was
°
stirred at 45 C (sand bath) for 24 hours. After this time, the
reaction mixture was evaporated under reduced pressure. The
corresponding product was purified by recrystallization in
CH2Cl2/n-pentane (1/3) and filtered, yielding the N-acetylan-
thranilic acid (2a) in 67% (0.58 g).
Acknowledgements
[13] A. Berkessel, in Modern Oxidation Methods (Eds.: J. E.
Bäckvall), Ed; Wiley-VCH: Weinheim, 2010, p 117–145.
[14] a) W. Schilling, Y. Zhang, D. Riemer, S. Das, Chem. Eur.
J. 2020, 26, 390–395; b) A. C. Nelson, E. S. Kalinowski,
N. J. Czerniecki, T. L. Jacobson, P. Grundt, Org. Biomol.
Chem. 2013, 11, 7455–7457.
We would like to thank the Spanish Ministerio de Economía,
Industria y Competitividad (CTQ2017-88171-P) and Spanish
Ministerio de Ciencia, Innovación y Universidades (PGC2018-
096616-B-I00) and the University of Alicante (VIGROB-316/19,
UADIF19-106) for the financial support. S.-J. Burlingham is
acknowledged for the English correction of the manuscript.
[15] The obtention of 3-pyrrolin-2-one among other minor
oxidation products such as 4-pyrrolin-2-one and malei-
1
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published by Wiley-VCH GmbH
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Oxidative Cleavage of Indoles Mediated by Urea Hydrogen
Peroxide or H2O2 in Polar Solvents
Adv. Synth. Catal. 2021, 363, 1–6
N. Llopis, P. Gisbert, A. Baeza*