A Bioinspired Organocatalytic Cascade for the Selective Oxidation of Amines under Air

Article abstract of DOI:10.1002/chem.201701402

A bioinspired organocatalytic cascade reaction for the selective aerobic oxidative cross-coupling of primary amines to imines is described. This approach takes advantages of commercially available pyrogallol monomeric precursor to deliver low loadings of natural purpurogallin in situ, under air. This is further engaged in a catalytic process with the amine substrate affording, under single turnover, the active biomimetic quinonoid organocatalyst and the homocoupled imine intermediate, which is then converted into cross-coupled imine after dynamic transimination. This organocatalytic cascade inspired by both purpurogallin biosynthesis and copper amine oxidases allows the aerobic oxidation of non-activated primary amines that non-enzymatic organocatalysts were not able to accomplish alone.

Full text of DOI:10.1002/chem.201701402

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Title: A Bioinspired Organocatalytic Cascade for the Selective
Oxidation of Amines under Air
Authors: Martine Largeron and Maurice-Bernard Fleury
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A Bioinspired Organocatalytic Cascade for the Selective
Oxidation of Amines under Air
Martine Largeron,* and Maurice-Bernard Fleury
various catalytic methods for the aerobic oxidation of amines to
imines given the widespread importance of imines as pivotal
intermediates in the synthesis of fine chemicals and
pharmaceuticals.[7] As a consequence, the use of CuAOs-like
catalytic systems has emerged in synthetic planning,[8] and
organic chemists have designed biomimetic quinone-based
catalysts (Scheme 1) with two objectives:[9] 1) to achieve
sustainable aerobic amine oxidation reactions; 2) to expand the
scope of possible substrates. For example, Wendlandt and Stahl
have reported the aerobic oxidation of various primary benzylic
amines to imines, at room temperature under 1 atm of O2, using
Abstract: We describe
a bioinspired organocatalytic cascade
reaction for the selective aerobic oxidative cross-coupling of primary
amines to imines. This approach takes advantages of commercially
available pyrogallol monomeric precursor to deliver in situ, under air,
low loadings of natural purpurogallin. This is further engaged in a
catalytic process with the amine substrate affording under single
turnover the active biomimetic quinonoid organocatalyst and the
homocoupled imine intermediate which is then converted into cross-
coupled imine after dynamic transimination. This organocatalytic
cascade inspired by both purpurogallin biosynthesis and copper
amine oxidases activity allows the aerobic oxidation of non-activated
primary amines that non-enzymatic organocatalysts were not able to
accomplish alone.
5-tert-butyl-2-hydroxybenzoquinone organocatalyst Q1,[10]
a
quinone initially developed for biochemical model studies.[6d]
Recently, Luo and co-workers have shown that 4-methoxy-5-
tert-butyl-o-quinone organocatalyst Q2 enables effective aerobic
oxidation, at room temperature under an O2 atmosphere, of -
branched primary benzylic amines considered as poor
substrates for CuAOs enzymes.[11]
Oxidation reactions play an important role in biology and are
recognized as key transformations in organic synthesis.[1] As a
result of current evolution, the use of ambient air as the sole
oxidant fulfills the requirements of “green chemistry” because it
is inexpensive and does not rise to any waste products.
However, the direct aerobic oxidation of organic substrates is
scarce because the energy barrier for electron transfer from the
organic substrate to the oxidant is generally high. To solve this
problem, nature has evolved a certain set of synthetic strategies
and uses an impressive array of enzyme catalysts. Excellent
examples are naturally occurring iron or copper-containing
metalloenzymes which have revealed their efficiency as
catalysts to perform controlled aerobic oxidations under very
mild conditions.[2] Hence, the development of biomimetic
methods that utilize environmentally benign oxidants is one of
the most important goals in oxidation chemistry today.
Among metalloenzymes, copper amine oxidases (CuAOs)
promote selective aerobic oxidation of primary amines to
aldehydes, coupled with the reduction of O2 to H2O2 through the
cooperation of
a
quinone-based organic cofactor 2,4,5-
trihydroxyphenylalanine quinone (TPQ) and a copper ion.[3] The
presence of the copper ion is essential for the production of TPQ
from the autocatalytic post-translational oxidation of a tyrosine
residue, while the oxidation of the amine substrate is mediated
by TPQ without direct involvement of the copper ion.[4] Yet it
could play a second role in orienting the TPQ ring correctly in
the active site and in facilitating the reduction of O2 to H2O2.[5]
Although quinone models that mimic the active site of CuAOs
have yielded important insight into the transamination
mechanism by which these enzymes operate with benzylamine
as the amine substrate,[6] surprisingly the synthetic scope of
such reactions had received little attention for a long time.
Scheme 1. Bioinspired quinone-based organocatalysts and cooperative
catalytic sytems for the aerobic oxidation of amines to imines.
More challenging, the possibility of expanding the scope to
the oxidation of secondary amines, a reaction type that natural
CuAOs are not able to accomplish, was also explored. This
reaction was possible through the development of cooperative
catalytic systems including a quinone-based organocatalyst.
For example, the group of Kobayashi has reported that a block
copolymer-incarcerated bimetallic Pt/Ir alloy catalyst combined
with 4-tert-butyl-o-quinone Q3 as the redox-active organic
cofactor allowed the aerobic oxidation of secondary amines to
imines, at 30°C under 1 atm of O2,[12] while Doris and co-
workers have described a similar synergistic action of Rh
Recently, there has been a boost in the development of
[*]
Dr. Martine Largeron, Prof. Dr. Maurice-Bernard Fleury
UMR 8638 CNRS-Université Paris Descartes, Sorbonne Paris Cité,
Faculté de Pharmacie de Paris, 4 avenue de l’Observatoire
75270 Paris Cedex 06, France
E-mail:martine.largeron@parisdescartes.fr
Supporting information for this article is given via a link at the end of
the document.
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nanoparticles, supported on carbon nanotubes as co-catalysts
quinone species 2ox (Scheme 2). Even more crucial was the
with 4-tert-butyl-o-quinone Q3 for the aerobic dehydrogenation of
presence of an active hydroxyl group at the 4-position which had
N-heterocycles, at room temperature under ambient atmosphere. been proved to be an essential component of the catalytic
[13]
Although these two reaction systems share common
characteristics with CuAOs such as the use of a quinone-based
organocatalyst together with a metal co-catalyst, mechanistic
studies revealed divergence in the reaction pathways because
secondary amines are not compatible with the enzymatic
transamination mechanism and often serves as inhibitors
through the formation of irreversible covalent adducts.[14]
Accordingly, Wendlandt and Stahl have brought definitive
evidence for a non-biomimetic addition-elimination pathway
involving a hemiaminal intermediate which was characterized by
NMR spectroscopy. For this purpose, they used 1,10-
phenanthroline-5,6-dione Q4 in combination with ZnI2 as an
efficient cooperative system to promote, under 1 atm of O2 at
room temperature, dehydrogenation of secondary amines and a
diverse range of N-heterocycles.[15]
activity associated with enzymatic[4,6] and non enzymatic
catalytic systems[17,20] through the formation of a highly reactive
H-bonded cyclic transition state (CTS). However, the limited
availability of purpurogallin 2red led us to concentrate on its well
established biosynthesis which involves the oxidative
dimerization of pyrogallol 1red generated from gallic acid.[21]
In contrast, the biomimetic aerobic catalytic oxidation of
non-activated primary alkylamines, that are natural substrates
for CuAOs,[16] has received little attention, probably because the
generated alkylimines very easily isomerize into the unstable
enamine tautomers. In 2012, we reported the first biomimetic
aerobic catalytic oxidation of non-activated primary alkylamines
through the synergistic combination of two redox couples: the o-
iminoquinone organocatalyst IMQ, previously discovered from
electrochemical investigations,[17] is the substrate-selective
catalyst and the biocompatible copper salt serves as an electron
transfer mediator.[18] Although this system was capable to work
under ambient air with high atom economy and was compatible
with both activated benzylic and non activated aliphatic primary
amines, some challenges still remained to be tackled. In
particular, the use of a commercially available quinone-based
organocatalyst would offer enhanced practicality. In this vein,
novel strategies using simple low-cost precursors for quinone
cofactor mimetics have been recently reported by the groups of
Doris (Q5),[19a] Carbery (Q6)[19b] and Oh (Q7),[19c] but these
cooperative systems still require transition noble or non-noble
biocompatible metal co-catalyst and, in most cases, they failed
to oxidize non activated aliphatic primary amines.[19b,c]
Since the oxidation of the primary amine substrates by
CuAOs is mediated by TPQ without direct involvement of the
copper ion,[4] we thought that a more eco-friendly biomimetic
organocatalytic method, avoiding contamination of the final
products by metal residues, would be highly desirable but still
challenging. In this paper, we describe an unprecedented
bioinspired organocatalyzed cascade reaction, which allows the
oxidative coupling of both activated and non activated primary
amines to imines under ambient air.
Scheme 2. Proposed bioinspired cascade reaction for the organocatalyzed
aerobic oxidation of primary amines to imines under air
Based on this insight, we designed a double biomimetic
reaction pathway for the chemoselective organocatalytic
oxidative coupling of primary amines to imines under air as
described in Scheme 2. The cascade reaction would involve
aerobic oxidation of commercially available pyrogallol 1red to
form the corresponding o-quinone 1ox which should then suffer
homodimerization to yield the 6/7-fused bicyclic compound
intermediate. The latter would afford purpurogallin 2red after
decarboxylation and oxidation steps. Aerobic oxidation of 2red
would then generate a highly reactive o-quinone species 2ox
which should be intercepted by the primary amine substrate to
produce the reduced o-aminophenol form 3red and homocoupled
imine through the transamination process reported for CuAOs
enzymes. The final step under single turnover would be the
reoxidation of 3red to generate o-iminoquinone 3ox which would
react directly with the amine substrate leading to the Schiff-base
H-bonded CTS by passing 2ox.[5,6g]
To evaluate the validity of this bioinspired cascade reaction
sequence, we performed optimization studies by using 4-
methylbenzylamine 4 as the amine substrate. If our hypothesis
is right, part of the reaction conditions should be identical to that
required for the CuII/IMQ-catalyzed cooperative process.[18b]
Accordingly, a combination of one equivalent of amine 4 with
0.04 equivalent of pyrogallol 1red (corresponding to the
generation of 2 mol% of purpurogallin 2red) gave optimal results.
As expected, after 24h, under ambient air, complete conversion
into imine 5 (Scheme 3) was observed only in MeOH, because
strong solvation of the o-quinone 2ox or o-iminoquinone 3ox by
MeOH was necessary to enhance the electrophilicity of its
quinonoid moiety, thereby favoring the nucleophilic attack of the
At the beginning of our investigations, we were aware that
commercially
available
quinone-based
organocatalysts
reminiscent of TPQ would not be sufficiently reactive to promote
the aerobic oxidation of non activated primary amines without
any additives.[9] Based on our recent studies,[17,18] we were drawn
to the structure of natural purpurogallin (2,3,4,6-tetrahydroxy-5H-
benzocyclohepten-5-one) 2red as a potential precursor of a
highly reactive o-quinone-based organocatalyst 2ox because of
the presence of the tropolone scaffold which should direct attack
of the amine substrate at the 3-position of the generated o-
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amine
substrate.
Then,
N-(4-methylbenzyl)-1-(p-
elevated temperature, oxygen pressure or expensive metals.
Optimization of the reaction parameters showed that mixing 4-
methylbenzylamine 4 and sec-benzylamine in the ratio 1:1 upon
increasing pyrogallol loading[10, 19b] to 10 mol% (8 mol% followed
by 2 mol% after 24h) thus generating 5 mol% of 3ox, in MeOH, at
25°C, under ambient air, gave exclusive formation of the desired
cross-coupled imine 7 in 90% isolated yield after 60h (Table 1).
The real-time monitoring of the cross-coupling reaction by 1H
NMR spectroscopy indicated that the homocoupled product 5
was initially formed and accumulated during the first hours of the
reaction. Then, it gradually converted into the cross-coupled
product 7 to become the exclusive product. These observations
indicated that 7 was obtained through the transamination
process reported in Scheme 2, which leads to the homocoupled
imine intermediate 5, followed by dynamic transimination. [10,18,19]
Just one equivalent of each primary amine was sufficient to
achieve exclusive transformation into the cross-coupled imine 7
through the well-known oxidative self-sorting process which has
widely been exploited to obtain thermodynamically disfavored
products.[10, 23] As shown in Table 1, a broad range of substituted
benzylic amines were tolerated, including those bearing
electron-donating groups (products 11-13), electron-withdrawing
groups (products 14, 15, and 19) or fluorine (product 17). A
thiophene moiety was also tolerated (product 20), as was
furfurylamine which allowed the exclusive formation of the cross-
coupled imine 21. Both branched and linear aliphatic amines
could be efficiently coupled with benzylic amines in high isolated
yields, within 24-60h depending on the basicity of the cross-
coupled amine R’-NH2. Complete selectivity was observed
except for aminomethylcyclohexane (product 10) and n-
hexylamine (product 13), for which small amounts of
homocoupled imine (7%) were also isolated. As observed
earlier,[10, 18b] poor nucleophilic 4-methoxyaniline afforded cross-
coupled imine in only 55% isolated yield (product 9) as the
conversion did not exceed 68% after 60h.
The synthesis of aliphatic imines was intrinsically more
challenging because of their relative instability and isomerization
into the enamine tautomer which decomposes under ambient
air.[18b, 24] Nevertheless the reaction conditions used through this
bioinspired cascade reaction sequence were favorable for
trapping the generated unstable alkylimines in situ for further
reactions. So, in a second series of experiments, we examined
the aerobic oxidative cross-coupling of a range of non-activated
primary aliphatic amines with N-methyl-o-aminoaniline as an in
situ imine trap (Table 1).[25] This was not a trivial exercise
because this reaction had proved to be unsuccessful in the
absence of CuII co-catalyst when IMQ (Scheme 1) was used as
the sole organocatalyst.[25b] Pleasingly, at 60°C (See Table S1 in
the Supporting Information), the organocatalyst 3ox was
sufficiently reactive to activate, under ambient air, the -CH
bond of diverse primary aliphatic amines to give 1,2-
disubstituted benzimidazoles 22-27 in good yields, except for
sterically constrained -branched alkylamine for which the yield
did not exceed 52% (product 28).
tolyl)methanimine 5 was obtained in 90% isolated yield.
Scheme 3. Control studies
Control studies revealed that no reaction occurred under
the same experimental conditions when 1red was fully omitted
from the reaction mixture. Interestingly, as for natural CuAOs, -
branched amines such as sec-benzylamine were found to be
poor substrates for the biomimetic organocatalyzed reaction with
less than 5% conversion into imines, whereas secondary amines
were not reactive at all (Scheme 3). These results were fully
consistent with the enzymatic transamination mechanism and
ruled out an addition-elimination process. Note that the
transamination process could engage only 1ox by passing 2ox.
To gain more insight into the cascade reaction, we examined the
catalytic efficiency of o-iminoquinone 6ox generated in situ from
2-aminoresorcinol 6red under the optimal reaction conditions. As
previously reported from electrochemical studies,[17] aerobic
oxidation of 6red produced a poorly reactive o-iminoquinone
catalyst 6ox which mainly decomposed to melanin-like polymers,
giving only 5% of imine 5. In contrast, when purpurogallin 2red
was utilized as the starting material for producing 2ox, high
catalytic activity was observed at the early stages of the reaction.
Nevertheless, under aerobic conditions, the instability of the
highly reactive o-quinone 2ox which slightly decomposed finally
led to a decreased yield of imine 5 (75%) when compared to that
obtained when 1red was used as the starting material (90%).
Most likely, when starting from 1red, the continuously low
concentration of the in situ generated o-quinone 2ox should
protect it against the polymerization reaction.
We further explored the scope of this cascade reaction by
focusing on the oxidative cross-coupling of primary amines
which is known to be a challenging transformation[10,18,19] as self-
coupling is usually preferred. For this reason, the catalytic
oxidative coupling of alcohols and amines reigns supreme
although, with few exceptions,[22] this method generally requires
Recently, it has been reported that the evolutionary
selection of viable quinone-based redox cofactors appears
strongly linked to the ability of the catalytically produced quinols
to undergo facile reoxidation back to their starting quinones.[4]
Accordingly, the results of this study clearly highlight the ability
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of 3red to undergo oxidation to 3ox which occurs under ambient
air, without the assistance of electron transfer mediator. In
addition, its catalytic efficiency is enhanced through the
participation of both tropolone scaffold and 4-hydroxy substituent
in directing the nucleophilic attack of the amine substrate at the
3-position of 3ox. Also, the presence of the active 4-hydroxy
group, which is engaged in an intramolecular hydrogen bond
with the imine nitrogen to form a highly reactive Schiff base CTS
(Scheme 2) is of overriding importance for the development of
the catalytic process.[20] The combination of all these elements
allows the oxidation of non-activated primary aliphatic amines
that until now remained challenging substrates for non-
enzymatic organocatalysts.
conditions, the active biomimetic organocatalyst 3ox and the
homocoupled imine intermediate, followed by dynamic
transimination. Noteworthy, the present organocatalytic cascade
reaction, which has been inspired by both purpurogallin
biosynthesis and copper amine oxidases activity, would not be
easily conceivable at this level of complexity from first chemical
concepts.
Acknowlegments
The authors would like to thank CNRS and Paris Descartes
University for financial support
Keywords: biomimetics • cross-coupling • imines • organocatalysis • primary
Table 1. Insight into the substrate scope of the 3ox-mediated aerobic oxidative
amines
cross-coupling of amines.
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In summary, we have developed
a
bioinspired
organocatalytic cascade reaction for the activation of the -C-H
bond of primary amines which are converted to cross-coupled
imines under exceptionally mild conditions. The reaction
sequence starts from inexpensive commercially available
pyrogallol 1red and allows, under ambient air, the in situ
formation of not easily accessible natural purpurogallin 2red
which is further engaged in the CuAOs enzymatic
transamination process for producing, under single turnover
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Entry for the Table of Contents
Bioinspired Organocatalytic Cascade
COMMUNICATION
Dual mimicking of purpurogallin
biosynthesis and copper amine
oxidases activity allows the
M. Largeron,* M. –B. Fleury
Page No. – Page No.
chemoselective oxidative cross-
coupling of primary amines to imines
under environmentally benign metal-
free conditions
A Bioinspired Organocatalytic
Cascade for the Selective Oxidation
of Amines under Air
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