Simple and efficient syntheses of 2-hydroxy-3H-phenoxazin-3-ones by aerobic oxidative cross-cyclocondensation in water

Article abstract of DOI:10.1039/d0gc03861j

A novel, simple and versatile synthetic approach that utilized natural renewable low-toxic gallic acid as an organocatalyst was developed for efficient aerobic oxidative cross-cyclocondensations of equimolar 2-aminophenols and 2-hydroxylphenols to afford various 2-hydroxy-phenoxazin-3-ones with moderate to high isolated yields at room temperature in water.

Full text of DOI:10.1039/d0gc03861j

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Simple and efficient syntheses of 2-hydroxy-
H-phenoxazin-3-ones by aerobic oxidative
cross-cyclocondensation in water†
3
Cite this: Green Chem., 2021, 23,
136
1
Received 14th November 2020,
Accepted 11th January 2021
a
a
a
b
Wenhao Li,‡ Wenxue Duan,‡ Qingxuan Tang, Zhan-Ting Li * and
a
DOI: 10.1039/d0gc03861j
Guanyu Yang
*
rsc.li/greenchem
9
A novel, simple and versatile synthetic approach that utilized of 4%. Small quantities of HPXO were found as byproducts in
natural renewable low-toxic gallic acid as an organocatalyst was the reaction of o-aminophenol and p-benzoquinone in acetic
1
0
3 6
developed for efficient aerobic oxidative cross-cyclocondensations acid, and K [Fe(CN) ] oxidation of 3-hydroxyanthranilic acid
1
1
of equimolar 2-aminophenols and 2-hydroxylphenols to afford in ethanol. Moreover, the common method for HPXO synth-
various 2-hydroxy-phenoxazin-3-ones with moderate to high iso- eses with hydroxy substitution of 2-amino-PXO requires strong
7
,8,12
lated yields at room temperature in water.
acidic media (Fig. 1A).
Therefore, to develop new environ-
ment-friendly methods for the synthesis of HPXO with a high
yield is highly desirable.
3
H-Phenoxazin-3-one (PXO), a widespread natural chromo-
1
phore, was used as a dye and pigment in ancient times, and
later developed as a probe for bio-imaging in modern days.
PXO derivatives are reported to demonstrate bioactivities to be
used for the treatment of malarial, cancer, inflammatory, bac-
terial infection, neurodegenerative and other diseases.
Actinomycin D is one of the most extensively studied PXO
derivatives, which embodies a 2-amino-PXO scaffold and dis-
plays
Xanthommatin, a natural 2-amino-PXO biochrome, is abun-
dant in insects, arachnids, and cephalopods. It is of great
interest to develop synthetic methodology to prepare new PXO
derivatives. The previous synthetic efforts have focused on
For sustainable development, green synthesis is highly
desirable focusing on environment-friendly manufacturing,
and safe and low cost production. Over the past few decades,
aerobic oxidations in aqueous solution continue to receive
considerable attention from industry and academia due to the
use of the most environment-friendly solvent and oxidant with
2
3
13
the lowest cost. Undoubtedly, aerobic oxidation in water is
4
both
antibiotic
and
anticancer
bioactivity.
desirable since it would avoid the use of flammable organic
solvents and the risk of explosion. Recently, we successfully
developed a novel and highly efficient methodology to prepare
disulfanes in water that used naturally renewable, inexpensive
and low-toxic gallic acid (GA) as an organocatalyst, inexpensive
5
6
2
-amino-PXOs. Yoo and Rill discovered that hydroxyl-actino-
MnCO
3
as a co-catalyst, and dioxygen as the terminal
mycin D, which had 2-hydroxy-3H-phenoxazin-3-one (HPXO)
as the central chromophore structure instead of original
14
oxidant. Remarkably, this simple metal–organic cooperative
catalytic protocol follows a single-electron-transfer route.
Herein we expand this GA/Mn system to catalyze the cross-
2
-amino-PXO, showed unusually high selectivity to DNA
7
binding. An efficient synthetic method for HPXOs is expected
to be highly valuable. Nevertheless, there are few reports on
8
the synthesis of HPXO. For instance, laccase-mediated homo-
dimerization of 3-amino-2-hydroxybenzenesulfonic acid in
methanol/H O gave HPXO-1,6-disulfonic acid with a poor yield
2
a
Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou,
4
50001, China. E-mail: yangguanyu@zzu.edu.cn
b
Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and
Innovative Materials, Fudan University, Shanghai 200438, China.
E-mail: ztli@fudan.edu.cn
†
Electronic supplementary information (ESI) available. CCDC 2012640–2012644,
2020211, 2020212 and 2023111. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/d0gc03861j
These authors contributed equally.
Fig. 1 The previous and present methods to synthesize HPXO
derivatives.
‡
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cyclocondensations of 2-aminophenols (1) and 2-hydroxylphe-
nols (2) to prepare HPXOs (3), a synthetic transformation that
has not been reported previously (Fig. 1B).
1
4
Based on the optimal conditions of our previous research,
the initial experiment was carried out using equimolar
-aminophenol (1a) and 2-hydroxylphenol (2a) as the test sub-
strates with 0.25 mol% GA and Mn(OAc) (0.25 mol%) under
.3 MPa of dioxygen at pH 9 and for 3 h at room temperature.
For the convenience of operation, the experiment used
Mn(OAc) rather than MnCO since both of them have similar
2
2
0
2
3
catalytic activity and Mn(OAc) has a higher solubility in water.
2
HPLC detection showed that the initial reaction afforded a
mixture of products, including ca. 48% HPXO (3a), 43%
2
-amino-PXO (4a), and 9% other products. The result indi-
cated that cross-cyclocondensation of 2a to 3a and homo-
dimerization of 1a to 4a occurred together. Solubility tests
revealed that, in basic water, 2a dissolved much more quickly
and had a higher solubility than 1a. In the earlier stage of the
reaction, a considerable amount of 1a was not dissolved,
which might partially account for the yield of multiple pro-
ducts. Subsequently, the reaction was pretreated with ultra-
sonication, and different pH values were screened with a lower
reactant concentration (Fig. 2). As pH changed from 7.0 to
1
1.0, the yield of the cross-cyclocondensation product also
varied. Remarkably, at pH = 10.0, 3a could be obtained with a
6.4% HPLC yield. However, at pH = 11, the yield of 3a
Scheme 1 The control experiments and proposed mechanism.
9
dropped. The possible reason is that 3a degraded under the
strong basic conditions.
To gain some insights into reaction route of cross-cyclocon- When fresh o-benzoquinone, which was prepared according to
1
5
densation, control experiments were carried out (Scheme 1). the reported method, was added into the aqueous solution
HPLC traces (Scheme 1A) showed that, in the control experi- of 2-aminophenol, the orange 3a precipitated immediately,
ment of oxidation of 2a alone at pH 10, about half of 2a was and o-benzoquinone almost disappeared (Scheme 1B). As
2
+
converted to o-benzoquinone in 20 seconds. Under the same described before, the redox cycle of GA/Mn could catalyze
1
4
conditions, the cross-cyclocondensation of 1a and 2a gave a the single-electron aerobic oxidation. Moreover, electron
high yield of 3a as the major product and 4a as the byproduct. paramagnetic resonance study of the oxidation of GA indicated
that GA forms its radicals as a function of pH and radical con-
1
6
centration was 1000 times higher at pH 13 than that at pH 9.
Thus, we proposed that in the cross-cyclocondensation the
more radical species that were formed from GA at the higher
pH would significantly accelerate the areobic oxidation, and 2a
converted rapidly to the corresponding o-benzoquinone, which
was beneficial for its subsequent 1,4-additions with the
nucleophilic N atom of 1a (Scheme 1C). Consequently, the
cross-cyclocondensation completed within 0.5 h and selectively
afforded 3a. Notably, the gram-scale test gave a 98% isolated
yield of 3a by a simple work-up of acidification, centrifugation
and recrystallization, well illustrating its practical application.
Finally, the above reaction conditions were applied to
expand the substrate scope. Table 1 provides the results of the
corresponding cross-cyclocondensations between equimolar 1
and 2. The corresponding HPXO products 3a–z were obtained
with moderate to high isolated yields by simple work-up of
acidification, centrifugation and recrystallization. Whether
substituents belong to electron-donating groups, such as
methyl and methoxyl, or electron-withdrawing groups, such as
fluoro, chloro, bromo, carboxyl, and sulfonic, all reactions
Fig. 2 The pH effect on cross-cyclocondensation between 1a and 2a.
Reaction conditions: 1a (1.0 mM), 2a (1.0 mM), H O (50 mL), ultra-
sonication, GA (0.25 mol%), Mn(OAc) (0.25 mol%), O (0.3 MPa), 1 h,
50 mL autoclave. HPLC detection. The pH values were adjusted with
2
2
2
1
NaOH.
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Table 1 The syntheses of HPXZs 3a–z by the cross-cyclocondensa-
a
tions [product number, reaction time (min), isolated yield]
Scheme 2 The probable reaction route of regioselective cross-cyclo-
condensation between 1 and 3-substituted 2.
A possible reaction route is shown in Scheme 2. During the
cross-cyclocondensation, by basic deprotonation, 1a converted
to its anion with an intermolecular H bond between N and O
atoms. Moreover, the intermediate o-benzoquinone contained
two Michael addition electrophiles. Then two consecutive
Michael additions took place; the first is an intermolecular
aza-Michael addition at the 5C site of o-benzoquinone and the
second one is an intramolecular oxa-Michael addition at the
4C site. When 3-substituted 2-hydroxylphenol was used, aza-
Michael additions at the 5C site generated 4-substituted hydro-
xyphenoxazinone, while at the 4C site gave a 1-substituted
product. However, since the steric hindrance of substituent at
the 3C site of 2 could completely suppress aza-Michael
additions at the 4C site, the cross-cyclocondensations afforded
4-substituted-2-hydroxyl-phenoxazinones 3d–y with excellent
regioselectivity. In contrast, smaller F could not restrain the
occurrence of aza-Michael additions at the 4C site, and so the
reaction of 3-F-2-hydroxylphenol and 1a gave the mixed pro-
ducts of 3z–4 and its positional isomer 3z–1 in the ratio of
1
8
3 : 17 ( H NMR ratio). Moreover, our tests found that the reac-
tion of 1a with 2,3-dihydroxybenzoic acid or its ester could not
afford the desired HPXO but 4a as a main product, maybe
because the cross-cyclocondensations were prevented by the
steric hindrance of much bigger carboxyl groups. Nevertheless,
these further demonstrated the substituent-oriented regio-
selectivity of the cross-cyclocondensation. However, 3u–w and
a
Reaction conditions: 1s (1.0 mM), 2s (1.0 mM), GA (0.25 mol%), Mn
(OAc)
2
(0.25 mol%), H O (50 mL), pH 10, ultrasonication, 25 °C,
2
b
1
50 mL autoclave. 1 (10.0 mM), 2 (10.0 mM).
3y could be obtained by the reactions between 2-aminophenols
and 3-cyano-2-hydroxylphenol, where the cyano group was
completely oxidatively hydrolysed to the carboxyl group.
were completed within less than 1 h, whereas the electronic
properties of the substituents for both substrates did not
impose a significant effect. For potential applications of the
HPXO derivatives as drugs and fluorescent probes, the intro-
Conclusions
duction of water-soluble groups should be indispensable. In summary, we have developed a novel, highly efficient and
Fortunately, compounds 3s–y that bear one or two carboxyl or versatile methodology for the preparation of 2-hydroxy-phenox-
sulfonic group(s) could be produced successfully. However, azinones using natural renewable gallic acid as an organo-
probably owing to their high water solubility, their isolated catalyst. Mn(OAc) is used as a cocatalyst, dioxygen as terminal
2
yields were not as high as their HPLC yields.
oxidant and water as solvent. Under very mild conditions, the
It was interesting to find the excellent substituent-oriented methodology allows the syntheses of various 2-hydroxy-phe-
regioselectivity for products in the cross-cyclocondensation of noxazinones in moderate to high yields through the aerobic
3
-substituted 2. No matter whether the substituents were elec- oxidative cross-cyclocondensation of equimolar 2-aminophe-
tron-donating or electron-withdrawing groups, the reactions nols and 2-hydroxyphenols. The reactions proceeded in a
gave 4-substituted hydroxyphenoxazinones as the sole product tandem sequence of aerobic oxidation and double Michael
(see single crystal diffraction patterns in ESI†) without the pos- 1,4-additions in a simple one-pot procedure. And the excellent
itional isomer 1-substituted products in almost all cases. substituent-oriented regioselectivity existed in the cross-cyclo-
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condensation of 3-substituted 2-hydroxylphenols. Notably, the
gram scale test maintained high reaction efficiency. Thus, the
methodology with a low catalyst loading and simple isolation
paves the way to future development of sustainable reactions
for the synthesis of industrially and biomedically important
HPXO derivatives.
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