A biologically inspired CuI/topaquinone-like co-catalytic system for the highly atom-economical aerobic oxidation of primary amines to imines

Article abstract of DOI:10.1002/anie.201200587

Acting together: Low catalytic amounts of Cu^I and topaquinone-like catalyst 1_ox (see scheme) are sufficient to activate the α-C-H bond of primary amines, which are converted into alkylated imines under ambient conditions. This atom-economical process tolerates the presence of various reactive functional groups and allows selective cross-coupling of two amines. Copyright

Full text of DOI:10.1002/anie.201200587

Angewandte
Chemie
DOI: 10.1002/anie.201200587
Homogeneous Catalysis
A Biologically Inspired CuI/Topaquinone-Like Co-Catalytic System for
the Highly Atom-Economical Aerobic Oxidation of Primary Amines to
Imines
Martine Largeron* and Maurice-Bernard Fleury
Imines are versatile synthetic intermediates in a variety of
organic transformations and are essential pharmacophores in
numerous biologically active compounds.[1] Great progress
has been made in the past decade for the synthesis of imines,
including oxidation of secondary amines,[2] oxidative self- or
cross-coupling of primary amines,[3] and direct synthesis from
amines and alcohols in the presence of a catalyst.[4] However,
most of the methods have some limitations, such as prolonged
reaction times, high reaction temperatures, environmentally
unfriendly oxidants, or low selectivity. Furthermore, metal-
catalyzed oxidation reactions often utilize expensive and
limited available precious metals such as palladium, ruthe-
nium, gold, iridium, and vanadium. Consequently, the devel-
opment of new efficient environmentally benign procedures
for the synthesis of imines continues to be a challenging and
active area of research.[5]
Simulation of the functions of amine oxidase enzymes that
govern the metabolism of amines may also lead to the
development of methods for the biomimetic catalytic oxida-
tion of amines to imines under mild conditions.[6] In this
respect, we recently found that the electrogenerated o-
Scheme 1. Ionic transamination mechanism of the catalytic oxidation
of primary amines to imines mediated by electrogenerated o-iminoqui-
iminoquinone species 1ox (step 1, Scheme 1) was able to
replicate the activity and specificity of copper-containing
amine oxidases (CuAOs) toward primary amines.[7] The
catalytic cycle produced N-alkylidenealkylamine as the
product of amine oxidation through the ionic pyridoxal-like
transamination process reported for CuAO cofactors
(Scheme 1). The rate-limiting step involves a-proton abstrac-
tion and the subsequent electron flow from the a-carbon atom
to the o-iminoquinone moiety, which aromatizes to the highly
reactive Schiff base cyclic transition state 1’ox (step 4,
Scheme 1), thus allowing the activation of the imine function
for further nucleophilic attack by the amine (step 5,
Scheme 1).[7b] This 1ox-mediated electrocatalytic oxidation of
primary amines allowed the generation of unstable imines
(step 6, Scheme 1) under metal-free conditions, without any
stoichiometric reagents, at ambient atmosphere. These con-
ditions are particularly favorable for using the imine in situ
for further reactions. For example, we have recently devel-
oped a facile one-pot metal-free 1ox-mediated oxidation/imine
formation/reduction sequence for the atom-economical che-
none 1ox, which mimics the cofactor of amine-oxidases.
moselective N-alkylation of benzylic primary amines with
amines; this sequence allows the synthesis of benzylic
secondary amines, under mild conditions.[8]
Nevertheless, it seemed doubtful that our electrochemical
procedure[7] will ever be able to compete with more conven-
tional chemical approaches at a large preparative scale. In
contrast, the process would be most attractive if 1ox could be
generated through aerobic oxidation of 1red. So, inspired by
the enzymatic reaction of CuAOs[9] and by recent break-
throughs on the aerobic oxidation of amines to imines,[5,6] we
demonstrate herein that a synergistic combination of copper
and organocatalyst 1ox constitutes a novel approach to imines
from primary amines, under very mild conditions, which
include dioxygen in air as the oxidant together with ambient
temperature and pressure.
Based on the efficient reactivity between electrocatalyst
1ox and various amines,[7] we hypothesized that the oxidation
process started with atmospheric oxygen, as shown in
Scheme 2, and continued in a cascade-like manner by passing
the oxidation potential of oxygen through copper salt to the
organic o-iminoquinone mediator 1ox, which finally oxidized
the amine substrate after forming the Schiff base cyclic
transition state 1’ox (step 4, Scheme 1). To evaluate the validity
[*] Dr. M. Largeron, Prof. Dr. M.-B. Fleury
Universitꢀ Paris Descartes, UMR CNRS 8638
4, avenue de l’Observatoire, 75270 Paris Cedex 06 (France)
E-mail: martine.largeron@parisdescartes.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200587.
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Table 1: Aerobic CuI/1ox-catalyzed oxidation of different amines.[a]
Entry
1
Substrate
Product
Yield[b] [%]
96
Scheme 2. Aerobic oxidation of primary amines to imines catalyzed by
CuI/o-iminoquinone 1ox.
2
3
4
93
90[c]
97
of this concept, we began our investigations with benzylamine
as the amine substrate. If our hypothesis is right, part of the
optimum conditions should be identical to that required for
the electrochemical process. Accordingly, MeOH was pre-
ferred over other solvents, such as THF, MeCN, or CHCl3,
because strong solvation of the o-iminoquinone 1ox by MeOH
was necessary to enhance the electrophilicity of its quinonoid
moiety, thereby favoring the nucleophilic attack (step 2,
5
6
96
95
7
85
Scheme 1) of the amine. Likewise, a combination of one
[10]
equivalent of amine with 0.02 equivalent of 1red
,
which
corresponds to 2 mol% of organocatalyst 1ox, was found to be
ideal for the reaction.[7b] In the absence of copper catalyst, the
reaction proceeded very slowly, and the conversion of
benzylamine into N-benzylidenebenzylamine reached 66%
in seven days, owing to the slow spontaneous aerobic
oxidation of 1red. When, in turn, 0.2 mol% of copper(I) 3-
methylsalicylate (CuMeSal) was added as the co-catalyst
(0.002 equiv), only ten hours were needed for full conversion
of benzylamine (85% conversion after three hours). Then, N-
benzylidenebenzylamine was isolated in 96% yield as the sole
8
9
88[c]
88
10
11
78
40[d]
12
13
50[d]
55[d]
14
15
25[d]
0
1
product (as observed by H NMR spectroscopy) after evap-
oration of the solvent at ambient temperature. No improve-
ments were observed when CuI loading was increased.
Different copper catalysts such as CuI and Cu(OAc)2 were
also screened. All the copper salts catalyzed the reaction, but
a reduction of reaction time was observed with CuMeSal. In
a separate control experiment, 1red was fully omitted from the
reaction mixture. Then, no reaction occurred at room
temperature when copper was used as the sole catalyst.[5a,d]
Interestingly, when monitoring the progress of the synergistic
catalytic process in MeOD by 1H NMR spectroscopy, we
found that only N-benzylidenebenzylamine was formed, with
no evidence for the formation of benzaldehyde; this result is
in agreement with the formation of the Schiff base inter-
mediate 1’ox as shown in Scheme 1 (step 4).
–
[a] Reagents and conditions: amine substrate (20 mm); 1ox (0.4 mm;
2 mol% relative to amine); CuI: CuMeSal (0.04 mm; 0.2 mol% relative
to amine); MeOH (10 mL), 10 h, RT. [b] Yields of the imine refer to the
isolated unpurified product, which, unless otherwise stated, was pure by
1H NMR spectroscopy (see the Supporting Information). [c] Imine
product directly precipitated in the bulk solution. [d] Yields obtained by
conversion to the corresponding DNPH by aqueous acidic work-up of
the reaction mixture with 2,4-dinitrophenylhydrazine.
catalysis because of deactivation of the catalysts, which is
caused by the strong coordination of these amines to the
metal center. The synthesis of aliphatic imines is inherently
more challenging because of their instability and difficult
isolation. Therefore, the possibility of expanding the scope of
this novel method to the synthesis of aliphatic imines was also
explored (Table 1, entries 11–13). Although N-alkylideneal-
kylamine could be observed during the first hours of the
Next, the scope of the biomimetic CuI/1ox co-catalytic
system was examined with regard to a range of structurally
diverse primary amines. High catalytic activity was found for
the conversion of benzylic amines (Table 1, entries 1–8), and
the imine product yield did not markedly depend on the
substitution of the phenyl ring. In particular, halo-substituted
benzylamines (Table 1, entries 2 and 3) performed well and
lead to halo-substituted imines, which could be used for
further transformations along with the imine functionality. It
should be noted that this approach was also applicable to
heteroatom-containing amine substrates, such as thiophene
(Table 1, entry 9) and furan (entry 10), the imine products of
which are usually inaccessible by transition-metal-complex
1
reaction through monitoring the H NMR spectrum (see the
Supporting Information), its instability did not permit to
isolate it as such. Consequently, the yield was obtained by
conversion to the 2,4-dinitrophenylhydrazone (DNPH) by
aqueous acidic work-up of the reaction mixture with 2,4-
dinitrophenylhydrazine.[7b] Interestingly, as for the CuAOs, a-
branched amines (Table 1, entry 14) were found to be inferior
2
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substrates for the biomimetic CuI/1ox co-catalytic system,
whereas secondary amines were not reactive at all (entry 15).
In subsequent studies, we attempted the synthesis of cross-
coupling products A by reacting 4-methylbenzylamine in the
presence of different primary amines (Table 2). The real-time
nucleophilic attack by the alkylating aliphatic primary amine
on the Schiff base intermediate 1’ox (step 5, Scheme 1).
Accordingly, the presence of an excess of the alkylating
primary amine (2 equiv) did not increase the amount of cross-
coupling product A versus that of homo-coupling product B,
and 4-methylbenzaldehyde has never been observed during
the catalytic process. As shown in Table 2, a good imine
selectivity was observed in all cases. Note that the CuI/1ox-
catalyzed aerobic oxidative imination of 4-methylbenzyl-
amine by ethanolamine showed good tolerance of an alcohol
group (Table 2, entry 8).
Table 2: Aerobic CuI/1ox-catalyzed oxidative cross-coupling of amines.[a]
In conclusion, we have achieved chemoselective biolog-
ically inspired CuI/1ox-mediated aerobic oxidation of primary
amines. Low catalytic amounts of biocompatible CuI metal
catalyst (0.2 mol%) and organocatalyst 1ox (2 mol%) are
À
sufficient to activate the a-C H bond of primary amines
Entry
Alkylating amine
Imine selectivity
A:B[b]
which are converted into alkylated imines under ambient
conditions. This atom-economical green process tolerates the
presence of various reactive functional groups and is highly
selective in the case of cross-coupling of two amines. Studies
are underway to investigate further synthetic applications.
1
2
85:15
83:17
3
4
70:30
81:19
Experimental Section
5
6
79:21
95:5
N-Benzylidenebenzylamine.[11] Typical procedure: Benzylamine
(5 mmol, 1 equiv), reduced organocatalyst 1red (0.1 mmol,
0.02 equiv),[10]
and
copper
3-methylsalicylate
(0.01 mmol,
0.002 equiv) were mixed in MeOH (10 mL) in an air atmosphere.
The reaction mixture was stirred at room temperature for ten hours.
The progress of the reaction was monitored by 1H NMR spectroscopy.
After completion of the reaction, the solvent was evaporated at room
temperature to give N-Benzylidenebenzylamine as an almost pure
7
8
76:24
80:20
9
98:2
1
product, the identity and purity of which were confirmed by H and
13C NMR spectroscopy, after comparison with an authentic sample.
[a] Reagents and conditions: 4-methylbenzylamine (10 mm), alkylating
amine (10 mm), 1ox (0.4 mm; 4 mol% relative to amine), CuI: CuMeSal
(0.04 mm; 0.4 mol% relative to amine), MeOH (10 mL), 10 h, RT; the
conversion of 4-methylbenzylamine was roughly quantitative in all cases.
Received: January 20, 2012
Published online: && &&, &&&&
1
[b] Molar ratio based on the H NMR spectrum of the crude product.
Keywords: amines · chemoselectivity · imines · oxidation ·
.
homogeneous catalysis
monitoring of the reaction between 4-methylbenzylamine and
aminomethylcyclohexane (equimolar amounts) by H NMR
1
spectroscopy indicated that both self-coupling product B
(singlet around d = 8.40 ppm) and cross-coupling product A
(singlet around d = 8.20 ppm) were initially formed, with
a preference for homo-coupling product B (see Figure 1 in the
Supporting Information, spectra a and b). However, after
30 min, imine B gradually turned to cross-coupling product A,
which finally became the major product after ten hours
(spectra c and d, Figure 1 in the Supporting Information).
From these results, we envision two different pathways. First,
homo-coupling product B is extruded as the sole imine
product through the reaction shown in Scheme 1 and further
N-alkylated by the second primary amine. In this case, copper
could promote reaction of the homo-coupling product B with
the alkylating primary amine through an addition–elimina-
tion mechanism leading to the cross-coupling product A.
Second, both homo- and cross-coupling products are pro-
duced competitively through the reaction shown in Scheme 1
(steps 5 and 6). At this point, it seems that the formation of
the cross-coupling product Awould preferably result from the
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4
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Communications
Homogeneous Catalysis
M. Largeron,*
M.-B. Fleury
&&&& — &&&&
A Biologically Inspired CuI/Topaquinone-
Like Co-Catalytic System for the Highly
Atom-Economical Aerobic Oxidation of
Primary Amines to Imines
Acting together: Low catalytic amounts of
CuI and topaquinone-like catalyst 1ox (see
scheme) are sufficient to activate the a-
ambient conditions. This atom-econom-
ical process tolerates the presence of
various reactive functional groups and
allows selective cross-coupling of two
amines.
À
C H bond of primary amines, which are
converted into alkylated imines under
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!