Multicatalytic dearomatization of phenols into epoxyquinols: Via a photooxygenation process

Article abstract of DOI:10.1039/c9cc03068a

A multicatalytic photooxygenation of substituted phenols in the presence of rose bengal and cesium carbonate under green LED light is reported. This transformation enabled the introduction of both atoms of singlet oxygen and led to the one-pot synthesis o

Full text of DOI:10.1039/c9cc03068a

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DOI: 10.1039/C9CC03068A
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Multicatalytic Dearomatization of Phenols into Epoxyquinols via a
Photooxygenation Process
Louis Péault, Pierrick Nun, Erwan Le Grognec, Vincent Coeffard*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A multicatalytic photooxygenation of substituted phenols in the several reasons: i) the oxygen source is natural dioxygen; ii)
presence of rose bengal and cesium carbonate under green LED most of the photooxygenation processes demonstrate excellent
light is reported. This transformation enabled the introduction of atom economy as the transformation is initiated by light rather
both atoms of singlet oxygen and led to the one-pot synthesis of than an extra reagent and iii) mild reaction conditions are
9
epoxyquinols in a stereoselective way.
usually required. The high electrophilicity of singlet oxygen and
its ease of synthesis make this oxidant an efficient tool for a
Dearomatization is an attractive process to achieve the
10
diverse panel of oxidative transformations. For instance,
photooxygenation of para-substituted phenols followed by in-
situ reductive work up led to the selective formation of para-
quinol architectures (Scheme 1), and this sequence has found
widespread applications in total synthesis or in the preparation
3
synthesis of sp -rich tridimensional molecular architectures
1
from aromatic compounds. Besides the increase of molecular
complexity, this strategy offers a wealth of molecular targets in
light of the vast reservoir of aromatic substrates available to
synthetic chemists. Within the field of dearomatization, phenol
valorisation allows for the rapid and efficient construction of
densely functionalized oxygenated compounds from readily
11
12
of functionalized building blocks. Nevertheless, the reductive
protocol lowers the synthetic appeal of this transformation
because one oxygen atom from dioxygen is transferred to the
reductive agent (Scheme 1, a). In order to take advantage of the
full potential of photooxidative dearomatization, we recognized
that a full transfer of the oxygen atoms will push the limit of
photooxygenation into untrodden synthetic directions. Our
plan was to trigger the singlet-oxygen mediated oxidation of
para-substituted phenol by using a multicatalytic system
2
available substrates. The hydroxyl group directly attached to
the aromatic ring increases the electron density in the pi system
and this feature has been harnessed to implement oxidative
3
dearomatization.
Strategies
in
which
oxidative
dearomatization of phenols can be achieved includes
4
hypervalent iodine-mediated reactions, single electron
5
transfer (SET) processes,
transformations.
and alternative oxidative
13
involving a photosensitizer and a base (Scheme 1,b).
6
Nevertheless, the requirement of
stoichiometric amounts of oxidant, the lack of control of the
site-selectivity and the formation of by-products after the
oxidation step impinge on the synthetic interest of oxidative
dearomatizations. One approach in which these limitations can
be circumvented is through the use of singlet oxygen-mediated
7
1
2
processes. Singlet oxygen ( O ) is an excited state of molecular
oxygen which can be efficiently produced upon irradiation of a
8
photosensitizer (PS) in the presence of oxygen. Organic dye-
sensitized photooxygenation of aromatic compounds such as
phenols was deemed particularly worthy of investigation for
Univ. Nantes, CNRS, CEISAM UMR CNRS 6230, F-44000, Nantes - France.
E-mail: vincent.coeffard@univ-nantes.fr
Electronic Supplementary Information (ESI) available: Experimental procedures,
Scheme 1 Expanding the field of phenol photooxygenation.
1
13
spectroscopic data and copies of
DOI: 10.1039/x0xx00000x
H
and
C
NMR spectra. See
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Journal Name
Based on literature data, basic conditions would enable the
intramolecular addition of the hydroperoxide anion to the
View Article Online
DOI: 10.1039/C9CC03068A
enone moiety (A to B) leading to the installation of the epoxide
14
function in a stereoselective way (Scheme 1). Our strategy
would offer a selective and expedient way to synthesize
epoxyquinols which are commonplace in natural products such
as epoxysorbicillinol and macrophorin A (Fig. 1). 15 At the outset
of our studies, we surmised that the introduction of an electron-
Fig. 1 Natural product frameworks.
1
stabilizing substituent (R ) at the ortho-position of the phenol
would influence both the regioselectivity and the kinetics by
The use of 5 mol% of cesium carbonate led to a mixture of
(19%) and (12%) while only the hydroperoxide was
obtained in 28% yield in the absence of the base (entries 4 and
). As expected, these results showed the importance of the
base for the transformation of the hydroperoxide into the
desired product 2a. High loading of cesium carbonate led to
degradation while low loading did not enable the selective
formation of 2a. Switching from methanol to ethanol or
acetonitrile did not improve the yield (entries 6 and 7). By using
the reaction conditions reported in entry 3, we studied the
influence of the photosensitizer loading. An increase of the
reaction yield was observed when lowering the photosensitizer
loading from 4 mol% to 1 mol% while the use of 0.5 mol% gave
similar levels of yields than using 4 mol% (entries 3, 8-10).
Therefore, the best reaction conditions (entry 9) involve the use
stabilization of the anion
B (Scheme 1). Based on our work
2
a
3
3
devoted to the catalysed domino photooxygenation of
16
2
-alkenylphenols, we identified these compounds as ideal
5
substrates and rose bengal (RB) as the most relevant
photosensitizer to implement our strategy. First, the reaction
conditions were optimized by studying the photooxygenation of
3
(E)-4-methyl-2-styrylphenol 1a as a model reaction (Table 1).
Initially, we employed 4 mol% of rose bengal and 1 equiv. of
cesium carbonate in methanol to oxidise phenol 1a (entry 1).
Under these conditions, a complex reaction mixture was
obtained and similar results were observed by using 50 mol% of
cesium carbonate (entry 2). Decreasing the amount of base had
a positive impact on the reaction outcome because the desired
product 2a was obtained in 53% yield (entry 3). Only one
diastereomer was observed and full analyses were carried out
to confirm the structure and the relative stereochemistry of 2a
2 3
of 1 mol% of RB and 15 mol% Cs CO in methanol. Under these
reaction conditions, the epoxyquinol 3a was isolated in 50%
yield (entry 9). Having established the best reaction
conditions, the scope of the photooxidative dearomatization
using a multicatalytic system was explored (Scheme 2). The
reaction proceeded smoothly with phenols decorated by a
methyl group on the aromatic part of the styryl moiety.
Regardless of the methyl position, good isolated yields were
obtained ranging from 47% (2d) to 65% (2b). The introduction
of a halogen atom on the phenyl ring (1e-g) gave slightly better
yields than their phenyl counterpart 1a. For instance, the
fluorine product 2e was obtained in 62% yield and compounds
(
see electronic supplementary information, ESI, for details).
Under the reaction conditions reported in entry 3, other
inorganic (Na CO ) and organic (AcONa, Et N) bases were
2
3
3
considered but diminished yields were observed.
Table 1 Reaction optimizationa
2f and 2g were isolated in 57% and 64% yields respectively. Use
of the substrate 1j, which contains two chloro substituents, led
to a lower yield than compared to the reaction with 1f. Electron
withdrawing groups such as nitro and ester substituents were
well tolerated and compounds 2h was isolated in 49% yield
while the ester derivative 2i was obtained in 65% yield.
Nevertheless, oxidation of a phenol bearing an electron
donating group (OEt) at the para position of the phenyl ring led
to complete decomposition, probably because of competing
overoxidation by singlet oxygen. Phenols 1k and 1l bearing an
alkenyl group substituted by ester or acetyl functional groups
were amenable to the photooxygenation by providing 2k and 2l
Entry
Catalyst loading
4 mol% RB, 1 equiv. Cs
4 mol% RB, 50 mol% Cs
4 mol% RB, 15 mol% Cs
4 mol% RB, 5 mol% Cs
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
MeCN
MeOH
MeOH
MeOH
Yield 2a (%)b
1
2
3
4
5
6
7
8
9
2
CO
3
-c
c
2
CO
CO
3
-
2
3
53
d
2
CO
3
19
e
4 mol% RB, no Cs CO
2
3
28 (3)
4 mol% RB, 15 mol% Cs
4 mol% RB, 15 mol% Cs
2 mol% RB, 15 mol% Cs
1 mol% RB, 15 mol% Cs
2
CO
3
43
n.r.
59
2
CO
2
CO
2
CO
3
2
in 55% and 75% yields, respectively. Variation to the R group
3
f
3
65 [50]
was investigated and the derivative 1m was smoothly oxidised
to the product 2m in 70% yield. Pleasingly, the substrate 1n
substituted by an additional methyl group on the phenol ring
gave rise to the desired product in 40% yield. The reaction
1
0
0.5 mol% RB, 15 mol% Cs
2
CO
3
47
a
2
Reaction conditions unless otherwise noted: 1a (0.25 mmol), RB (cat.), base, O ,
green LED, solvent (5 mL), 3h, rt; n.r.: no reaction. Yields were determined by H
b
1
NMR using an internal standard. Complex reaction mixture was obtained. d 12% proceeded well by replacing the styryl moiety by an ester
c
of 3 was also observed. compound 2a was not detected. f Isolated yield under
square bracket.
e
function (2o, 46%). The oxidation of 1p led to epoxide 2p in 26%
yield along with some as-yet unidentified side products.
2
| J. Name., 2012, 00, 1-3
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Scheme 2 Substrate scope. Reaction conditions:
1
(0.25 mmol), RB (0.0025 mmol), Cs
2
CO
3
(0.0375 mmol), O
2
, green LED, MeOH (5 mL), 3h, rt. Isolated yields are
3
reported. For the substrate 1q, the photooxygenation was followed by a reductive step: PPh (0.25 mmol), 1h, rt (see ESI for details).
Starting from 1q, the major product was 2’q (60%) while the less
To interrogate the nature of active oxygen species involved
substituted epoxide 2q was isolated in 11% yield. The reaction into the oxidation process, quenching experiments were
was also tested on 4-methylphenol and 2-formyl-4- performed. Under optimized conditions, oxidative
methylphenol but both failed to afford the desired products dearomatization of phenol 1a produced the desired product 2a
see ESI for details). The photooxidative dearomatization turned in 50% yield. The reaction in the presence of 2 equiv. of radical
(
out to be robust to scale up. Starting from one gram of 1a, the trap 2,2,6,6-Tetramethylpiperidinyloxy (TEMPO) had only a
product 2a was isolated in 41% yield after 13 h of reaction time. slight effect on the isolated yield which would rule out a radical
In order to get a better insight of the reaction mechanism, mechanism for the photooxygenation of 1a into 2a. In addition,
control experiments were carried out (Scheme 3).
running the reaction in the presence of sodium azide (3 equiv.)
which is a strong physical quencher of singlet oxygen shut down
the reaction. Therefore, singlet oxygen plays a pivotal role in the
photooxygenation of phenol 1a into the product 2a
.
Optimization studies proved that basic conditions are essential
for the formation of the epoxide function of 2a because
performing the reaction without cesium carbonate stopped the
process at its early stage with the isolation of the hydroperoxide
intermediate
3 (Table 1, entry 5). Next, we wondered whether
cesium carbonate would influence the photooxygenation step.
A dramatic increase of the kinetic was observed for the
photooxygenation of para-cresol
4 in the presence of 15 mol%
of cesium carbonate which could be due to the increase of the
electron density on the phenyl ring by phenol deprotonation.
Based on the above results, a plausible catalytic cycle starting
from 1a is depicted in Scheme 4. A similar mechanism could be
envisaged with other substrates 1.
Scheme 3 Control experiments.
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1
7
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I
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In summary, a singlet oxygen-mediated dearomative
process of para-substituted phenols has been developed. Using
a catalytic system composed of rose bengal and cesium
carbonate under green LED light irradiation, a series of
epoxyquinols bearing three contiguous stereocentres has been
prepared in a stereoselective way. The reaction is easy to
implement and involves mild conditions, readily prepared
phenolic substrates and commercially available catalysts.
We thank Ecole Normale Supérieure Paris-Saclay for the
award of a Master scholarship to LP. We acknowledge financial
support from University of Nantes and CNRS.
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Conflicts of interest
There are no conflicts to declare.
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5
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0
5 To the best of our knowledge, only one example of one-pot
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product is isolated along with the 4-hydroperoxy-2,5-
cyclohexadienon-1-one product as the major compound. See
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