A dual biomimetic process for the selective aerobic oxidative coupling of primary amines using pyrogallol as a precatalyst. Isolation of the [5 + 2] cycloaddition redox intermediates

Article abstract of DOI:10.1039/c9gc03992a

A bioinspired organocatalytic cascade reaction mimicking both purpurogallin biosynthesis and copper amine oxidases (CuAOs) activity is described, at room temperature under ambient air, for the activation of the α-C-H bond of primary amines. The reaction sequence uses low-cost commercially available pyrogallol as a precatalyst which undergoes an in situ oxidative self-processing step, resulting in its conversion into natural purpurogallin, a [5 + 2] cycloaddition redox intermediate. This is further involved in the CuAOs-like transamination mechanism for producing, under single turnover, the active biomimetic organocatalyst which mediates the selective oxidative coupling of primary amines, including the non-activated substrates of CuAOs. Without any metal cocatalyst or additives, the protocol gives access to cross-coupled imines as well as 1,2-disubstituted benzimidazoles. The isolation of not easily accessible [5 + 2] cycloaddition redox intermediates provides direct and clear evidence for the proposed dual biomimetic process.

Full text of DOI:10.1039/c9gc03992a

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DOI: 10.1039/C9GC03992A
ARTICLE
A dual biomimetic process for the selective aerobic oxidative
coupling of primary amines using pyrogallol as a precatalyst.
Isolation of the [5+2] cycloaddition redox intermediates
Received 00th January 20xx,
Accepted 00th January 20xx
Martine Largeron,*a Patrick Deschamps, a Karim Hammad a and Maurice-Bernard Fleury a
DOI: 10.1039/x0xx00000x
A bioinspired organocatalytic cascade reaction mimicking both purpurogallin biosynthesis and copper amine oxidases
(CuAOs) activity is described, at room temperature under ambient air, for the activation of the -C-H bond of primary
amines. The reaction sequence uses low-cost commercially available pyrogallol as a precatalyst which undergoes an in situ
oxidative self-processing step, resulting in its conversion into natural purpurogallin, a [5 + 2] cycloaddition redox
intermediate. This is further involved in the CuAOs-like transamination mechanism for producing, under single turnover, the
active biomimetic organocatalyst which mediates the selective oxidative coupling of primary amines, including the non-
activated substrates of CuAOs. Without any metal cocatalyst or additives, the protocol gives access to cross-coupled imines
as well as 1,2-disubstituted benzimidazoles. The isolation of not easily accessible [5+2] cycloaddition redox intermediates
provides direct and clear evidence for the proposed dual biomimetic process.
Copper amine oxidases (CuAOs) are a family of metalloenzymes
which is involved in the metabolism of amines.4 CuAOs couple the
selective oxidation of unbranched primary amines to aldehydes with
the reduction of dioxygen to hydrogen peroxide, through the
synergistic action of a quinone-based organic cofactor, 2,4,5-
trihydroxyphenylalanine quinone or topaquinone (TPQ) and a copper
ion, which is not directly implicated in the amine oxidation step
(Scheme 1).5-7
Introduction
The concept of waste prevention is central, influencing all aspects of
modern society. Due to the harmful effects of chemical waste on the
environment, catalysis plays a major role in chemistry for achieving
both environmental and economic objectives. By using catalysts to
perform chemical transformations, the amounts of both reagents
and waste generated are considerably reduced. In particular,
biocatalysis, which refers to the use of enzymes for synthetic
applications, and bioinspired catalysis, which involves chemical
species mimicking certain features of enzymes, have been identified
as green methodologies by taking the benefits of catalysis with
significant improvements.1 These naturally derived catalysts are
generally highly active under mild conditions, at ambient
temperature and pressure, and exhibit high selectivity. Given that
they are found in biological systems, biocatalysts are relatively
renewable, nontoxic and biodegradable. However, they may not
catalyse the reaction with non-natural substrates or not yield the
desired products. This activity gap has inspired chemists to introduce
artificial cofactors into protein scaffolds leading to the development
of artificial enzymes,2 but also to design bioinspired catalysts.3 These
small molecules, which are devoid of protein scaffolds, have some
advantages over naturally occurring biocatalysts as they may expand
the scope of possible substrates and increase the scale of production.
They are also useful for environmentally friendly catalytic chemistry,
where it is important to avoid the use of toxic or expensive metal
reagents, energy-consuming processing steps and undesirable
solvents.
H2O2 + NH3
O2 + H2O
O
R
NH2
R
O
O
CuII
OH
TPQ
Scheme 1 Selective aerobic oxidation of primary amines to
aldehydes mediated by CuAOs cofactors.
CuAOs have inspired considerable efforts to mimic their
reactivity with synthetic quinone catalysts, earlier to demonstrate
the transamination mechanism by which these enzymes operate,8
while recent studies have focused on synthetic applications.9 Thus,
the aerobic oxidation of amines has been achieved with biomimetic
or bioinspired quinone-based catalysts to accomplish cross-
imination,10
oxidative
-C-H
functionalization,11
cross-
dehydrogenative coupling,12 deaminative cross-coupling and N-
nitrosation of amines.13 Biomimetic catalytic systems promote
selective aerobic oxidation of unbranched primary amines, at room
aUniversité de Paris, CiTCoM, UMR 8038, CNRS, F-75006 Paris, France.
E-mail : martine.largeron@parisdescartes.fr. https://orcid.org/0000-0002-1725-8118
†Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Journal Name
R'
temperature, without reacting with secondary and tertiary amines
and follow a transamination mechanism reminiscent of that reported
R
N
R
View Article Online
DOI: 10.1039/C9GC03992A
R
N
R'-NH2
R
NH2
for natural CuAOs (Scheme 2),10 while bioinspired catalysts surpass
the activity of natural CuAOs by increasing the scope of substrates to
-branched,12a,14 secondary12a,13,15 and tertiary amines12,13 following
abiological pathways. Nevertheless, the procedures still suffer some
drawbacks: 1) the majority of biomimetic catalysts has to be
synthesized prior use affecting the economics as well as the eco-
friendly nature of the methods; 2) when commercially available, the
quinone catalysts are often expensive or require the cooperative
action of additives such as metal co-catalyst. This may constitute a
problem in the synthesis of medicinally relevant compounds due to
the contamination of the final products by metal residues; 3) very
few quinone-catalysed amine oxidation protocols are applicable to
non-activated primary aliphatic amines, the natural substrates for
CuAOs.
Recently, the concept of “second-order” biomimicry has been
defined to describe a system in which in situ modification or
processing of pre-catalyst components affords the active biomimetic
catalyst, as opposed to “first-order” biomimicry, in which the active
biomimetic catalyst is synthesized directly.16 Obviously, “second-
order” biomimicry introduces new opportunities for the discovery of
efficient active biomimetic organocatalysts generated in situ from
simple and low-cost precursors, without turning to chemical
synthesis.
1)
O
R
N
NO2
R1
R1
NO2
Ar
R
R
NH2
2)
XH
4)
Ar
Ar
3)
H2N
N
X
N
R
Ar
N
R = CH2Ar
O
O
O
HO
HO
O
O
HN
2
1
OH
O
3
O
Largeron et al10b,d, 11a,c
Doris et al10c
Stahl et al10a
1): MeOH, Cu(OAc)2/air
rt, 10h
1): H2O or MeOH
AuONT/air, rt, 24h
1): MeCN, O2 balloon
rt, 20h
3): X = NR', MeOH, Cu(Br)2/air
45°C, 24h
In a preliminary communication, we have recently reported the
first example of “second-order” biomimicry for the selective aerobic
oxidation of unbranched primary amines to imines under
exceptionally mild conditions (Scheme 3).17
O
R'
Cl
OMe
O
O
Purpurogallin biosynthesis mimicry
O
O
O
4,5
7
OH
O
Merrifield resin
OH
OH
6
O
Wang et al11g
4): EtOH, air, 80°C, 24h
HO
HO
MeOH, air, rt
HO
HO
Oh et al10e,13
Luo et al11d
2
1) 4: R' = Ph
3): MeCN, O2 balloon, 24h
X = NH, TsOH, 60°C
MeCN, O2 balloon
Cu(OAc)2, rt, 24h
2): 5: R' = 4-FPh
air, 80°C, 12h
10red
11red
X = O, PhCl, Na2HPO4, 100°C
Pyrogallol precatalyst
Purpurogallin intermediate
first single
turnover
OH
OH HO
HO
O
O HO
OH
p
O
O
O
OH
OH
HN
O
n
m
HN
o
R
NH2
R' NH2
+
HN
HN
HN
H2N
Vijay Kumar et al11f
CuAOs activity mimicry
12ox
8 (Polydopamine)
MeOH
air,rt
3): H2O, O2 balloon, 24h
X = NH, TsOH, 60°C
active organocatalyst
NH3
O
OH
OH
H2N
HO
O
iPr
R
R'
R
R
N
N
O
O
iPr
12red
Cu
iPr
9 [Cu(II) complex]
O
O
R
N
Scheme 3 Proposed “second-order” biomimicry for the aerobic
oxidative cross-coupling of primary amines to imines.
R
Murugavel et al10f
1): MeCN, O2 stream, rt, 30min
iPr
O
This one-pot cascade reaction sequence, which mimics both
Scheme 2 Selective aerobic oxidation of unbranched primary purpurogallin biosynthesis and CuAOs activity, starts from
amines mediated by biomimetic quinone-based catalysts 1-9. commercially available low-cost pyrogallol 10red as a precatalyst,
Examples of synthetic applications.
allowing in situ formation of not easily accessible natural
2 | J. Name., 2012, 00, 1-3
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purpurogallin (2,3,4,6-tetrahydroxy-5H-benzocyclohepten-5-one) of 11red which contrasted with the large excess of benzylamine
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11red. This is further engaged in the CuAOs-like transamination utilized. Obviously, the low amount of 1D1OreI:d10s.u10s3c9e/pCt9ibGleC0t3o99b2Ae
mechanism affording, under single turnover, the active biomimetic formed in situ, combined with its very low solubility in organic media,
organocatalyst 12ox, which mediates the oxidative coupling of would create serious problems in the course of the isolation
primary amines under ambient air. However, the proposed reaction procedure, especially during the column chromatography. So, we
pathway was only based on control experiments and we were aware envisioned some modifications of our initial protocol. First, we
that a real proof of the transient presence of purpurogallin was highly changed 10red to 17red, because the isolation of the corresponding
desirable. In this full paper, we present the results of new purpurogallin analogue 18red should be facilitated by the presence
experiments aimed at validating the “second-order” biomimetic of two benzyl groups (Scheme 5). To ensure that 17red and 10red
process, through the isolation of [5+2] cycloaddition redox behaved similarly, the aerobic catalytic oxidation of benzylamine 15
intermediates including purpurogallin.
was performed under the optimal reaction conditions,17 using 17red
as the starting material. The reaction proceeded smoothly and full
conversion into imine 16 could be attained after a prolonged reaction
time of 36h. Second, we decided to modify the molecular ratio
between 17red and amine 15 to facilitate the isolation of
purpurogallin-like intermediate 18red from the bulk solution.
Accordingly, the reaction was carried out in MeOH, at room
temperature, under ambient air, in the presence of one equivalent
of 15 and 0.25 equivalent of 17red. When 30% of 15 was converted
to imine 16, the reaction was stopped by addition of dry ice. After
evaporation of the solvent and column chromatography, two [5 + 2]
cycloaddition new redox products 18red and 19red were isolated in
5 and 15% yields, respectively (Scheme 5).
Results and discussion
The limited availability of natural purpurogallin 11red led us to
examine its well-established biosynthesis, which involves the
oxidative dimerization of pyrogallol 10red generated from gallic acid
13. Two molecules of o-quinone are engaged in a [5 + 2]
cycloaddition reaction affording, after tautomerization reaction, the
benzotropolone scaffold 14 (Scheme 4). Attack of water on the
carbonyl bridge of 14 yields a carboxylic intermediate, which is prone
to further oxidation and decarboxylation, leading to purpurogallin
11red.18 Accordingly, we chose to utilize 10red as a precatalyst for
generating 11red in situ.
OH
OH
HO
HO
HO
HO
- CO2
O
OH
4
OH
5
HO
HO
3
6
N
CO2H
HO
O
10red
19red
13
2
7
Ph
Ph
Ph
1
8
9
O
O
Ph
OH
O
O
HO
HO
O
CO
HO
O
O
H2N
15
[5 + 2] cycloaddition
tautomerization
14
OH
HO
CO
20
OH
OH
O
H2O
HO
HO
HO
HO
Ph
2
HO
O
OH
OH
OH
OH
HO
HO
O
HO
17red
Ph
HO
- CO2
H2O
CO2
11red
HO2C
O
Scheme 4 Established biosynthesis of purpurogallin 11red.
O
OH
OH
Early attempts to isolate 11red as a key intermediate in the
proposed dual bioinspired organocatalytic process were performed
using benzylamine 15 as the amine substrate. Previous optimization
studies had revealed that a combination of one equivalent of
benzylamine with 0.04 equivalent of 10red (4 mol% allowing the
generation of 2 mol% of 11red) was ideal for the reaction. Complete
conversion of 15 into N-benzylidene-benzylamine 16 (see Scheme 7)
was then observed after 24h, at room temperature, under ambient
air, using MeOH as the solvent.17 Under these experimental
conditions, the reaction medium could contain no more than 2 mol%
HO
HO
18red
Ph
Ph
Scheme 5 [5 + 2] cycloaddition redox products 18red and 19red
isolated during the aerobic oxidation of benzylamine mediated
by 17red. Ortep view of 19red. Displacement ellipsoids are
drawn at the 50% probability level.
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The structure of 18red was established on the basis of extensive H-bonded cyclic transition state (CTS) (see Scheme 8)V. iNewoAterticwleeOnhlainde
spectroscopic data including 2D NMR experiments (See Experimental also shown that the aerobic oxidation of 2-aDmOinI:o1r0e.1s0o3r9ci/nCo9lG(C40m39o9l%2A)
and ESI), while the X-Ray crystallographic data undoubtedly produced a poorly reactive o-iminoquinone catalyst, that mainly
confirmed the proposed structure 19red as a single diastereomer of decomposed to melanin-like polymers, giving only 5% of imine 16.17
relative configuration 6R,9R (Scheme 5 and Table S1).
When compared to highly reactive o-iminoquinone 2 (Scheme 2), this
From these results, it could be deduced that [5+2] cycloaddition result confirmed the essential role of the acetyl group for successful
redox intermediates could be formed in MeOH, under ambient air, operation of the catalytic process.20c
starting from a pyrogallol derivative, in the presence of benzylamine.
Note pyrogallol 17red was stable in methanol under ambient aerobic
quinone-based catalyst
conditions and did not produce spontaneously the aerobic
H2N
Ph
Ph
N
Ph
dimerization product, purpurogallin 18red. The presence of
benzylamine was required for producing the monoanionic form of
pyrogallol 17red (pKa around 9) which was further oxidized to the
orthoquinone redox species. Two molecules of orthoquinone were
further engaged in the [5+2] cycloaddition reaction initiating the
formation of purpurogallin 18red. The latter would result from a
nucleophilic attack of intermediate 20 (Scheme 5) by water,
oxidation and decarboxylation steps, following a way which parallels
that established for purpurogallin biosynthesis (Scheme 4).
Interestingly, another [5+2] cycloaddition reaction product 19red
was also isolated. Its formation very likely would arise from a
competitive nucleophilic attack of benzylamine 15 on the carbonyl
group in the five-membered ring of intermediate 20, resulting in a
ring-opening reaction.19 Subsequent oxidation step involving amide
intermediate 21 would afford 22 which would rearrange into
compound 19red as proposed in Scheme 6.
15
16
OH
O
O
OH
O
OH
OH
H2N
HO
HO
HO
HO
HO
R
R
R = Me : 3red
R = Me : 2red
11red
R = Ph
R = Ph
O
OH
O
OH
O
OH
OH
HO
HO
N
Ph
Ph
HO
HO
18red
19red
Ph
Ph
Scheme 7 Structural analogy between the redox precursors of
bioinspired active quinone-based catalysts and products 18red and
19red.
HO
OH
HO
OH
O
OH
HO
HO
HO
HO
CO
Ph
Ph
Therefore, we were encouraged to consider that not only 18red
but also 19red, could be involved in the aerobic catalytic oxidation of
benzylamine 15 to imine 16. Consequently, to clarify their respective
role in supporting the catalytic efficiency, each compound (2 mol%)
was separately tested in the presence of 15, under the optimal
reaction conditions.
20
Ph
O
21
Ph
H2N
N
H
15
O
After 36h, almost full conversion (87%) of 15 into 16 could be
observed starting from 18red, while the benzylamine conversion did
not exceed 40% using 19red. As a consequence, 18red proved to be
the better candidate for generating the quinone-based catalyst
responsible for the high catalytic efficiency observed when
compound 17red was used as the starting material (full conversion
after 36h). Then, the continuously low concentration of the in situ
generated o-quinone species 18ox (see Scheme 8) should protect it
against the competitive formation of melanin-like polymers. Finally,
18red exhibited a behaviour close to that already observed with
O
O
OH
O
OH
OH
O
HO
HO
HO
N
Ph
Ph
HO
O
22
Ph
Ph
19red
N
H
Scheme 6 Proposed reaction mechanism for the formation of natural purpurogallin 11red.17 Taking all together, 18red was
compound 19red.
considered as the most effective [5+2] cycloaddition intermediate in
the bioinspired aerobic oxidative cascade reaction sequence allowing
At this stage, note that both compounds 18red and 19red displayed the oxidation of primary amines to imines.
two features that we have previously observed with redox
The second part of the reaction sequence concerns the CuAOs
precursors of bioinspired quinone-based catalysts of the same series: activity mimicry. Once again, we showed that -branched primary
first, the presence of a carbonyl group adjacent to the pyrogallol amines such as sec-benzylamine were poor substrates for the
moiety; second, the presence of an active hydroxyl group (red OH in biomimetic catalytic process (5-10% conversion), while secondary
Scheme 7). This was found to be an essential component of the amines were not reactive at all. These results were fully in agreement
catalytic activity associated with enzymatic7a,7d,8 and non-enzymatic with the enzymatic transamination mechanism which has been well
catalytic systems9c,10a-d,20 through the formation of a highly reactive
4 | J. Name., 2012, 00, 1-3
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established through the utilization of bioinspired quinone-based additives. These environmentally mild conditions are particularly
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catalytic systems (Scheme 8).8,10,14a,20a,c
favourable for using the imine in situDfOoIr: 10fu.1r0t3h9e/rC9rGeCa0c3ti9o9n2sA.
Accordingly, we have focused on two synthetic applications, first, the
oxidative cross-coupling of primary amines, second, the synthesis of
1,2-disubstituted benzimidazoles.
O
O
OH
OH
4
OH
OH
5
4
HO
O
O
3
6
1)
R
R
The oxidative cross-coupling of primary amines is known to be a
challenging transformation as self-coupling is usually preferred.
Recently, selective formation of cross-coupled imines has been
reported, but the procedures generally require elevated
temperature, oxygen pressure, metal cocatalyst, additive or
problematic solvent.10,22 Our dual bioinspired cascade reaction
sequence proved to be effective for producing cross-coupling imines.
The optimized reaction conditions we had previously reported17
were applied by mixing two primary amines in a ratio 1:1 upon
increasing pyrogallol 11red loading to 10 mol% (generating 5 mol%
of active organocatalyst 12ox), in MeOH, at room temperature,
under ambient air. Note MeOH was found to be the best solvent for
the aerobic oxidative coupling of primary amines to imines because
it provided the ideal balance of 11ox (or 12ox) solvation by
enhancing the electrophilicity of the quinonoid moiety and reaction
rate.20,23 Although MeOH was initially considered as problematic
according to Safety, Health and Environment (SH&E) criteria, it was
finally ranked as recommended in the CHEM21 solvent guide.24 The
result of the 12ox-mediated aerobic cross-coupling of primary
amines is illustrated in Table 1 (See Experimental). The reaction is
quite effective for various sec-primary amines 24a-l and unbranched
aliphatic primary amines 24m and 24n. A single colourless crystal of
imine 24j suitable for X-ray diffraction analysis was obtained from
MeOH (Chart 1 and Table S1). Complete selectivity was observed
except for cross-coupled imines 24m and 24n since the analysis of
HO
MeOH, air
rt
2
R
R
11ox or 18ox
R = H: 11red
H2N
Ph
R = CH2Ph: 18red
15
2)
single turnover
H2O
H
O
O
OH
O
OH
OH
H2N
HO
R
N
3)
R
R
HO
15
Ph
N
Ph
R
R
16
R = H: 12red
H-bonded CTS
R = CH2Ph: 23red
Transamination mechanism
5)
4)
air, rt
NH3
O
OH
OH
Ph
H2N
HN
O
15
R
R
active organocatalyst
R = H: 12ox
R = CH2Ph: 23ox
Scheme 8 Proposed transamination mechanism for the aerobic the reaction mixture by 1H NMR revealed the presence of 7% of the
oxidation of primary amines to imines mediated by o-iminoquinone corresponding homocoupled imine (See ESI). However, with poor
active organocatalyst 12ox or 23ox.
nucleophilic 4-methoxyaniline, the conversion did not exceed 68%
after 60h, leading to the cross-coupled imine 24o in only 55% isolated
The presence of the benzotropolone scaffold not only favoured yield.
attack of the amine at the 3-position of the generated o-quinone
More challenging, the possibility of expanding the reaction scope
species 11ox or 18ox (Scheme 8, step 1), but also facilitated -proton to the synthesis of scarcely stable aliphatic imines has also been
abstraction and the subsequent electron flow from the -carbon to explored. Due to their isomerization into enamine tautomer, which
the o-quinone moiety, which aromatizes to
a Schiff base decomposes under ambient air, the generated alkylimines have been
intermediate (Scheme 8, step 2). Crucial also was the presence of an generally trapped in situ for further reactions.10d,11g So, we have
active hydroxyl group at the 4-position, which was previously proved performed the aerobic oxidative cross-coupling of a range of non-
to be an essential requirement for the successful operation of the activated primary aliphatic amines with N-substituted-o-
catalytic process in the studied series.9c,10a-d,20 The activation of the aminoanilines as in situ imine trap. This reaction led to 1,2-
imine function for further nucleophilic attack by the amine 15, disubstituted benzimidazoles which are privileged and significant
leading to the extrusion of imine 16 (Scheme 8, step 3), was provided structural components of pharmaceuticals.25 For this reason,
by the intramolecular hydrogen bond between the 4-hydroxyl group numerous strategies have been developed for the regiocontrolled
and the imine nitrogen, generating a highly reactive H-bonded synthesis of 1,2-disubstituted benzimidazoles.26 In particular, the
CTS.9c,20c Similar effects of phenolic hydroxyl groups on the reactivity catalytic oxidative coupling of amines has provided a straightforward
of ketimine derivatives have been previously reported.21 Aerobic protocol to synthesize substituted benzimidazoles derivatives
oxidation of the generated aminophenol form 12red or 23red after through the variation of both commercially available
single turnover generated the active o-iminoquinone organocatalyst cyclocondensation partners.11a,c,d,f,27 However, with only few
(Scheme 8, step 4), which can undergo transamination with exceptions,11a,c,d the molecular diversity is limited to derivatives
benzylamine substrate (Scheme 8, step 5) and close the catalytic bearing benzylic or allylic substituents at the 2-position of the
cycle by passing 11ox or 18ox.
benzimidazole framework, because of the difficulty of oxidizing non-
The bioinspired organocatalytic cascade reaction reported here activated primary amines.
allows the selective oxidation of primary amines to imines under
ambient air, at room temperature, without any metal cocatalyst or
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Table 1 12ox-mediated aerobic oxidative cross-coupling of aminesa
Table 2 Representative isolated 1,2-disubstituted benzimidazoles 25a-oa
View Article Online
DOI: 10.1039/C9GC03992A
R'
10red
(8 - 10 mol%)
R'
H
R'NH2
R
NH2
+
R
N
N
N
R'
10red
air, MeOH, rt
(10 mol%)
R
+
R
NH2
A (1 equiv)
Amine A
B (1 equiv)
24a-o
A (1 equiv)
Amine A
N
H2N
B (1 equiv)
air, MeOH, 45-60°C
Amine B
Cross-coupled imine
Yield
(%)b
25a-o
Amine B
1,2-Benzimidazole
Yield
(%)b
24a
85
NH2
N
H2N
H2N
H
N
NH2
NH2
25a
76
N
N
24b
87
NH2
N
Cl
Cl
H2N
Cl
Cl
H
N
25b
75
NH2
24c
83
N
S
H2N
H
N
N
H2N
N
Ph
S
NH2
NH2
NH2
25c
61
NH2
24d
89
Ph
Ph
N
N
O
H2N
H2N
H2N
N
Ph
N
O
H
N
25d
70
24e
89
NH2
N
N
MeO
F3C
N
H2N
MeO
F3C
H
p-Cl-Ph
25e
71c
NH2
24f
90
N
N
p-Cl-Ph
H2N
H2N
N
H2N
H
N
25f
64
NH2
24g
88
NH2
N
N
N
Ph
Ph
Ph
F
H2N
F
H
N
Ph
NH2
25g
63
Ph
N
N
NH2
24h
84
N
Ph
H2N
H2N
H
N
NH2
25h
67
N
N
24i
90
NH2
NH2
N
H2N
H
N
NH2
25i
N
N
62
24j
NH2
H2N
90
H2N
N
H
N
25j
74
N
N
NH2
H2N
24k
NH2
80
H2N
Cl
Cl
H
N
N
25k
52
N
N
NH2
Cl
Cl
H2N
O
O
24l
89
NH2
H
N
25l
40
H2N
N
N
NH2
O
O
N
H2N
H2N
H2N
24m
H
N
NH2
N
25m
75
NH2
N
N
93c
H2N
24n
93c
NH2
N
H
N
NH2
25n
76c
MeO
N
N
MeO
S
S
H2N
OMe
OMe
24o
55d
NH2
H
N
H2N
N
NH2
25o
73c
N
N
O
O
H2N
a8 mol% of 10red affording 4 mol% of 12ox, rt, 100% conversion, reaction
times: 24h for 24a-c, 24e, 24f, 24m and 24n; 48h for 24d and 60h for 24g-l
and 24o; additional aliquot of 10red (2 mol%) was added after 24h. bIsolated
yields after column chromatography. cYields of the cross-coupled imine were
determined by 1H NMR. d68% conversion.
a8 mol% of 10red affording 4 mol% of 12ox,100% conversion, reaction times
60h, 60°C for 25a-l; 45°C for 25m-o; additional aliquot of 10red (2 mol%)
was added after 24h. bYields of the isolated product. c72h.
6 | J. Name., 2012, 00, 1-3
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Green Chemistry
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Journal Name
ARTICLE
Under the optimized reaction conditions previously reported,17 which mediates the oxidative coupling of primary amines. Without
View Article Online
DOI: 10.1039/C9GC03992A
but at a slightly more elevated temperature of 60°C, the any metal cocatalyst or additives, the method gives access to diverse
organocatalyst 12ox was sufficiently reactive to activate the -C-H cross-coupling imines, or 1,2-disubstituted benzimidazole
bond of diverse non-activated primary aliphatic amines to give 1,2- derivatives in the presence of o-aminoanilines. This method
disubstitued benzimidazoles 25a-j in good isolated yields (Table 2 constitutes an appropriate illustration of the potential of “second
and Experimental). A single colourless crystal of benzimidazole 25d order” biomimicry in terms of atom economy, while preserving the
suitable for X-ray diffraction analysis was obtained from the benefit of the eco-friendly nature of the bioinspired catalytic
chloroform/petroleum ether solvent system (Chart 1 and Table S1). processes. A rational application of this concept should allow the
Note this reaction was unsuccessful in the absence of Cu (II) discovery of efficient catalysts generated from simple, low-cost
cooperative catalyst when 2 was used as the sole organocatalyst.11c
As previously reported for catalysed aerobic oxidation of non-
activated alcohol,28 a decreased reactivity for sterically constrained
-branched alkylamines was observed affording the benzimidazoles
25k and 25l in 52 and 40% yields, respectively. As expected, the
procedure could also be applied to common benzylic amines
including heterocyclic amines containing a sulphur or oxygen atom
which gave 1,2-disubstituted benzimidazoles 25n and 25o in good
yields, after a prolonged reaction time of 72h.
precursors, introducing new opportunities in green chemistry.
R'
H
N
45-60°C
air
N
N
R'
R
R
N
H
N
25a-o
2)
R'
self-sorting step
H2N
1 equiv
Transimination
reaction
10red, air, rt
MeOH
R
NH2
R
N
R
Transamination
mechanism
1 equiv
Transimination
reaction
R' NH2
1 equiv
24j
25d
self-sorting step
1)
Chart 1 Ortep views of imine 24j and 1,2-benzimidazole 25d.
R'
Displacement ellipsoids are drawn at the 50% probability level.
R
N
24a-o
Finally, cross-coupled imines 24a-o were obtained through the
transamination mechanism reported in Scheme 8, yielding the
homocoupled imine intermediate, which was progressively
consumed in favour of the cross-coupled imine through dynamic
transimination (Scheme 9, path 1).10,17 Its formation could be driven
by continuous oxidation of the extruded primary amine R-CH2-NH2
(self-sorting step) which was re-engaged in the transamination
mechanism. So, just one equivalent of each amine was sufficient to
achieve exclusive formation of the cross-coupled imine product. This
oxidative strategy, known as oxidative self-sorting, has extensively
been utilized to obtain thermodynamically disfavoured products. 29
In the presence of o-aminoanilines, the resulting cross-coupled
imines were engaged in cyclocondensation and oxidation reaction
steps to furnish 1,2-disubstituted benzimidazoles 25a-o (Scheme 9,
path 2).
Scheme 9 Biomimetic cascade reaction sequence affording cross-
coupled imines 24a-o or 1,2-disubstituted benzimidazoles 25a-o.
Experimental
Isolation of the [5 + 2] cycloaddition redox products 18red and
19red in the course of the aerobic oxidation of benzylamine 15
mediated by 17red
Benzylamine 15 (2 mmol) and pyrogallol derivative 17red (0.5 mmol)
were mixed in MeOH (25 mL), under ambient air. The reaction
mixture was stirred at room temperature. The progress of the
1
reaction was monitored by H NMR spectroscopy. When 30% of
benzylamine 15 was converted into N-benzylidene benzylamine 16,
the reaction was stopped by addition of dry ice. After evaporation of
the solvent under reduced pressure at 30°C, the residue was purified
by column chromatography (toluene-acetone, 90/10 v/v) on silica gel,
to afford the [5+2] cycloaddition redox intermediates 18red (0.025
mmol) and 19red (0.075 mmol) in 5 and 15% yields, respectively.
Caution: particular attention is required during the column
chromatography which has to be realized quickly to minimize the
aerobic oxidation of products 18red and 19red to melanin-like
polymers.
Conclusion
New information about the reaction mechanism of an
organocatalytic cascade reaction for the activation of the -C-H bond
of primary amines are disclosed through the isolation of [5 + 2]
cycloaddition purpurogallin-like intermediates. The one pot
protocol, mimicking both purpurogallin biosynthesis and CuAOs
activity, utilizes inexpensive commercially available pyrogallol pre-
catalyst, for delivering in situ, under ambient air, at room
temperature, low loadings of the active biomimetic organocatalyst,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Green Chemistry
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ARTICLE
Journal Name
1,7-dibenzyl-2,3,4,6-tetrahydroxy-5H-benzo[7]annulen-5-one
(18red). Orange solid (10 mg, 5%): mp 172-176 °C; Rf = 0.5 (toluene-
acetone, 80/20 v/v); 1H NMR (300 MHz, DMSO D6)  4.03 (s, 2H), 4.32
(s, 2H), 6.77 (d, J = 12.4 Hz, 1H), 7.08-7.26 (m, 10H), 7.49 (d, J = 12.4
Hz, 1H), 15.57 (s, 1H, D2O exchanged); 13C{1H} NMR (75 MHz, DMSO
D6)  31.4, 39.1, 115.9, 117.3, 126.1, 126.7, 128.26 (x2), 128.33,
128.68, 128.74 (x2), 128.88 (x2), 129.1 (x2), 130.1, 130.8, 134.8,
140.1, 141.0, 150.5, 151.2, 152.6, 182.1; HRMS (ESI-) m/z calcd for
C25H20O5 [M – H] 399.1232. Found 399.1238. 1D and 2D NMR
spectra for compound 18red are reported in the ESI. Key HMBC
correlations are shown in Chart 2.
View Article Online
DOI: 10.1039/C9GC03992A
O
5
OH
OH
7
4
6
8
HO
HO
3
N
11
O
1
10
2
9
19red
O
OH
OH
5
4
HO
HO
3
6
Chart 3 Key HMBC correlations of compound 19red.
2
7
8
9
1
Representative experimental procedure for the organocatalyzed
aerobic oxidative cross-coupling of two primary amines
18red
Equimolar amounts of benzylamine (2.5 mmol) and 1-
ethylpropylamine (2.5 mmol), pyrogallol 10red (0.2 mmol, 8 mol%,
corresponding to the generation of 4 mol% of purpurogallin 11red)
were mixed in MeOH (10 mL), under ambient air. The reaction
mixture was stirred at room temperature for 24h. The progress of
Chart 2 Key HMBC correlations of compound 18red.
(6R,9R)-1,7,11-tribenzyl-2,3,4,6-tetrahydroxy-6,9-dihydro-5H-6,9-
(epiminomethano)benzo[7]annulene-5,10-dione (19red). Yellow the reaction was monitored by 1H NMR spectroscopy. After
crystal (40 mg, 15%): mp 244-248 °C; Rf = 0.4 (toluene-acetone, 80/20 completion of the reaction, the solvent was evaporated, at room
v/v); 1H NMR (400 MHz, CD3OD)  3.40-3.48 (m, 2H), 3.99 (d, J = 16.3 temperature, to give the cross-coupling imine product 24a as an
Hz, 1H), 4.48-4.56 (m, 3H), 4.82 (m, 1H), 5.54 (d, J = 7.0 Hz ,1H), 6.97 almost pure product, which was further purified by washing through
(m,2H), 6.96-7.189 (m, 13H); 13C{1H} NMR (100 MHz, CD3OD)  30.3, a small pad of base-washed silica (eluent: 1/2 petroleum ether/ethyl
35.2, 43.2, 48.3, 87.8, 105.2, 118.6, 125.5, 125.9, 126.8, 127.5 (x2), acetate + 2% triethylamine). Caution: particular attention is required
127.78 (x2), 127.82 (x2), 127.9 (x2), 128.0 (x2), 128.7, 128.8 (x2), during the column chromatography which has to be realized quickly
131.6, 131.8, 137.5, 137.6, 141.1, 145.6, 151.2, 153.5, 171.1, 191.9; to avoid the hydrolysis of the cross-coupled imine to aldehyde. The
HRMS (ESI-) m/z calcd for C33H27NO6 [M – H] 532.1760. Found above procedure is generally representative for all the products
532.1772. X-Ray analysis: A yellow crystal of 0.27  0.22  0.05 mm, shown in Table 1. Any deviations from this protocol are specified in
crystallized from a mixture toluene/methanol was used. Empirical the footnotes of Table 1.
formula C33H27NO6, M = 533.55, T = 100(2) K. Triclinic system, space
group P-1, Z = 4, a = 12.6327(6) Å, b = 15.2434(7) Å, c = 15.9800(7) Å, X-Ray analysis of imine 24j. A colorless crystal of 0.23  0.19 0.04
 = 102.027(2)°,  = 105.432(2)°,  = 112.595(2)°, V = 2566.4(2) Å3, mm, crystallized from methanol was used. Empirical formula
dcalc = 1.381 g cm-3 , F(000) = 1120,  = 0.776 mm-1, (CuK) = C17H17N, M = 235.1, T = 100(2) K. Triclinic system, space group P-
1.54178 Å. 77250 intensity data were collected with a VENTURE 1, Z = 2, a = 5.6742(2) Å, b = 8.7921(4) Å, c = 13.5713(5) Å,  =
PHOTON100 CMOS Bruker diffractometer (Cu-K radiation) 103.259(1) °,  = 95.099(1)°,  = 95.624(1)°, V = 651.48(4) Å3, dcalc
=
controlled by APEX3 software package, giving 9064 unique 1.200 g cm-3 , F(000) = 252,  = 0.526 mm-1, (CuK) = 1.54178 Å.
reflections. Refinement of 743 parameters on F2 led to R1(F) = 0.0375 21496 intensity data were collected with a VENTURE PHOTON100
calculated with 7934 observed reflections as I ≥ 2 sigma (I) and CMOS Bruker diffractometer (Cu-Kα radiation) controlled by APEX3
wR2(F2) = 0.1045 considering all the 9064 data. Goodness of fit = software package, giving 2166 unique reflections. Refinement of 166
1.011. CCDC deposition number: 1965257. 1D and 2D NMR spectra parameters on F2 led to R1(F) = 0.0439 calculated with 1995 observed
for compound 19red are reported in the ESI. Key HMBC correlations reflections as I ≥ 2 sigma (I) and wR2(F2) = 0.1122 considering all the
are shown in Chart 3.
2166 data. Goodness of fit = 1.072. CCDC deposition number:
1981805.
8 | J. Name., 2012, 00, 1-3
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Green Chemistry
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Journal Name
ARTICLE
Reuter, V. Köhler, J. C. Lewis, T. R. Ward, Chem. Rev. 2018,
General experimental procedure for the organocatalyzed aerobic
oxidative coupling reaction affording 1,2-disubstituted
benzimidazoles
View Article Online
118, 142; (c) M. T. Reetz, Acc. Chem. RDeOs.I:21001.190,3592/C,93G3C60;3(9d9)2EA.
N. Mirts, A. Bhagi-Damodaran and Y. Li, Acc. Chem. Res. 2019,
52, 935.
3
4
For selected reviews, see: (a) J. Piera and J. E. Bäckvall, Angew.
Chem. Int. Ed. 2008, 47, 3506; (b) L. Que Jr and W. B. Tolman,
Nature, 2008, 455, 333; (c) L. Que Jr and W. N. Oloo, Acc.
Chem. Res. 2015, 48, 2612; (d) M. M. Pereira, L. D. Dias and
M. J. F. Calvete, ACS catal. 2018, 8, 10784.
Equimolar amounts of primary amine (1.25 mmol) and N-
substituted-o-aminoaniline (1.25 mmol) with pyrogallol 10red (0.1
mmol, 8 mol%, which corresponds to the generation of 4 mol% of
purpurogallin 11red), were mixed in MeOH (25 mL), in an air
atmosphere. The reaction mixture was stirred at 60°C for 24h. Then,
an additional aliquot of 0.025 mmol of 10red (2 mol%) was
introduced into the reaction mixture and the reaction was continued
for 36h. The solvent was then removed by evaporation under
reduced pressure, and the residue was purified by column
chromatography on silica gel (eluent: 1/1 petroleum ether/ethyl
acetate) to afford 1,2-disubstituted benzimidazoles 25a-o. The above
procedure is generally representative for all benzimidazoles shown
in Table 2. Any deviations from this protocol are specified in the
footnotes of Table 2.
For selected reviews, see: (a) J. P. Klinman, Chem. Rev. 1996,
96, 2541; (b) J. P. Klinman, Biochim. Biophys. Acta, 2003, 1647,
131; (c) B. J. Brazeau, B. J. Johnson and C. M. Wilmot, Arch.
Biochem. Biophys., 2004, 428, 22; (d) P. Matyus, B. Dajka-
Halasz, A. Földi, N. Haider, D. Barlocco, K. Magyar, Curr. Med.
Chem. 2004, 11, 1285; (e) M. Strolin Benedetti, K. F. Tipton
and R. Whomsley, Fondam. Clin. Pharmacol., 2007, 21, 467;
(f) A. Boobis, J. B. Watelet, R. Whomsley, M. Strolin Benedetti,
P. Demoly and K. T. Tipton, Drug Metab. Rev., 2009, 41, 486.
S. M. Janes, D. Mu, D. Wemmer, A. J. Smith, S. Kaur, D. Maltby,
A. L. Burlingame and J. P. Klinman, Science, 1990, 248, 981.
S. Suzuki, T. Okajima, K. Tanizawa and M. Mure, Cofactors of
amine oxidases. Copper ion and its substitution and the 2,4,5-
trihydroxyphenylalanine quinone. In Copper Amine Oxidases.
5
6
X-Ray analysis of 1,2-benzimidazole 25 d. A colorless crystal of 0.21
 0.16 0.10 mm, crystallized from a mixture chloroform/petroleum
ether was used. Empirical formula C16H14N2, M = 234.29, T = 100(2)
Structures,
Catalytic
Mechanisms,
and
Role
in
Pathophysiology, ed. G. Floris and B. Mondovi, CRC Press,
Taylor and Francis Group Publishing, New York, 2009; p. 19.
(a) M. Mure, S. A. Mills and J. P. Klinman, Biochemistry, 2002,
41, 9269-9278; (b) M. Mure, Acc. Chem. Res., 2004, 37, 131;
(c) J. L. Dubois and J. P. Klinman, Arch. Biochem. Biophys.,
2005, 433, 255; (d) J. P. Klinman and F. Bonnot, Chem. Rev.
2014, 114, 4343.
7
8
K.
Triclinic
system,
space
group
P-1,
Z = 4, a = 10.3880(4) Å, b = 10.8621(4) Å, c = 11.9356(4) Å,  =
103.368(1)°,  = 111.316(21)° ,  = 90.267(1)°, V = 1214.77(8) Å3, dcalc
= 1.281 g cm-3 , F(000) = 496,  = 0.591 mm-1, (CuK) = 1.54178 Å.
29618 intensity data were collected with a VENTURE PHOTON100
CMOS Bruker diffractometer (Cu-Kα radiation) controlled by APEX3
software package, giving 3491 unique reflections. Refinement of 325
parameters on F2 led to R1(F) = 0.0314 calculated with 3328 observed
reflections as I ≥ 2 sigma (I) and wR2(F2) = 0.784 considering all the
3491 data. Goodness of fit = 1.099. CCDC deposition number:
1981802
For selected examples, see: (a) Y. Lee and L. M. Sayre, J. Am.
Chem. Soc., 1995, 117, 3096; (b) M. Mure and J. P. Klinman, J.
Am. Chem. Soc., 1995, 117, 8698; (c) M. Mure and J. P.
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Stahl, Angew. Chem. Int. Ed. 2015, 54, 14638; (c) M. Largeron,
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Chin. Chem. Lett. 2018, 29, 1193; (e) M. Largeron, Pure Appl.
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9
Conflicts of interest
There are no conflicts to declare.
10 For selected recent examples, see: (a) A. E. Wendlandt and S.
S. Stahl, Org. Lett. 2012, 14, 2850; (b) M. Largeron and M.-B.
Fleury, Angew. Chem. Int. Ed. 2012, 51, 5409; (c) D. V. Jawale,
E. Gravel, E. Villemin, N. Shah, V. Geersten, I. N. N.
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M. Palaniandavar and R. Murugavel, ACS Catal. 2019, 9,
10940.
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Largeron, Chem. Eur. J., 2015, 21, 12606; (b) M. A. Leon, X.
Liu, J. H. Phan and M. D. Clift, Eur. J. Org. Chem. 2016, 2016,
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Lett. 2019, 21, 6731; (f) S. A. Pawar, A. N. Chand, and A. Vijay
Kumar, ACS Sustainable Chem. Eng. 2019, 7, 8274; (g) Q. Yang,
Y. Zhang, W. Zeng, Z.-C. Duan, X. Sang and D. Wang, Green
Chem. 2019, 21, 5683.
Acknowledgements
We thank CNRS and Paris Descartes University for financial
support. Pascale Leproux is acknowledged for running high
resolution mass spectra. The authors also wish to thank Regis
Guillot (ICMMO – Université Paris Saclay) for collecting the
crystallographic data.
Notes and references
1
For selected reviews or perspectives, see: (a) L. Marchetti and
M. Levine, ACS catal. 2011, 1, 1090; (b) C. K. Prier and F. H.
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2
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
13 T. Si, H. Y. Kim and K. Oh, ACS catal. 2019, 9, 9216.
Hu, Z. ban, Z. Zhan and G.-S. Huang, Adv. SynthV.ieCwaAtratilc.le2O0n1lin9e,
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10 | J. Name., 2012, 00, 1-3
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Page 11 of 11
Green Chemistry
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Journal Name
ARTICLE
Table of contents entry
View Article Online
DOI: 10.1039/C9GC03992A
Low-cost pyrogallol precatalyst undergoes an oxidative self-
processing step for delivering the active organocatalyst in situ
through a dual biomimetic process.
Dual biomimetic scenario
R'
R
NH2
R'
+
R
N
R' NH2
or
or
R'
H
N
N
R
OH
HO
HO
MeOH
air
H2N
N
10red
one pot organocatalytic cascade
cheap pyrogallol 10red as a precatalyst
high chemoselectivity
ambient air
metal-free and additives-free
minimum waste generation
This journal is © The Royal Society of Chemistry 20xx
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