Methylene Blue as a Photosensitizer and Redox Agent: Synthesis of 5-Hydroxy-1H-pyrrol-2(5H)-ones from Furans

Article abstract of DOI:10.1002/anie.201500744

A highly efficient and general singlet-oxygen-initiated one-pot transformation of readily accessible furans into 5-hydroxy-1H-pyrrol-2(5H)-ones has been developed. The methodology was extended to the synthesis of other high-value α,β-unsaturated γ-lactams. This useful set of transformations relies not only on the photosensitizing ability of methylene blue, but also on its redox properties: properties that have until now been virtually ignored in a synthetic context

Full text of DOI:10.1002/anie.201500744

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201500744
German Edition: DOI: 10.1002/ange.201500744
Synthetic Methods
Methylene Blue as a Photosensitizer and Redox Agent: Synthesis of
-Hydroxy-1H-pyrrol-2(5H)-ones from Furans**
5
Dimitris Kalaitzakis, Antonia Kouridaki, Dimitris Noutsias, Tamsyn Montagnon, and
Georgios Vassilikogiannakis*
In memory of Christopher S. Foote
Abstract: A highly efficient and general singlet-oxygen-
initiated one-pot transformation of readily accessible furans
into 5-hydroxy-1H-pyrrol-2(5H)-ones has been developed.
The methodology was extended to the synthesis of other
high-value a,b-unsaturated g-lactams. This useful set of trans-
formations relies not only on the photosensitizing ability of
methylene blue, but also on its redox properties: properties that
have until now been virtually ignored in a synthetic context.
from rose Bengal to methylene blue (MB). Thus, we will
exploit for the first time both the inherent photosensitizing
ability and the catalytic redox capability of methylene blue
within the same synthetic procedure.
In organic synthesis, MB has been quite sparsely
employed as an oxidant, and when it has been used it has
mostly been in photocatalysis, whereby the oxidation is
performed in the presence of light and a tertiary amine (a
[
2]
sacrificial electron donor). However, the ground state of
[
3]
W
e recently developed synthetic methodology for the
methylene blue also has a redox potential, which has been
[
1]
[4]
construction of g-lactam motifs from furans.
In this
reported to facilitate the oxidation of suitable substrates,
[5]
[6]
approach, singlet oxygen, generated in the presence of rose
Bengal (RB) and visible light, initiated a complex reaction
sequence which finally afforded important nitrogen-contain-
including carbohydrates and ascorbic acid, but until now
only under difficult conditions that have limited wider
application.
[1]
ing polycycles through the intermediacy of 2-pyrrolidinones
(Scheme 1). Herein, we are proposing to alter the outcome
We propose that 2-pyrrolidinones 6 (the keto tautomers of
pyrrol-2-ols) might be oxidized by MB in the presence of
molecular oxygen to afford the corresponding 5-hydroxy-1H-
pyrrol-2(5H)-ones 3 and thus provide access to 5-ylidenepyr-
rol-2(5H)-ones 4 and a,b-unsaturated g-lactams 5 (Scheme 1).
The targets of this methodology were carefully chosen, since
6
of the sequence simply by changing the photosensitizer used
5
-hydroxy-1H-pyrrol-2(5H)-ones 3 are highly important het-
erocyclic motifs. Not only do they exist in a large number of
[
7]
natural products, but they also exhibit significant biological
[
8]
activity. There are a number of methods for the synthesis of
[7,9–13]
these important scaffolds.
Many of these strategies,
however, require the preparation of a complex substrate, and/
or suffer from substrate limitations, and/or require harsh
reaction conditions. In a small number of cases, specifically
substituted furans have been utilized as starting materi-
[
11–13]
als.
The dehydrated counterparts, 5-ylidenepyrrol-2(5H)-ones
4
(Scheme 1), are also highly important compounds, as this
Scheme 1. Proposed synthesis of a,b-unsaturated g-lactam derivatives
motif occurs in many natural products and pharmaceuti-
3, 4, and 5 from furans.
[
7,14]
cals.
human metabolic degradation of hemoglobin
fragmentation products from abasic lesions of DNA.
They have also attracted attention as products of the
[
15]
and as
[16]
[*] Dr. D. Kalaitzakis, A. Kouridaki, D. Noutsias, Dr. T. Montagnon,
[7,10]
Prof. G. Vassilikogiannakis
Many of the methods developed for their synthesis
are
Department of Chemistry, University of Crete
Vasilika Vouton, 71003, Iraklion, Crete (Greece)
E-mail: vasil@chemistry.uoc.gr
based on the dehydration of 5-hydroxy-1H-pyrrol-2(5H)-ones
[10]
3.
Our study began with photooxidation of the commercially
available furan 1a [0.5 mmol, final concentration 83 mm;
Scheme 2, Eq. (1)] with a catalytic amount of MB (0.2 mol%,
Homepage: http://www.chemistry.uoc.gr/vassilikogiannakis
[
**] For the research leading to these results we received funding from
the European Research Council under the Seventh Framework
Programme of the European Union (FP7/2007-2013)/ERC grant
agreement no. 277588.
0
.17 mm) as the photosensitizer and subsequent reduction of
[
1]
the photooxidation product (excess Me S). Intriguingly,
2
upon the addition of benzylamine (1.1 equiv, 91 mm), instant
decolorization of the solution was observed, which suggested
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500744.
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[
Scheme 2, Eq. (6)]. This reaction could be accelerated by the
addition of benzylamine (0.3 equiv) to enable the complete
consumption of 6aa within 30 min.
The information from these experiments (for example,
acceleration by a base, solvent dependency) was incorporated
[17]
into a proton-coupled electron-transfer (PCET) mechanis-
tic proposal (Scheme 3). We suggest that Aaa (a tautomer of
Scheme 2. Control experiments. Bn=benzyl.
+
that MB had been reduced to leucomethylene blue (LMB).
After stirring for 6 h, analysis of the crude reaction mixture
[1]
revealed the formation of 2-pyrrolidinone 6aa and its
oxidized analogue 3aa in a 3:1 ratio. An increase in the
amount of MB used to 2 mol% (final concentration 1.7 mm)
led to the exclusive formation of 3aa in 2 h and 72% yield
[
Scheme 2, Eq. (2)]. This oxidation process (6aa!3aa)
occurred smoothly in complete darkness, thus indicating
[
2]
that the oxidation is not a light-induced process. When the
same reaction was performed on a larger scale (4 mmol of 1a,
with final concentrations of 160 and 3.2 mm for the furan and
MB, respectively), lactam 3aa was produced in 70% yield
Scheme 3. Possible PCET mechanistic explanation for the oxidation of
(
(
see the Supporting Information). In contrast, the use of RB
0.2 and 2 mol%) instead of MB under otherwise identical
2-pyrrolidinone 6aa.
conditions afforded exclusively 2-pyrrolidinone 6aa
[1]
[
Scheme 2, Eq. (3)], whereas the addition of a catalytic
amount of MB (2 mol%) to the reaction mixture after the
formation of compound 6aa led to the formation of product
6aa) might undergo both proton (to the base) and electron
transfer (to MB ), thus producing the captodative radical
+
3
aa. After the addition of BnNH , the characteristic absorp-
Baa, which might, in turn, be trapped by molecular oxygen to
afford the hydroperoxy radical Caa. Thus, molecular oxygen
from air is acting as the terminal oxidant in this process.
Hydrogen-atom transfer from LMBH would convert Caa into
7aa, and the MB radical (MBC) produced in this way would
propagate the cycle by generating Baa upon further electron
transfer (Aaa to MBC). Alternatively, Caa might abstract
a hydrogen atom directly from 6aa, thus regenerating Baa
and propagating the cycle. The hydroperoxy intermediate 7aa
2
+
tion of MB at 660 nm in the UV/Vis absorption spectrum
decreased to nearly zero, and a characteristic band for LMB
appeared at 250 nm (see the Supporting Information).
Neither the initial blue color of the reaction mixture nor the
characteristic 660 nm absorption band for MB were seen to
be regenerated over the course of the reaction. The partic-
+
ipation of O in the catalytic cycle was proven by degassing
the reaction solution with argon after the photooxidation
2
[
18]
[
Scheme 2, Eq. (4)]; in this case, no formation of the oxidized
may be reduced to the product 3aa by Me S, LMB,
or
2
product 3aa was observed. Finally, the solvent MeOH could
another of the reducing agents present in the mixture.
not be replaced with CH Cl [Scheme 2, Eq. (5)]. To further
Having optimized the reaction conditions, we explored
the behavior of other substrates (both furans and amines) to
probe the scope of the reaction. The desired 5-hydroxy-1H-
pyrrol-2(5H)-ones were prepared in good yields (50–76%
yield of the isolated product) and in short reaction times (2 h)
when a stoichiometric amount of the amine (1.1 equiv for
primary amines and 2 equiv for ammonia) was used
2
2
study the oxidation mechanism, we isolated 2-pyrrolidinone
aa from the reaction described in Scheme 2, Equation (3)
6
and added it to a solution of MB (2 mol% in MeOH). Full
consumption of compound 6aa was observed after stirring for
2
h, and analysis of the crude reaction mixture revealed the
formation of a mixture of 7aa and 3aa in a 3:1 ratio
2
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Scheme 5. One-pot synthesis of 5-ylidenepyrrol-2(5H)-ones 4.
PTSA=p-toluenesulfonic acid, TFA=trifluoroacetic acid.
predominantly to the Z isomer of the final product (com-
pounds 4cb and 4 fb, Z/E 4:1), whereas with benzylamine, the
E isomers (compounds 4aa, 4ca, and 4ha) were produced
exclusively. In the case of furan 1h, the use of HCOOH for
the final dehydration step gave the formate ester 4ha,
whereas the use of PTSA (0.5 equiv in CHCl3 at reflux)
afforded the fully dehydrated lactam 4ha’. The use of a more
challenging amine with two nucleophilic functionalities
(ethanolamine, 2 f) did not affect the course of the reaction;
in this case the E lactam 4 ff was obtained when HCOOH was
employed for the dehydration step of the sequence. Strikingly,
when l-Lys-OEt was used, dehydration with TFA (2 equiv in
CH Cl ) selectively afforded 4ie. This product constitutes
Scheme 4. One-pot synthesis of 5-hydroxy-1H-pyrrol-2(5H)-ones 3.
(
Scheme 4). In particular, the reaction with benzylamine (2a)
resulted in every case in the formation of the desired g-
hydroxy g-lactam (products 3aa–ga). The presence of water
did not affect the reaction outcome, as the use of aqueous
ammonia (2b) or aqueous methylamine (2c) led to the
corresponding lactams 3ab, 3cb, 3 fb, and 3dc in good yields.
Importantly, sensitive moieties, such as an iodide (in furan
1
1
c), an olefin (in furan 1d), or even a keto group (in furan
g), remained untouched during the cascade reaction
2
2
sequence. Furthermore, different furan substitution patterns
see 1e and 1 f) are tolerated, thus increasing the synthetic
scope of the current methodology. Branched amines (such as
d) are not suitable substrates for this reaction; product 3ad
not shown) was only produced in very low yield. We could
take advantage of this feature to distinguish between different
amine groups in the same substrate; for example, when we
used an ester of the naturally occurring amino acid l-lysine
a close analogue of DNA fragmentation products seen when
DNA lesions, formed by oxidative damage, interact with
(
[
16]
various l-lysine-rich proteins.
Compounds of type 3 and 4 are important intermediates
2
(
[19]
whose manipulation via an N-acyliminium ion (NAI) can
furnish complex nitrogen-containing polycycles. Thus, if an
intramolecular nucleophilic addition of an aromatic nucleus
[20]
to the NAI (a Pictet–Spengler cyclization) is incorporated
into the one-pot sequence, the sequence concludes with the
(l-Lys-OEt, 2e), 3ae was formed exclusively.
[
9a,b,10b,21]
Having synthesized a variety of 5-hydroxy-1H-pyrrol-
(5H)-ones, we now focused on the one-pot formation of their
formation of a tricycle 5 (Scheme 6).
This structural
2
motif is of high value owing to its appearance in many
[
22]
dehydrated counterparts, 5-ylidenepyrrol-2(5H)-ones 4. The
same protocol was applied, and all that was required to
efficiently obtain the desired products was the addition of an
acid in the final stage of the sequence (Scheme 5). When
ammonia was used and the intermediate 5-hydroxy-1H-
pyrrol-2(5H)-one was stirred in HCOOH, the reaction led
synthetic targets, such as the Erythrina alkaloids.
More
specifically, the use of commercially available 2-(3,4-dime-
thoxyphenyl)ethanamine (2g) gave the desired products of
type 5 (Scheme 6) via the corresponding g-hydroxy g-lactams
of type 3. HCOOH was found to be the acid of choice for the
formation of the intermediate N-acyliminium ion, which
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Communications
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[
1H-pyrrol-2(5H)-ones or 5-ylidenepyrrol-2(5H)-ones. The
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Angewandte
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Communications
Synthetic Methods
D. Kalaitzakis, A. Kouridaki, D. Noutsias,
T. Montagnon,
G. Vassilikogiannakis*
&&&& — &&&&
A reagent with two hats: A highly efficient
and general singlet-oxygen-initiated one-
pot transformation of readily accessible
furans into 5-hydroxy-1H-pyrrol-2(5H)-
ones was developed (see scheme, right)
and extended to the synthesis of other
high-value a,b-unsaturated g-lactams.
This useful set of transformations relies
on both the photosensitizing ability and
the redox properties of methylene blue
(MB), the reactivity of which differs from
that of rose Bengal (RB).
Methylene Blue as a Photosensitizer and
Redox Agent: Synthesis of 5-Hydroxy-1H-
pyrrol-2(5H)-ones from Furans
6
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!