Heterogeneous Manganese-Catalyzed Oxidase C?H/C?O Cyclization to Access Pharmaceutically Active Compounds

Article abstract of DOI:10.1002/cctc.201901659

Heterogeneous manganese-catalyzed C?H oxidative couplings were accomplished to gain access to pharmaceutically relevant 2-aminophenoxazin-3-ones and to diaminophenazine and purpurogallin moieties in excellent yields. The user-friendly K-OMS-2 oxidase strategy proved to be more versatile and robust than enzymatic catalysts-based procedures allowing a wider substrate scope and being effectively reusable as proven by leaching measurements and XRD analyses.

Full text of DOI:10.1002/cctc.201901659

Accepted Article
Title: Heterogeneous Manganese-Catalyzed Oxidase C–H/C–O
Cyclization to Access Pharmaceutically Active Compounds
Authors: Luigi Vaccaro, Francesco Ferlin, Alberto Marini, Lutz
Ackermann, Daniela Lanari, and Nicola Ascani
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ChemCatChem
10.1002/cctc.201901659
COMMUNICATION
Heterogeneous Manganese-Catalyzed Oxidase C–H/C–O
Cyclization to Access Pharmaceutically Active Compounds
[
a]
[a]
[a]
[b]
[c]
Francesco Ferlin , Alberto Marini , Nicola Ascani , Lutz Ackermann , Daniela Lanari , and Luigi
Vaccaro*[a]
Dedication ((optional))
Abstract: Heterogeneous manganese-catalyzed C–H oxidative
couplings were accomplished to gain access to pharmaceutically
relevant 2-aminophenoxazin-3-ones and to diaminophenazine and
purpurogallin moieties in excellent yields. The user-friendly K-OMS-2
oxidase strategy proved to be more versatile and robust than
enzymatic catalysts-based procedures allowing a wider substrate
scope and being effectively reusable as proven by leaching
measurements and XRD analyses.
mimicking the selectivity of enzymes while offering higher
chemical stability, versatility and durability. Heterogeneous
[
8]
[9]-[12]
catalytic systems based on carbon- or inorganic materials
[
9]
such as ferromagnetic nanoparticles, or nanostructured metal
oxides,[ noble metals, or a combination of those,[12] represent
10]
[11]
some prominent examples of this tendency.
We have been inspired by the fact that, to the best of our
knowledge, there is no example in the literature reporting the use
of manganese-based nanostructured materials for C–H oxidative
process able to mimic peroxidase ability in the synthesis of
phenoxazinones or flavins (Figure 1).
Oxidative C–H activation/functionalization represents one of the
most powerful tools for creating or decorating with high precision
organic compounds and access target molecular structures.[
The development of innovative metal catalytic systems able to
directly functionalize carbon–hydrogen (C–H) bonds continues to
progress at a rapid pace due to the significant chemical and
environmental advantages offered by these transformations over
traditional synthetic methods based on pre-functionalization
1], [2]
OH OH
N
NH
O
2
O
HO
O
Questiomycin A
O
antibiotic
OH
HO
O
OH
OH OH
O
HO
HO
[
3]
strategies.
At this concern, besides the major efforts and contributions from
chemists, Nature is undoubtedly magnificent source of
HO
HO
OH
a
Theaflavin
anti-HIV-1
Purpurogallin
TLR1/TLR2 inhibitor
inspiration when it comes to the ability of creating complex
molecular systems. Enzymes oxidases and peroxidases can
highly selective recognize substrates and promote specific
Figure 1. Relevant APIs prepared by a bio-synthetic approach.
[
4]-
reactions, including C–H activation/functionalization processes.
In this contribution we report that the manganese oxide molecular
sieve K-OMS-2, with a rigid MnO framework composed of MnO
2 6
octahedral building blocks and one-dimensional square tunnel
[
5]
Some representative targets for the definition of bio-inspired C–
H oxidation processes are reported in Figure 1.
While the development of specific enzymatic processes is an
important goal of synthetic chemistry,[ there are significant
challenges to be considered for their practical application e.g.
enzyme expression/purification, cofactor supply, but above all,
stability to organic solvents, oxygen tolerance, and substrate
structure (4.6 Å), which contain guest cations (in the present case,
6]
K+) are highly effective in mimicking peroxidase properties.[13] In
particular, we have focused our study on potassium-containing
Octahedral-Molecular-Sieves (K-OMS) first prepared and
[14]
developed by Suib.
[
7]
scope.
These structures are composed by manganese oxide tunnels with
A strategic challenge would be the development of metal catalytic
systems able to promote key oxidative C–H functionalizations
[15]
cryptomelane-type morphology.
The structure of this entities
can be tuned by exchanging the ions into the tunnels as well as
by isomorphic substitution. Recently, it has been demonstrated
that such materials can catalyze, among others, a plethora of
oxidation reactions and possess a great ability to reduce oxygen.
Furthermore, they are air- and moisture-stable and many
[
a]
Dr. F. Ferlin, Alberto Marini, Nicola Ascani, Prof. Dr. L. Vaccaro
Laboratory of Green S.O.C., Dipartimento di Chimica, Biologia e
Biotecnologie, Università di Perugia, Via Elce di Sotto 8, 06123
Perugia, Italy
[
16]
methodologies for their synthesis are described in literature.
Herein, we report on the use of K-OMS as a heterogeneous
oxidase system for the C‒H oxidation/dimerization reaction of o-
aminophenols. This process allows the access to 2-
aminophenoxazin-3-one and related diaminophenazine and
purpurogallin moieties and it is classically promoted by
E-mail: luigi.vaccaro@unipg.it
Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie, Georg-August-
Universität Göttingen, Tammannstrasse 2, 37077 Göttingen,
Germany.
[
b]
c]
[
Dr. D. Lanari
Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via
del Liceo 1, 06123 Perugia, Italy
peroxidase enzymes (e.g. Horseradish peroxidase enzyme,
HRP).[17] The typical narrow substrate scope of these processes
limit the access to the corresponding pharmaceutically relevant
active compounds.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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ChemCatChem
10.1002/cctc.201901659
COMMUNICATION
2
h. [b] Determined by GC analysis using sample of pure compounds
We have therefore aimed our study to prove the higher stability of
K-OMS oxidase systems over enzymes, paying attention to
expand the scope of the accessible molecular structures and
towards the identification of the optimal reaction conditions
allowing the minimal metal leaching and the full recovery and
as references. [c] Determined by ICP-AES analysis.
By taking o-aminophenol (1a) as representative substrate, we
started our study on the influence of different media and oxidants
on the reaction (Table 1). On each final reaction mixture, we have
also evaluated the leaching of the manganese species in the
different media used and the manganese content in the recovered
catalysts, in order to have information on the nature of the
mechanism of the reaction. The results are illustrated in Table 1.
In ethanol, toluene or DMF manganese dissolved poorly, whilst,
aqueous pH 7 phosphate buffer represents the medium in which
the highest content of metal was found after the reaction
completion.
EtOH was therefore selected as medium for further optimization
of the reaction conditions being the safest medium that also gave
the best combination of high chemical efficiency and low leaching.
The optimal conditions (Table 1, entry 6) resulted in complete
conversion of the starting material in 2 h, with 97% isolated yield
of the desired product 2a.
reuse of the heterogeneous inorganic catalytic system.
Following the reported methodology,[
15b]
we have prepared the K-
OMS system as illustrated in Figure 2. The catalyst we have used
in this study, was first calcined and, after being washed, isolated
by size exclusion filtration. ICP-AES analysis of the resulting
material gave a manganese loading of 62% w/w. The manganese
average oxidation state was calculated to be 3.8 and the
synthesized K-OMS-2 features the crystal cryptomelane tunnel
structure as proven by XRD spectra, being in accordance with
[
18]
literature.
Moreover EtOH can easily solubilize aminophenols 1 and it is also
compatible with Horseradish peroxidase enzyme (HRP), allowing
the direct comparison of K-OMS-2 with this enzyme under the
same reaction conditions.
2 2 2
In fact, when H O /O system was used as oxidant K-OMS-2 and
HRP efficiencies resulted to be comparable in terms of initial
reaction rate and kinetic of product formation (see ESI). It is also
noteworthy that the use of K-OMS is not strictly limited to the
classical temperature range stability of HRP. In fact, increasing
the temperature from 27 °C to 50 °C or 70 °C, HRP activity
decreases due to its denaturation process, while the K-OMS
remains, as expected, highly active (Table 2).
Figure 2. Schematic overview for the synthesis of K-OMS-2
Table 2. Comparison of reaction between HRP and K-OMS-2.
Catalyst (1.6 mol %)
N
NH2
NH2
OH
H O (3 equiv)
2 2
EtOH (0.25 M)
T °C, 2h
O
O
Figure 3. XRD-pattern of synthesized K-OMS-2
1a
2a
Entry[a]
Catalyst
2 mol%)
T (°C)
Conversion[c]
Table 1. Manganese leaching in different solvent
(
(Isolated yield)
K-OMS-2 (1.6 mol %)
N
NH2
NH2
OH
H O (3 equiv)
2 2
1
2
3
4
5
6
K-OMS-2
K-OMS-2
K-OMS-2
HRP[b]
27
50
70
27
50
70
> 99 % (97 %)
> 99 % (97 %)
> 99 % (97 %)
> 99 % (97 %)
95 % (90 %)
13 %
solvent (0.25 M)
7 °C, 2h
O
O
2
1
a
2a
Entry[a]
Medium
Conversion[b]
Isolated yield)
Mn leaching
[
c]
(
(ppm)
20
31
8
HRP[b]
1
2
3
4
5
6
pH 7 Buffer
> 99 %
> 99 %
82 %
HRP[b]
2
H O
[
2 2
a] Reaction conditions: 2-aminophenol 1a (1 mmol), H O (3 mmol, 3
DMF
DMC
equiv.), K-OMS-2 (1.3 mg, 1.6 mol %), EtOH 4mL (0.25 M), 27 °C, 2h.
[b] HRP (2 mol %, 0.02 equiv, 10 μL of a 12 μM ethanolic solution),
EtOH 4mL (0.25 M), 27 °C, 2h. [c] Determined by GC analysis using
sample of pure compounds as references.
> 99 %
> 99%
13
6
Toluene
EtOH
> 99 % (97 %)
7
As for the enzyme catalyzed process, to fully regenerate the K-
OMS catalyst a terminal oxidizing agent is needed.
[
a] Reaction conditions: 2-aminophenol 1a (1 mmol), H
2 2
O (3 mmol, 3
equiv.), K-OMS-2 (1.3 mg, 1.6 mol %), solvent (4mL, 0.25 M), 27 °C,
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ChemCatChem
10.1002/cctc.201901659
COMMUNICATION
The recoverability and reusability of K-OMS-2 was therefore
investigated by using different conditions and terminal oxidants
and the data are illustrated in Table 3.
It should be noted that when the reaction of 2-aminophenol (1a)
was catalyzed by K-OMS-2 without any other additional oxidizing
agent a yield of 2a of only 63% was obtained (Table 3, entry 1).
are similar (TONHRP = 83, TOFHRP = 41 and TONOMS = 63, TOFOMS
= 31), if considering that we have been recycled our catalytic
system up to 10 times the TON associated to the K-OMS-2
catalyst rise up to 630.
Nonetheless, using H
O
2 2
as terminal oxidant, deactivation of K-
th
OMS-2 occurred after the 4 recycle run (Table 3, entry 2). A
similar behavior was observed when molecular oxygen (1 atm)
was used as the sole sacrificial oxidant (Table 3, entry 3). Further
control experiments also evidenced that higher pressure of
oxygen and inert atmosphere did not facilitated the recoverability
of the catalytic system. A combination of both oxygen (1 atm) and
2 2
H O , resulted to be, very effective and successful reuse the K-
OMS-2 was confirmed for representative 10 runs without any loss
in catalyst efficiency (Table 3, entry 4).
Table 3. Different oxidizing system and related recycling runs
K-OMS-2 (1.6 mol %)
N
NH2
O
Figure 4. XRD-pattern of fresh and used catalysts
NH2
OH
oxidant
EtOH (0.25 M)
O
After the definition of optimized reaction conditions (Table 3, entry
2
7 °C, 2h
4
), we compared the activity of our catalytic system with other
1
a
2a
common oxidation catalysts (Table 4).
Entry[a]
Oxidant
-c
Reuse of
K-OMS
Conversion each
run[ (Yield)
b]
Table 4. Different catalysts/oxidants used in the reaction
Catalyst (1.6 mol %)
H O (3 equiv)
2 2
1
2
3
4
1 run
4 runs
3 runs
10 runs
63 % (58 %)
> 99 % (97 %)
> 99 % (97 %)
> 99 % (97 %)
N
NH2
NH
2
H
2
O
2
(3 eq)
(1 atm)
(3 eq)/
EtOH (0.25 M)
7 °C, 2h
O
O
OH
2
O
2
1a
2a
Conversion[b]
Entry[a]
Catalyst
-
Reusability
2 2
H O
(
Yield)
O
2
(1 atm)
(3 atm)
(1 atm)
5
6
7
O
2
4 runs
1 run
1 run
> 99 % (94 %)
52 % (50 %)
50 % (46 %)
1
2
3
4
5
6
7
8
12 %
> 99 %
84 %
90 %
86 %
68 %
89 %
90 %
-
N
2
K-OMS-2
YES
NO
NO
NO
NO
NO
NO
c
Argon (1 atm)
MnO
2
[
a] Reaction conditions: 2-aminophenol 1a (1 mmol), K-OMS-2 (1.3
KMnO
4
mg, 1.6 mol %), EtOH (4mL, 0.25 M), 27 °C, 2h. [b] Determined by
GC analysis using sample of pure compounds as references. [c] the
reaction was carried out in closed vial.
After experimenting different options and oxidants, we concluded
optimal recovery and reuse of the catalyst is achieved by
centrifugation of the reaction mixture, washing and drying the
catalyst (see SI).
Mn(OAc) tetrahydrate
2
p-benzoquinone
FeCl
3
Fe(II) Phtalocyanine
XRD analyses of the catalyst recovered after each were
performed to possibly reveal any change in the crystal structure
that could be related to the its efficiency. It was found that the
[
2 2
a] Reaction conditions: 2-aminophenol 1a (1 mmol), H O (3 mmol, 3
equiv.), O (1 atm, balloon), catalyst (1.6 mol %), EtOH 4mL (0.25 M),
27 °C, 2h. [b] Determined by GC analysis using sample of pure
compounds as references. [c] β-MnO
available polymorph structure.
2
2
is used as commercially
2 2
combined use of molecular oxygen and H O is crucial to maintain
an unchanged oxidation state of the catalyst and therefore its
tunnel structure (Figure 4). On the contrary, when no terminal
oxidant was used the XRD analysis of the used material revealed
It is noteworthy that none of the catalysts proved to be a valuable
choice in terms of stability and recyclability of the catalyst. Control
experiment (Table 4, entry 1) in the absence of catalyst revealed
that the oxidation rate ion the presence of H
2
conversion. Iron catalyst/oxidant system were also used in order
to compare the most similar system to the active heme-type site
of HRP enzyme (Table 4 entries 7 and 8). It is important to notice
a
significant loss in crystallinity and therefore justify the
impossibility of its reuse for further reactions. These results also
suggested that the catalyst efficiency is closely linked to its 3D
tunnel structure. With these results in hand, we were interested
into the comparison of the catalytic parameters between K-OMS-
2 2
O only is small and
-amino-phenoxazin-3-one (2a) was formed in only 12%
2
and HRP. To this end, by calculating TON and TOF for the two
system we were pleased to note that, while for one run the data
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ChemCatChem
10.1002/cctc.201901659
COMMUNICATION
that MnO
2
and KMnO
4
(Table 4, entry 3 and 4) showed a very low
At this stage, as shown by the reusability experiments with related
XRD patterns, the reduced form of the catalyst is being oxidized
efficiency compared to K-OMS-2. This evidence additionally
suggests that the optimal reaction conditions are guaranteed by
the three-dimensional framework of the catalyst and not by its
single subunits.
by H
2 2 2
O /O to maintain the optimal mixed-manganese oxide
network.
We finally extended the substrate scope of our protocol using
different substituted-aminophenols 1 (Table 5). The applicability
of K-OMS-2 using our reaction conditions was demonstrated for
the synthesis of various 2-aminophenoxazin-3-ones 2 always
achieving excellent yields. The presence of a halogen atom in the
core structure was tolerated and paves the way for further
modification of the Questiomycin A scaffold, allowing for the
synthesis of architecturally more complex pharmaceuticals.
To additionally prove the capability of K-OMS-2 to act as enzyme
mimicking system, we extended the scope of the reaction to
specific substrates that are commonly converted by HRP. We
found
that,
K-OMS-2
can
effectively
convert
o-
phenylenediamine(1g) and pyrogallol (1h) to the corresponding
diaminophenazine (2g) and purpurogallin (2h) respectively, as
illustrated in Table 6.
Figure 5. Uv-vis absorption and plot for determination of kobs
.
Table 5. Substrates scope with substituted o-aminophenols1a-g.
K-OMS-2 (1.6 mol %)
N
NH
2
NH
OH
2
2 2 2
H O /O
In order to elucidate the mechanism of action of the K-OMS-2 in
the oxidative dimerization of o-aminophenol (1a) we performed
EtOH (0.25 M)
7 °C, 2h
O
O
R
2
R
kinetics studies using deuterium labeled o-aminophenol (d
4
-1a).
1
a-f
2a-f
This experiment revealed that a relevant KIE (k /k = 2.1) is
H
D
operative suggesting that dissociation of proton from the p-
quinoneimine intermediate constitutes the rate determining step
in which the actual C‒H activation takes place.
N
O
NH2
O
N
NH
2
O
O
I
I
2
a, 97%
2
b, 94%
Br
Br
NH
2
N
NH
O
2
N
NH
O
2
OH
OAP
1a
-2e
O
O
NH
O
2
Br
Br
d, 95%
2
c, 97 %
4.6 Å
2
H
2
O
2
/O
2
II
OAP
N
O
NH2
N
NH2
O
K-OMS-2
oxidized form
active catalyst)
O
(
O
2
H N
O
4.6 Å
Cl
Cl
OMe
OMe
2f, 98%
H
2
e, 90 %
N
K-OMS-2
reduced form
III
[
a] Reaction conditions: substituted aminophenol 1 (1 mmol), H
mmol, 3 equiv.), O (1 atm, balloon), K-OMS-2 (1.3 mg, 1.6 mol %),
EtOH 4mL (0.25 M), 27 °C, 2h.
2 2
O (3
OH
2
p-quinoneimine
NH
2
N
NH
O
2
N
O
O
O
Mn
APX
4.6 Å
2a
IV
Scheme 1. Plausible mechanism
These experimental evidences suggest a plausible mechanism as
follows: hydrogen peroxide mediated oxidation of o-aminophenol
(1a) forms the highly electrophilic species quinone-iminium ion (II)
which reacts with another o-aminophenol molecule to form the
key intermediate p-quinone imine (III) which undergoes
manganese catalyzed C–H activation to give the corresponding
mangana-cycle (VI) in which proto-demetalation occurs to give 2-
aminophenoxazin-3-one as product (2a).
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COMMUNICATION
Table 6. Use of K-OMS-2 for accessing diaminophenazine and
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K-OMS-2
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N
NH2
NH2
NH2
2
2
2
EtOH
2
7 °C, 2 h
N
9
NH2
0 %
1
g: o-phenylendiamine
2g: diaminophenazine
OH
K-OMS-2
/O
EtOH
OH O
OH
OH
OH
H
2
O
2
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1
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(
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0.25 M), 27 °C, 2h.
2 2
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inorganic-oxide framework can efficiently mimic the
microenvironment of peroxidase enzymes in the synthesis of
valuable compounds. K-OMS-2 is and effective heterogeneous
manganese oxidase system more stable than an enzymatic
catalyst and allows the preparation in excellent yields of novel
substituted phenoxazinones derivatives that are not accessible by
classic enzyme catalysis. The 3D tunnel structure is of key
importance for the overall high efficiency of the C‒H oxidative
coupling and also for the reusability of the catalyst. The
heterogeneous nature of manganese-based catalyst was proved
by leaching measurements and XRD analyses. Re-oxidation and
recycling of the active catalyst was optimized leading to asimple
and efficient methodology. We believe that these results might be
of general interest and inspire further application of manganese-
based heterogeneous catalysts in processes of key interest for
both industry and academia.
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Entry for the Table of Contents (Please choose one layout)
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Francesco Ferlin, Alberto Marini, Nicola
Ascani, Lutz Ackermann, Daniela
Lanari* and Luigi Vaccaro*
Page No. – Page No.
Heterogeneous Manganese-Catalyzed
Oxidase C–H/C–O Cyclyzation to
Access Pharmaceutically Relevant
Phenoxazinones
Heterogeneous manganese-catalyzed C–H oxidative couplings were accomplished
to access pharmaceutically relevant 2-aminophenoxazin-3-ones and proving the
access diaminophenazine and purpurogallin molecular moieties, always in excellent
yields. The user-friendly K-OMS-2 oxidase strategy proved to be more versatile and
stable than enzymatic catalysts opening to a wider substrate scope and being
effectively reusable as proven by leaching measurements and XRD analyses
.
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