One-Pot Synthesis of Functionalized Fused Furans via a BODIPY-Catalyzed Domino Photooxygenation

Article abstract of DOI:10.1002/chem.201706087

Six-membered ring fused furans containing a tetrasubstituted tertiary carbon were prepared in an unprecedented one-pot BODIPY-catalyzed domino photooxygenation/reduction process. A series of functionalized furans was synthesized from readily available 2-alkenylphenols and mechanistic studies were performed to account for the domino photosensitized oxygenation.

Full text of DOI:10.1002/chem.201706087

A Journal of
Accepted Article
Title: One-Pot Synthesis of Functionalized Fused Furans via a BODIPY
Catalyzed Domino Photooxygenation
Authors: Audrey Mauger, Jonathan Farjon, Pierrick Nun, and Vincent
Coeffard
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To be cited as: Chem. Eur. J. 10.1002/chem.201706087
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One-Pot Synthesis of Functionalized Fused Furans via a
BODIPY-Catalyzed Domino Photooxygenation
Audrey Mauger,[a] Jonathan Farjon,[a] Pierrick Nun,[a] and Vincent Coeffard*[a]
Abstract: Six-membered ring fused furans containing
a
tetrasubstituted tertiary carbon were prepared via an unprecedented
one-pot BODIPY-catalyzed domino photooxygenation/reduction
process. A series of functionalized furans was synthesized from
readily available 2-alkenylphenols and mechanistic studies were
performed to account for the domino photosensitized oxygenation.
Photosensitized oxygenation is
a convenient process to
introduce oxygen atoms into organic architectures. This strategy
requires the combination of light, oxygen and a photosensitizer
to produce highly reactive oxygen species (ROS) such as singlet
oxygen (1O2).[1] Singlet oxygen is an excited state of molecular
oxygen and its high reactivity towards electron-rich substrates
has been harnessed in various domains of science such as
medicine (photodynamic therapy), materials science and
wastewater treatment.[2] From a synthetic standpoint,[3] reactions
of singlet oxygen include Schenck-ene reactions,[4] [2+2]- and
[4+2]-cycloadditions,[5] heteroatom oxidation[6] and C-H
functionalization of inert bonds.[7] Over the past decades, there
has been a growing interest in domino reactions which can
produce an important increase of molecular complexity via one-
pot reactions without isolation of intermediates, work-up and
purification.[8] Within this context, multiple oxyfunctionalization by
means of singlet oxygen has enabled the straightforward
synthesis of oxygenated products. For instance, the ene/[4+2]-
cycloaddition cascade photooxygenation strategy has been
applied to acyclic polyenes and cyclohexa-1,4-dienes for the
preparation of functionalized oxygenated architectures.[9]
Scheme 1. Domino photooxygenation strategy.
Starting from readily available 2-alkenylphenols, we
envisioned that electrophilic singlet oxygen would first react with
the electron-rich phenol moiety leading to the hydroperoxide A.
This intermediate would react through a [4+2]-cycloaddition with
another molecule of singlet oxygen to afford B, which would be
further reduced to the targeted furans. Challenges to this
strategy
includes
chemoselectivity
issues
(phenol
dearomatization versus [2+2]-cycloaddition between 1O2 and the
alkene or Schenck-ene reaction if R2 is an alkyl group), further
Aromatic
substrates such as
styrene derivatives,[10]
undesired photooxygenation of the product
B
and
dihydronaphthalenes,[11] and furans[12] also underwent singlet
oxygen-mediated multiple oxyfunctionalization.[13] Despite
significant contributions, domino photooxygenation remains
implementation of a one-pot protocol. Nevertheless, the finding
of suitable conditions would pave the way to an untrodden route
towards functionalized six-membered ring fused furans found in
natural products such as Evodone,[16] Eupachinin A[17] and
Icacinlactone F.[18]
limited to
a scant number of substrates and reaction
combinations. In addition, to the best of our knowledge, singlet
oxygenation of phenol derivatives have never been embedded in
multiple domino oxyfunctionalization while para-substituted
phenols are known to react with singlet oxygen.[14] As part of our
ongoing research into the implementation of dearomative
processes,[15] we report herein an unprecedented domino
photooxygenation process towards fused furans from readily
available 2-alkenylphenols (Scheme 1).
[a]
A. Mauger, Dr. J. Farjon, Dr. P. Nun, Dr. V. Coeffard.
Université de Nantes, CNRS, Chimie Et Interdisciplinarité:
Synthèse, Analyse et Modélisation (CEISAM), UMR CNRS 6230,
Faculté des Sciences et des Techniques; 2, rue de la Houssinière,
BP 92208, 44322 Nantes Cedex 3 – France.
Figure 1. Natural compounds with cycloalka[b]furan moiety.
At the outset of our studies, we focused on the optimization
of the domino photooxygenation process. Our investigations
began with the reaction of phenol 1a in the presence of 2 mol%
of photosensitizer under oxygen atmosphere and light irradiation
(Table 1).
E-mail: vincent.coeffard@univ-nantes.fr
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Optimization of the reaction conditions.[a]
Figure 2. Photosensitizer 4.[20]
25°C had
a
negative impact both on the yield and
diastereoselectivity (entry 7). The influence of the reaction
medium was then investigated by screening various solvents
(entries 8-12). When CDCl3 was replaced by its C-H isotopomer,
a lower yield was obtained. While acetonitrile enabled the
domino photooxygenation process (23% yield), switching to
methanol, DMF or toluene was detrimental to the oxygenation
reaction. It is worthwhile noting that peroxide products 3a and
3’a turned out to be quite unstable and this prompted us to
investigate a one-pot reduction step to form table products such
as furans. Having established the best reaction conditions for
the domino photooxygenation step (Table 1, entry 6) we next
turned our focus toward the reduction step. Based on literature
data,[9b] a rapid screening of reducing agents (nBu2S, Co(salen),
Ph3P) showed that thiourea enabled both reduction of the
hydroperoxide and the endoperoxide moiety to afford furan 5a
(Table 2). From a practical point of view, a methanolic solution of
thiourea was added after the photooxygenation step owing to
the limited solubility of thiourea in CDCl3. A series of 2-alkenyl
phenols was prepared to test the scope of our protocol. The
photooxygenation reaction time was extended to 6 h to ensure
full conversion of the starting materials before addition of
thiourea.
Entry
1
PS
Solvent
CDCl3
2a:3a:3’a[b]
Yield [%][c]
n.r.
MB
-
2
TPP
RB
RB
RB
4
CDCl3
MeOH
MeOH
MeOH
CDCl3
CDCl3
CHCl3
MeOH
MeCN
DMF
0:77:23
100:0:0
100:0:0
100:0:0
0:75:25
0:65:35
0:68:32
-
15
5
3
4[d]
5[e]
6
10
16
65
46
48
n.r
23
<5%
8
7[f]
8
4
4
9
4
10
11
12
4
0:60:40
-
4
4
Toluene
0:70:30
[a] Reaction conditions unless otherwise noted: 1a (0.25 mmol), PS
(0.005 mmol), O2, hν (Xe), solvent (4.8 mL), 10°C. n.r.: no reaction. [b]
Determined by 1H NMR analysis on the crude reaction mixture. [c]
Combined isolated yields. [d] 4 mol% of RB was used. [e] 8 mol% of RB
was used. [f] The reaction was performed at 25°C.
Under optimized conditions, the reaction of 1a produced
furan 5a in 53% isolated yield. The introduction of a para-tolyl
substituent (R2) on the substrate did not impinge on the yield
producing 5b in 50% yield. Changing the methyl group on the
aromatic ring from the para-position to the meta- or ortho-
position led to lower levels of yields. As a result, 5c was
produced in 41% yield while 5d was isolated in 35% yield. The
presence of halogen substituents on the substrate was well
tolerated producing the corresponding furans 5e-h in 46-54%
yields. Nevertheless, an increase of the photosensitizer 4
loading (4 mol%) was required for the formation of 5h in order to
ensure full conversion of the starting material after 6 h of
reaction time. Under these conditions, furan 5h was obtained in
54% yield. Electron-donating group such as the ethoxy group on
1i was tolerated affording 5i in 30% yield. In contrast, substrate
1j did not undergo the desired transformation. Under the
photooxygenation conditions, E-Z isomerization of 1j was
observed in crude 1H NMR while no trace of the desired product
was detected. From a synthetic standpoint, it is interesting to
note that the reaction proceeded with similar levels of yields
when the reaction was performed in CHCl3 for 6 h. For instance,
furan 5a was prepared in 45% yield (53% in CDCl3) and the
product 5f was isolated in 53% yield (54% in CDCl3). In addition,
scaling up the reaction in CHCl3 to 3 mmol scale provided 5a in
42% yield after 13 h reaction time.
Commercially available photosensitizers were first tested in
the domino photooxygenation process. The reactions were run
in a typical singlet oxygenation solvent, i.e. CDCl3, for which 1O2
lifetime will be high enough to ensure an optimal reaction rate.[19]
While methylene blue (MB) did not promote the reaction,
tetraphenylporphine (TPP) afforded the products 3a:3’a in 15%
combined isolated yields along with several unidentified by-
products (entries 1 and 2). Two diastereomers were obtained
and full analyses were carried out to unambiguously confirm
their structure (see supporting information for full details). The
reaction using rose Bengal (RB) as a photosensitizer was then
investigated in methanol due to its insolubility in chloroform.
Regardless of the catalyst loading, the hydroperoxide 2a was
obtained in very low yields from 5% to 16% (entries 3-5). We
then turned our attention to the iodo-bodipy photosensitizer 4
which has been successfully applied to singlet oxygen-mediated
transformations such as photooxidation of naphthols (Figure
2).[20] Formation of the desired targets 3a:3’a was seen with 4
(65% yield) at 10°C, while the hydroperoxide could not be
detected in the crude reaction mixture (entry 6). While similar
results were obtained at 0°C, running the reaction at
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Table 2. Substrate scope.[a]
Scheme 2. Control experiments.
[20]
known to produce singlet oxygen 1O2
and superoxide anion
radical O2¯[22] depending on the reaction conditions. No reaction
occurred by running the photooxygenation of 1a with
1
¯ [23]
equivalent of BPN, a quencher of both 1O2 and O2
,
which
confirms the involvement of these species in the domino
1
[a] Reaction conditions unless otherwise noted: 1 (0.25 mmol), 4 (0.005
mmol), O2, hν (Xe), CDCl3 (4.8 mL), 10°C, 6 h followed by addition of
thiourea (1 mmol) in MeOH (2 mL), 40°C, 16 h. The yields in brackets were
obtained for reactions performed in CHCl3 for the photooxygenation step. [b]
4 mol% of 4 was used.
photooxygenation process. The formation of O2 is supported by
the observation that addition of a chemical 1O2 trap such as
anthracene has an important impact on the reaction kinetics.
While a mixture of diastereomers 3a/3’a was obtained in 36%
yield without anthracene, the addition of 3 equivalents of
anthracene led to the formation of 3a/3’a in only 12% yield along
with anthracene-9,10-endoperoxide (98% yield). To further shed
the light on the mechanism, the kinetic profile of the
photooxygenation of 1a was investigated (Figure 3, see
supporting information for full details).
Variations to the R1 substituent on the phenol ring were next
investigated. Ethyl-derived phenol 1k was also amenable to the
photooxygenation reaction providing access to 5k in 58% yield.
The yield decreased when a phenyl-substituted phenol 1l was
used in the reaction and product 5l was isolated in 35% yield.
We then turned our attention to the challenging substrate 1m
bearing a methyl group on the alkene. Similar substrates are
known to undergo singlet oxygen-promoted ene reaction or
oxidative cleavage of the double bond under photosensitized
oxygenation.[21] We were pleased to find that the conditions
enabled the selective formation of furan 5m in 56% yield. The
phenol 1n bearing an additional methyl group on the aromatic
ring is a suitable substrate for the photooxygenation process.
Under optimized conditions, 5n was obtained in 60% yield. In
order to get some insights about the reaction mechanism, a
series of experiments was carried out on the photooxygenation
of 1 (Scheme 2). With reference to our domino strategy depicted
in Scheme 1 and the results gathered in Table 1, the first singlet
oxygen molecule should react with the phenol moiety to give the
corresponding hydroperoxide. This hypothesis was fully
confirmed by performing the photooxygenation of the phenol 1o
bearing an electron-withdrawing substituent on the alkene which
hampers the [4+2] cycloaddition due to a lower reactivity of the
diene towards electrophilic singlet oxygen.[9b] Iodo-bodipy 4 is
Figure 3. Photooxygenation kinetic profile.
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COMMUNICATION
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The yield of the double oxygenated products 3a/3’a
increases as the reaction proceeds while the diastereomeric
ratio remains constant throughout the reaction (d.r., 75/25).
Interestingly, the hydroperoxide intermediate 2a was detected in
the reaction mixture from the very start of the reaction and it
reaches a maximum concentration after 1 h. In line with results
of Scheme 2, this observation indicates that photooxygenation of
1a would first lead to the intermediate 2a which would react with
a second equivalent of singlet oxygen to produce 3a and 3’a.
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73/27) and these results were in complete agreement with the
results depicted in Table 1 (entry 6). In addition, careful analyses
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side-products at the end of the photooxygenation protocol which
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Central to the implementation of the one-pot strategy is the
photosensitized
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Acknowledgements
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Keywords: heterocycles • photochemistry • homogeneous
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Entry for the Table of Contents (Please choose one layout)
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A. Mauger, J. Farjon, P. Nun, V.
Coeffard*
Page No. – Page No.
One-Pot Synthesis of Functionalized
Fused Furans via a BODIPY-
Catalyzed Domino Photooxygenation
Enlightening domin1O2: In this report, a one-pot photosensitized double
oxygenation/reduction process was developed. This strategy provided access to
six-membered ring fused furans containing a tetrasubstituted tertiary center.
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