The Power of Triplet and Singlet Oxygen in Synthesis: 2-Oxindoles, 3-Hydroxy-2-oxindoles, and Isatins from Furans

Article abstract of DOI:10.1021/acs.orglett.8b01404

A straightforward synthesis of substituted 2-oxindoles, 3-hydroxy-2-oxindoles, and isatins has been developed. Easily accessible furans were transformed into tetrahydropyranopyrrolones by a singlet oxygen initiated cascade reaction sequence. An acid-catal

Full text of DOI:10.1021/acs.orglett.8b01404

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
The Power of Triplet and Singlet Oxygen in Synthesis: 2‑Oxindoles,
3‑Hydroxy-2-oxindoles, and Isatins from Furans
Myron Triantafyllakis, Kalliopi Sfakianaki, Dimitris Kalaitzakis,* and Georgios Vassilikogiannakis*
Department of Chemistry, University of Crete, VasilikaVouton, 71003, Iraklion, Crete, Greece
S
* Supporting Information
ABSTRACT: A straightforward synthesis of substituted 2-
oxindoles, 3-hydroxy-2-oxindoles, and isatins has been
developed. Easily accessible furans were transformed into
tetrahydropyranopyrrolones by a singlet oxygen initiated
cascade reaction sequence. An acid-catalyzed rearrangement,
followed by aromatization, gave access to a variety of 2-
oxindole motifs, which were oxidized to 3-hydroxy-2-oxindoles
or isatins using methylene blue as a radical initiator and
molecular oxygen as a terminal oxidant.
2-Oxindoles, isatins, and 3-hydroxy-2-oxindoles constitute an
important class of aromatic alkaloids present in numerous natural
and non-natural products (Figure 1)1 which exhibit remarkable
scaffolds is via the oxidation of oxindoles.12 However, most of
these oxidations implement relatively harsh reaction conditions,
as well as metal catalysts or toxic reagents.
The development of a more flexible and mild protocol for
rapid access to the title compounds is, therefore, highly desirable.
Herein, we introduce an innovative approach for the synthesis of
2-oxindoles, 3-hydroxy-2-oxindoles, and isatins starting from
readily accessible furans of type 1 (Scheme 1). It is known that
the photooxygenation (singlet oxygen) of furans 1, followed by
treatment with Me2S and primary amines, gives access to highly
versatile intermediate β,γ-unsaturated γ-lactams of type 2.13 We
have recently developed a protocol for the in situ transformation
of these lactams into tetrahydropyranopyrrolones (THPP) 4
(Scheme 1) via a hetero-Diels−Alder reaction with α,β-
unsaturated carbonyl compounds.14 Rearrangement of these
THPPs, catalyzed by AlCl3, leads to dihydroindolones (DHI) 6.
Initially, we envisaged that oxindoles 7 could be accessed from
THPP 4 by an acid-catalyzed rearrangement (e.g., 4 → 5),
followed by in situ aromatization (Scheme 1). Furthermore, we
also anticipated that 2-oxindoles might be oxidized to the
corresponding 3-hydroxy-2-oxindoles 8 and isatins 9 using
methylene blue (MB) as a redox catalyst. Although MB is a dye
and has, therefore, generally been employed as a photocatalyst,15
our group recently unveiled its redox properties in the dark when
applied to the oxidation of the γ-carbon of γ-lactams of type 2
under aerobic conditions (2 → 3, Scheme 1).16 Since 2-
pyrrolidinones 2 and oxindoles 7 have common structural
features, we predicted that a similar protocol might be
implemented for the oxidation of the α-carbon of oxindoles
leading to the corresponding 3-hydroxy-2-oxindoles 8 and isatins
9 (Scheme 1).
Figure 1. Examples of biologically active 2-oxindoles, 3-hydroxy-2-
oxindoles, and isatins.
medicinal properties.2 They are also valuable synthetic
intermediates for the preparation of structurally complex drug
candidates.3 As a result, considerable efforts have been dedicated
to the synthesis of these high value heterocycles.4
Many synthetic methodologies have focused on the synthesis
of 2-oxindoles starting from substituted anilines,5 phenyl acetic
acids,6 or indoles.7 The majority of these methods, however,
require advanced prefunctionalized precursors and/or utilize
harsh reaction conditions. The synthesis of 2-oxindoles directly
starting from simpler nonbenzenic components has rarely been
studied.8
Aniline derivatives9 and indoles10 are also commonly used as
the starting point for the synthesis of isatins and 3-hydroxy-2-
oxindoles. Alternatively, nucleophilic additions to isatins have
been extensively investigated as a means to synthesize 3-hydroxy-
2-oxindoles.11 Another straightforward approach to both these
Received: May 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01404
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Proposed Scenario for the Synthesis of 2-Oxindoles
3-Hydroxy-2-oxindoles and Isatins from Furans
Scheme 2. Two-Step Synthesis of 2-Oxindoles from Furans
promoted in a methanolic solution of MB under basic conditions
(Table 1). Specifically, upon the addition of Et3N (1 equiv) to a
Initially, we investigated the first stage of the proposed
transformation (4 → 7) using as a substrate the easily accessible
cis-fused THPP 4a (Scheme 2).14 Treatment of 4a with
trifluoroacetic acid (TFA, 0.5 equiv) and the oxidant p-chloranil
(1 equiv) in toluene at 80 °C led to exclusive formation of the
desired oxindole 7a in only 1 h and with 75% isolated yield
(cond. A, Scheme 2). We chose toluene as the solvent due to the
enhanced solubility of p-chloranil in it. It is notable that the
reaction does not work at room temperature (cond. B) or
without the presence of the acid (cond. C). The presence of the
oxidant was also crucial for the reaction, since, without p-
chloranil (cond. D), the product 7a was isolated in just 21% yield.
Different amounts of the acid (0.2 equiv, cond. E or 1 equiv,
cond. F) or of the oxidant (0.5 equiv, cond. G) all resulted in
lower isolated yields (40−60%).
To explore the scope of the reaction, different substrates of
type 4 were synthesized from the corresponding furans 1 and
tested under the optimized conditions A (Scheme 2). For
compounds 4b−f and 4h−i bearing different R1, R2, and R3
groups the reaction afforded the corresponding oxindoles 7b−f
and 7h−i in good yields (58−74%). For compound 4g (having a
methyl group as R4), milder reaction conditions could be used
(0.2 equiv of TFA, cond. E, Scheme 2) in order to obtain the
desired product 7g (45% yield). In this case, using more acid
leads to a mixture of isomers of the uncyclized compound of type
5 (Scheme 1) with the double bond having migrated to different
positions.
Table 1. Optimization and Testing of the MB-Induced
Oxidation of Oxindole 7a to Isatin 9a
MB
Et3N
(equiv)
conv (%) in
18 h
yield
(%)
entry (mol %)
solvent
1
2
3
4
5
6
5
3
5
−
5
5
1
MeOH
MeOH
MeOH
MeOH
MeOH
100
50
75
0
73
ND
48
−
−
ND
1
0.5
1
−
1
0
MeOH
degassed
2
7
5
1
CH2Cl2
9
ND
solution containing 7a and a catalytic amount of MB (5 mol %) in
MeOH, a partial decolorization of the solution was observed
instantly, and after 18 h at room temperature, the desired isatin
9a was isolated in 73% yield (entry 1). The reaction was
performed in the dark, meaning that this is not a light-induced
process. With lower amounts of MB or Et3N, the reaction was
significantly slower (entries 2−3), while, in the absence of either
MB or Et3N, the reaction did not work (entries 4−5). The
presence of oxygen was essential for the oxidation step (entry 6).
We next turned our efforts toward examining the MB-induced
oxidation of 2-oxindoles to 3-hydroxy-2-oxindoles and isatins.
Various conditions were tested using compound 7a, and in
accordance with our previous studies,16 the oxidation was
B
DOI: 10.1021/acs.orglett.8b01404
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Furthermore, in the nonprotic solvent CH2Cl2, the conversion
was low after 18 h (entry 7).
Scheme 4. Plausible Reaction Mechanism
After validation of the optimal conditions (Table 1, entry 1),
various 2-oxindoles were subjected to this new oxidation
protocol with the results presented in Scheme 3. For compounds
Scheme 3. MB-Induced Oxidation of 2-Oxindoles to Isatins
and 3-Hydroxy-2-oxindoles
under the reaction conditions. Indeed, treatment of isolated
hydroperoxide 7C (starting from 7i) with Et3N (1 equiv) in
MeOH for 18 h afforded 8i and the N-oxide of Et3N (see SI).
When R2 = H, isatins 9 can be obtained via the enediol form of
8. Since enediols are prone to aerobic oxidation, 8 can be readily
oxidized to 9 by molecular oxygen without the involvement of
MB. Extra support for this assessment is derived from the fact
that 3-hydroxy-2-oxindole 8a (synthesized by reduction of 9a
with NaBH4) was transformed to the corresponding isatin 9a
when subjected to Et3N (1 equiv) in MeOH without the
presence of MB (8 h, 50% yield, Scheme 3). Employing MB in
this step accelerates the oxidation process via another radical
propagating cycle (Scheme 4, R2 = OH) affording 9a in just 2 h
(cond. H, 74% yield, Scheme 3).
It is notable that during the early stages of the oxidation of 3-
unsubstituted 2-oxindoles 7a−g (2 h), the formation of the
corresponding dimeric compounds of type 10 (Scheme 4) was
observed, as a result of the condensation of isatins 9 with the
unreacted oxindoles 7. However, these dimers were finally
consumed by the reaction producing the corresponding isatins as
the sole products. This consumption was achieved either via a
reverse aldol reaction, followed by re-entry into the reaction
sequence described above, or by the MB-induced oxidation of
the dimer’s α-position to the corresponding hydroperoxide
followed by C−C bond cleavage with concomitant expulsion of
water. The fact that we did not observe the formation of any
intermediate hydroperoxide in these cases (R2 = H) means that
the expulsion of water must occur very rapidly independent of
whether it is the dimer or monomer that is oxidized by MB.
In conclusion, a general and highly versatile methodology for
the synthesis of substituted 2-oxindoles, 3-hydroxy-2-oxindoles,
and isatins has been presented herein. 2-Oxindoles could be
easily obtained (two steps) from a variety of readily accessible
furan precursors, under mild and atom-economic conditions,
using sustainable singlet oxygen chemistry. The synthesis of 3-
hydroxy-2-oxindoles and isatins was accomplished via a metal-
free, MB-initiated, but not light-dependent, oxidation of the
corresponding oxindoles wherein molecular oxygen was the
terminal oxidant.
7a−g (R2 = H), the reaction afforded the desired isatins 9a−g
effectively, regardless of the substituents at any of the R1, R3, and
R4 positions (71−79% isolated yield). When the same conditions
were employed to 3-substituted 2-oxindoles 7h and 7i, the 3-
hydroxy-2-oxindoles 8h and 8i were isolated as the sole products
(70% and 71% isolated yields, respectively).
Since the oxidation proceeds only under basic conditions in
the protic solvent MeOH, we propose a MB-induced proton
coupled electron transfer (PCET)17 initiation step (Scheme 4).
Specifically, the enol tautomer of 7 might undergo proton
transfer (PT) to the base and electron transfer (ET) to MB. This
PCET step is responsible for the reduction of MB to the colorless
leucomethylene blue (LMB), thus explaining the decolarization
of the solution upon addition of the base. As a result, the radical
intermediate 7A is formed and may be trapped by the molecular
oxygen leading to radical 7B. A hydrogen atom transfer (HAT)
from 7 to 7B regenerates the propagating radical 7A at the same
time as affording hydroperoxide 7C. From 7C, two possible
pathways are proposed for the formation of the final product 8 or
9. In path a, when R2 = H the dehydration of hydroperoxide 7C
leads directly to isatin 9. In path b, the reduction of 7C by a
reducing agent present in the reaction solution (such as LMB and
Et3N) affords 8. This hypothesis was supported by the
observation that the 3-substituted oxindole 7i was revealed to
have formed a mixture of the corresponding hydroperoxide of
type 7C and product 8i, in a 3:2 ratio, after just 1 h of reaction
[see Supporting Information (SI)]. Since 8i was the sole product
after 18 h of reaction, it is reasonable to assume that the
intermediate hydroperoxide is reduced to the final product 8i
C
DOI: 10.1021/acs.orglett.8b01404
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Huang, P.-M. RSC Adv. 2017, 7, 45227. (c) Pang, Y.; Guan, M.; Zeng, R.;
Zhao, Y. Org. Chem. Front. 2017, 4, 2408.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01404.
■
S
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Detailed experimental procedures and spectral data
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
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Xia, C.; Tay, M. G.; Liu, C. Adv. Synth. Catal. 2017, 359, 3484. (b) Li, W.;
Duan, Z.; Zhang, X.; Zhang, H.; Wang, M.; Jiang, R.; Zeng, H.; Liu, C.;
Lei, A. Angew. Chem., Int. Ed. 2015, 54, 1893. (c) Ilangovan, A.; Satish, G.
Org. Lett. 2013, 15, 5726. (d) Yue, Q.; Wang, Y.; Hai, L.; Guo, L.; Yin,
H.; Wu, Y. Synlett 2016, 27, 1292. (e) Liu, M.; Zhang, C.; Ding, M.;
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*E-mail: dkalaitzos@uoc.gr.
*E-mail: vasil@uoc.gr.
ORCID
Georgios Vassilikogiannakis: 0000-0002-9099-383X
Notes
The authors declare no competing financial interest.
(i) Jia, Y.-X.; Katayev, D.; Kundig, E. P. Chem. Commun. 2010, 46, 130.
̈
ACKNOWLEDGMENTS
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The research leading to these results has received funding from
the European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007-2013)/ERC Grant
Agreement No. 277588. We thank the Greek General Secretariat
of Research and Technology for matching (reward) funds (KA:
4143 and 4154).
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DOI: 10.1021/acs.orglett.8b01404
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