A metalloenzyme-like catalytic system for the chemoselective oxidative cross-coupling of primary amines to imines under ambient conditions

Article abstract of DOI:10.1002/chem.201405843

The direct oxidative cross-coupling of primary amines is a challenging transformation as homocoupling is usually preferred. We report herein the chemoselective preparation of cross-coupled imines through the synergistic combination of low loadings of Cu^II metal-catalyst and o-iminoquinone organocatalyst under ambient conditions. This homogeneous cooperative catalytic system has been inspired by the reaction of copper amine oxidases, a family of metalloenzymes with quinone organic cofactors that mediate the selective oxidation of primary amines to aldehydes. After optimization, the desired cross-coupled imines are obtained in high yields with broad substrate scope through a transamination process that leads to the homocoupled imine intermediate, followed by dynamic transimination. The ability to carry out the reactions at room temperature and with ambient air, rather than molecular oxygen as the oxidant, and equimolar amounts of each coupling partner is particularly attractive from an environmentally viewpoint.

Full text of DOI:10.1002/chem.201405843

DOI: 10.1002/chem.201405843
Full Paper
&
Homogeneous Catalysis
A Metalloenzyme-Like Catalytic System for the Chemoselective
Oxidative Cross-Coupling of Primary Amines to Imines under
Ambient Conditions
Martine Largeron* and Maurice-Bernard Fleury[a]
Abstract: The direct oxidative cross-coupling of primary
amines is a challenging transformation as homocoupling is
usually preferred. We report herein the chemoselective prep-
aration of cross-coupled imines through the synergistic com-
bination of low loadings of CuII metal-catalyst and o-imino-
quinone organocatalyst under ambient conditions. This ho-
mogeneous cooperative catalytic system has been inspired
by the reaction of copper amine oxidases, a family of metal-
loenzymes with quinone organic cofactors that mediate the
selective oxidation of primary amines to aldehydes. After op-
timization, the desired cross-coupled imines are obtained in
high yields with broad substrate scope through a transamina-
tion process that leads to the homocoupled imine inter-
mediate, followed by dynamic transimination. The ability to
carry out the reactions at room temperature and with ambi-
ent air, rather than molecular oxygen as the oxidant, and
equimolar amounts of each coupling partner is particularly
attractive from an environmentally viewpoint.
Introduction
cient and selective (>95%) oxidative cross-coupling protocols
for various amines have been reported to date, but they re-
quire high reaction temperatures (1008C) together with
oxygen pressure.[10]
Imines, commonly known as Schiff bases, represent a very im-
portant class of N-containing intermediates widely utilized as
electrophiles in many organic transformations, such as reduc-
tion, addition, condensation, and cyclization. They are also es-
sential pharmacophores in numerous biologically active com-
pounds. Imines have traditionally been prepared through con-
densation of amines with aldehydes or ketones, but new mild
and practical catalytic methods,[1] including oxidative coupling
of alcohols and amines[2] together with oxidation of secondary
amines,[3] have also been developed. For a long time, little at-
tention had been given to the oxidation of primary amines
probably due to poor product selectivity.[4] The discovery of
homogeneous and heterogeneous catalytic systems that oper-
ate effectively with molecular oxygen as the sole oxidant has
contributed to revitalize interest in this area.[5] Recently, non-
noble transition-metal catalysis,[6] metal-free catalysis,[7] and
photocatalysis[8] have led to homocoupled imines in high
yields and selectivity. However, save for a few exceptions,[6b,d]
these catalytic systems require elevated temperature (70–
1308C) and/or oxygen pressure. In addition, the condensation
of amines is not an efficient way to prepare cross-coupled
imines due to the concomitant formation of self-coupling pro-
ducts.[6a,7a,9] To the best of our knowledge, only two highly effi-
The general interest in amine oxidation has also stimulated
efforts to mimic the biological activity of metalloenzymes,[11] in
particular copper amine oxidases (CuAOs) that promote selec-
tive aerobic oxidation of primary amines to aldehydes in
nature through the cooperation between a quinone-based co-
factor (topaquinone) and copper.[12] Recently, metalloenzyme-
like catalytic systems have been developed for the aerobic oxi-
dation of primary amines to imines under mild conditions.[13] In
particular, the topaquinone analog 5-tert-butyl-2-hydroxy-1,4-
benzoquinone has been described as an efficient biomimetic
organocatalyst for the chemoselective aerobic oxidative self-
coupling of primary amines to imines at room temperature
and under 1 atm of molecular oxygen. The exclusive selectivity
for primary benzylic amines allowed the preparation of various
cross-coupled imines in high yields, from the oxidative conden-
sation of benzylamine with anilines or with primary aliphatic
amines.[13b]
We have ourselves described a biomimetic homogeneous
catalytic system for the aerobic oxidation of primary amines to
imines, based on the synergistic combination of copper and
a topaquinone-like organocatalyst 1ox, first discovered from
electrochemical investigations.[14] Low catalyst loadings
(2 mol% of 1red precursor of 1ox and 0.2 mol% of CuI) were suf-
ficient to oxidize benzylic and aliphatic amines to self-coupled
imines under ambient conditions. The oxidation process start-
ed with atmospheric oxygen and continued in a cascade-like
manner by passing the oxidation potential of oxygen through
the copper salt to the organic o-iminoquinone mediator 1ox,
which finally oxidized the amine substrate (Scheme 1). This cat-
[a] Dr. M. Largeron, Prof. Dr. M.-B. Fleury
UMR 8638 CNRS-Universitꢀ Paris Descartes (Paris 5)
Sorbonne Paris Citꢀ
Facultꢀ 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 available on the WWW under
http://dx.doi.org/10.1002/chem.201405843.
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Table 1. Optimization of the CuII/1ox-catalyzed aerobic oxidative cross-
coupling of 4-methylbenzylamine 2a with 1-ethylpropylamine 3a.[a]
Scheme 1. Aerobic oxidation of primary amines to imines catalyzed by CuII/
1ox cooperative system.
Entry
Copper
Catalyst
Solvent
Conversion
[%]
Imine Selectivity 4a:5[b]
1
2
3
4
5
6
7
8
CuMeSal
CuI
CuCN
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
THF
100
100
100
100
100
90
95:5
95:5
95:5
95:5
95:5 (100:0)[c]
92:8
84:16
52:48
alytic process combines two redox couples: the o-iminoqui-
none organocatalyst 1ox is the substrate-selective catalyst and
the copper salt serves as an electron transfer mediator. This is
reminiscent of other biomimetic catalytic systems that use
transition metals as substrate-selective catalysts coupled with
electron transfer mediators.[15]
CuBr2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
83
60
CHCl3
[a] The reactions were carried out using equimolar amounts of amines 2a
and 3a on a 2.5 mmol scale, in the presence of 4 mol% of 1red and
0.4 mol% of copper salt, in 10 mL of solvent, at room temperature, under
ambient air for 10 h. [b] Molar ratio based on the 1H NMR spectrum of
the crude product. [c] After 6 h, an additional aliquot of 1red (1 mol%)
was added. CuMeSal: copper(I) 3-methylsalicylate.
Interestingly, the oxidative condensation of 4-methyl benzyl-
amine with several aliphatic amines produced the correspond-
ing cross-coupled imine in good yields, together with N-(4-
methylbenzyl)-1-(p-tolyl)methanimine derived from homo con-
densation as the minor product (5–30%). This investigation of
the performance of our bioinspired catalytic system led to
a preliminary communication.[16] At this stage, only 4-methyl-
benzylamine or benzylamine[9,10,13b,d] had been engaged in the
oxidative cross-coupling with alkylating amines. So, the devel-
opment of a more general method that would operate effec-
tively with complete selectivity, under ambient conditions,
would be highly desirable but still challenging.
cooperative organocatalyst 1ox, room temperature, and ambi-
ent air as the source of oxidant was retained throughout. As
shown in Table 1, the initial oxidation state of the copper cata-
lyst had no significant impact on the reaction efficiency (en-
tries 1–5). The reaction progressed in all of the solvents used
(entries 5–8). But, after 10 h, complete conversion was ob-
served only in MeOH probably because strong solvation of the
o-iminoquinone 1ox by MeOH was required to enhance the
electrophilicity of its quinonoid moiety, thereby favoring the
nucleophilic attack of 4-methylbenzylamine 2a.[14]
Optimization of the reaction parameters showed that mixing
4-methylbenzylamine 2a and 1-ethylpropylamine 3a in the
ratio 1:1 with Cu(OAc)2 (0.4 mol%) and o-aminophenol 1red
(4 mol%), in MeOH under ambient conditions, afforded the de-
sired cross-coupled product 4a with 95% selectivity after 10 h
(entry 5). In addition, exclusive formation of 4a could be at-
tained when an additional aliquot of o-aminophenol 1red
(1 mol%) was introduced after 6 h (95% conversion). Probably,
the in situ-generated o-iminoquinone organocatalyst 1ox poly-
merized slightly. Control studies revealed that copper catalyst
and organocatalyst 1ox worked cooperatively to facilitate the
aerobic oxidation of amines to imines under ambient condi-
tions. In the absence of copper, the reaction proceeded very
slowly owing to the spontaneous aerobic oxidation of 1red to
1ox, whereas no reaction occurred at room temperature when
a copper salt was used as the sole catalyst.
In this full paper, we have tried to achieve exclusive forma-
tion of cross-coupled imines and to expand the substrate
scope. Diverse benzylic amines, including heterocyclic amines
containing sulfur and oxygen atoms, could be converted with
complete selectivity into the corresponding cross-coupled
imines in high yields. The synthesis of aliphatic imines was in-
herently more challenging because of their instability due to
subsequent tautomerization to the enamine form, which de-
composed under ambient air. Although the cross-coupled ali-
phatic imine could be formed with complete selectivity as
1
shown through monitoring the H NMR spectrum, we were not
able to isolate it as such. So, we decided to engage the gener-
ated alkylimine in situ in a Diels–Alder reaction with the Dani-
shefsky’s diene to produce N-alkylpyridin-4-one derivatives. Fi-
nally, all the results led us to revise the reaction pathway we
had previously proposed for the oxidative cross-coupling of
primary amines to imines.[16]
Results and Discussion
Choice of the optimal reaction conditions
First, we performed optimization studies of the CuII/1ox-mediat-
ed aerobic oxidative cross-coupling process by using 4-methyl-
benzylamine 2a and 1-ethylpropylamine 3a as the amine sub-
strates. Only the copper source and solvent were varied, while
the use of o-aminophenol 1red precursor of the o-iminoquinone
Scope and functional group tolerance of CuII/1ox-mediated
oxidative cross-coupling of two primary amines
To explore potential applications of this method, the optimized
reaction conditions (Table 1, entry 5) were first applied to the
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catalytic oxidative cross-coupling of 4-methylbenzylamine 2a
with a range of primary amines 3 (Table 2). Both branched and
linear aliphatic amines (entries 1–6) could be efficiently cou-
pled with 4-methylbenzylamine 2a in high yields, with com-
plete selectivity, except for n-hexylamine 3e and aminomethyl-
cyclohexane 3 f, for which small amounts of homocoupled
imines (4–5%) were also isolated (entries 5 and 6). 1-Phenyle-
than-1-amine 3g (entry 7) together with 2,3-dihydro-1H-inden-
2-amine 3h (entry 8) reacted efficiently with 2a, leading to
cross-coupled imines that directly precipitated from the bulk
solution. As has been observed earlier,[13b] anilines 3i–k (en-
tries 9–11) were less reactive, but afforded cross-coupled
imines with good levels of conversion after 48 h, provided
a second 2 mol% portion of o-aminophenol 1red was added
after 24 h (entries 9 and 10), with the exception of p-chloroani-
line 3k, for which the conversion did not exceed 60%
(entry 11). Interestingly, introduction of ether or alcohol groups
(entries 12–14) allowed the synthesis of functionalized cross-
coupled imines, notably without oxidation of the alcohol frag-
ment (entry 14).
In a second series of experiments, a range of primary amine
substrates 2 were screened in the presence of 1-ethylpropyl-
amine 3a (Table 3). High yields of cross-coupled imines were
obtained from substituted benzylamines 2a–j regardless of the
electronic character and the position of the substitu-
ents (entries 1–10). The free amino group of p-
aminobenzylamine 2g did not affect the cross-cou-
Table 2. Cu(OAc)2/1ox-catalyzed aerobic oxidative cross-coupling of 4-methylbenzyl-
amine 2a with a range of primary aliphatic and aromatic amines 3.[a]
pling reaction although the yield slightly decreased
(75%, entry 7). Likewise, a sterically bulky group, 1-
naphthyl, was well tolerated (entry 11). Furthermore,
heterocyclic amines 2l and 2m, containing sulfur and
oxygen atoms, could be cross-coupled with 3a in
high yields with complete selectivity (entries 12 and
13).
Entry Alkylating Amine 3
Imine
Product 4 [%]
Conversion Imine Selectivity 4:5[b] Yield
Much more challenging, the possibility of expand-
ing the reaction scope to the synthesis of scarcely
stable aliphatic imines was also explored. The catalyt-
ic oxidative cross-coupling of aminomethylcyclopro-
pane 6 and 4-methoxyaniline 3i was chosen as the
[%][c]
1
3a
4a
100
100:0
97
2
3
3b
3c
4b
4c
100
100
100:0
100:0
97
96
1
example and monitored by H NMR spectroscopy. In
the reaction of equimolar amounts of both amines 6
and 3i, the time course revealed the formation of
only heterocoupled product 7 at the early stages of
the reaction. Although 1-cyclopropyl-N-(4-methoxy-
phenyl) methanimine 7 could be observed through
4
5
6
3d
3e
3 f
4d
4e
4 f
100
100
100
100:0
95:5
96:4
95
90
90
1
monitoring the H NMR spectrum (see the Support-
7
3g
4g
100
100:0
90[d]
ing Information), its instability did not permit its iso-
lation. Nevertheless, the mild conditions required for
the generation of unstable cross-coupled aliphatic
imine 7 proved to be useful for acting in situ as a di-
enophile in Diels–Alder reactions. After roughly 60%
conversion of aminomethyl cyclopropane 6, the reac-
tion mixture was mixed with Danishefsky’s diene 8 to
form the dihydro-4-pyridone derivative 9 in 45% iso-
lated yield (Scheme 2). Similar acid-free tandem oxi-
dative aza Diels–Alder reactions have been previously
reported for the synthesis of N-aryl and N-alkylben-
zaldimines.[17] In addition to dihydro-4-pyridone 9,
(Z)-enaminone 10 was also isolated in 52% yield. The
formation of 10 indicated that both 1-cyclopropyl-N-
(4-methoxyphenyl) methanimine 7 and Danishefsky’s
diene 8 partially hydrolyzed under our experimental
conditions, leading to benzaldehyde, 4-methoxyani-
line 3i, and (3E)-4-methoxybut-3-en-2-one. The latter
further reacted with 4-methoxyaniline 3i to generate
the (Z)-enaminone 10 as previously reported.[18] As
further proof of the partial hydrolysis of methanimine
7, when the same reaction was performed using 4-
methylbenzylamine 2a as the amine substrate, which
8
3h
3i
4h
4i
100
95[e]
90[e]
100:0
100:0
100:0
90[d]
90[d]
80[d]
9
10
3j
4j
11
12
13
3k
3l
4k
4l
60[e]
100
100
92:8
93:7
100:0
55[d]
90
3m
4m
95
14
3n
4n
100
94:6
85
[a] The reactions were carried out using equimolar amounts of amines 2a and 3 on
a 2.5 mmol scale, in the presence of 5 mol% of 1red (4 mol%+1 mol% added after
6 h) and 0.4 mol% of Cu(OAc)2, in 10 mL of methanol, at room temperature, under
ambient air for 10 h. [b] Molar ratio based on the 1H NMR spectrum of the crude prod-
uct. [c] Yields of the cross-coupled imine refer to the isolated unpurified product,
which, unless otherwise stated, was pure by 1H NMR spectroscopy (see the Support-
ing Information). [d] Cross-coupled imine product directly precipitated from the bulk
solution. [e] Conversion after 48 h, provided a second 2 mol% portion of o-aminophe-
nol 1red was added after 24 h.
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that the homocoupled product was initially formed
and accumulated at early stages of the reaction.
After roughly 30 min, the homocoupled imine gradu-
ally converted into the cross-coupled product that fi-
nally became the exclusive product after ten hours.
Of particular note, only the reaction of 4-methylben-
zylamine 2a with n-hexylamine 3e (Table 2, entry 5)
or aminomethylcyclohexane 3 f (Table 2, entry 6) re-
vealed the simultaneous formation of homo- and
cross-coupled products (4e or 4 f) from the outset of
the reaction, but with a preference for the homocou-
pled product 5. These observations indicated that
the homocoupled product was first generated as the
sole imine product through the transamination
mechanism reported earlier.[14,16] The homocoupled
product was further alkylated by the second primary
amine R’ÀNH2 through a transimination process[19] to
give the cross-coupled product, the formation of
which could be driven by continuous oxidation of
the extruded primary amine RÀCH2ÀNH2 (self-sorting
step) as shown in Scheme 3. As a consequence, just
one equivalent of each primary amine was sufficient
to achieve exclusive formation of the cross-coupled
imine product. This oxidative strategy, known as oxi-
dative self-sorting, has previously been exploited to
obtain thermodynamically disfavored products.[13b,20]
We have further validated our mechanistic process
by reacting the isolated homocoupled imine 5 with
two equivalents of 1-ethylpropylamine 3a under the
standard conditions (Table 1, entry 5). Then, full con-
version of the homocoupled imine 5 into the cross-
coupled imine 4a was observed after ten hours, pro-
viding support for the two-step mechanism.
Table 3. Cu(OAc)2/1ox-catalyzed aerobic oxidative cross-coupling of a range of primary
amines 2 with 1-ethylpropylamine 3a.[a]
Entry
Amine
Substrate 2
Imine
Product 4
Conversion
[%]
Yield [%][b]
1
2
2a
2b
4a
4o
100
100
97
96
3
2c
4p
100
97
4
5
2d
2e
4q
4r
100
100
94
95
6
7
2 f
4s
4t
100
95
92
75
2g
8
2h
2i
4u
4v
4w
100
100
100
94
92
96
9
10
2j
11
12
13
2k
2l
4x
4y
4z
100
100
100
94
94
95
2m
The synthesis of cross-coupled aliphatic imines was
found to be troublesome because of their instability.
The main problem associated with these imines is re-
lated to the formation of the tautomeric enamine
form, which decomposed under ambient air.[21] Nev-
ertheless, the fact that aliphatic imines can be engag-
ed in situ for further reactions, leading to N-alkylpyri-
din-4-one derivatives, demonstrates that aliphatic
amines are well oxidized to imines under our experi-
[a] The reactions were carried out using equimolar amounts of amines 2 and 3a on
a 2.5 mmol scale, in the presence of 5 mol% of 1red (4 mol%+1 mol% added after
6 h) and 0.4 mol% of Cu(OAc)2, in 10 mL of methanol, at room temperature, under
ambient air for 10 h. [b] Yields of the cross-coupled imine refer to the isolated unpuri-
fied product, which, unless otherwise stated, was pure by 1H NMR spectroscopy (see
the Supporting Information).
was oxidized to stable benzaldimine 4i, dihydro-4-pyridone 11
was isolated in 80% yield at the exclusion of (Z)-enaminone
byproduct 10 (Scheme 2).
mental conditions as previously reported.[16] Whereas transi-
tion-metal-catalyzed oxidations to dehydrogenate aliphatic
amines to imines require vigorous reaction conditions, the syn-
ergistic action of our bioinspired homogeneous cooperative
catalyst lowers the activation energy, enabling high reactivity
that neither catalyst can accomplish alone.
Mechanistic considerations
On the basis of our one previous example of the cross-cou-
pling reaction, we had proposed that both homo- and cross-
coupled products would be produced competitively through
the ionic transamination mechanism described earlier.[16] Our
present investigation into the substrate scope of the CuII/1ox-
mediated cross-coupling of two primary amines led us to
revise our original proposal to the one depicted in Scheme 3.
Indeed, in almost all of the cases, the real-time monitoring of
Conclusion
New insights into the scope and mechanism of the bioinspired
CuII/1ox-catalyzed aerobic oxidative cross-coupling of primary
amines to imines have been delineated. Low loadings of bio-
compatible CuII metal-catalyst and topaquinone-like organoca-
talyst 1ox were sufficient to activate the a-CÀH bond of various
primary amines, which were converted to cross-coupled imines
1
the cross-coupling reactions by H NMR spectroscopy indicated
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Experimental Section
General considerations
1H NMR and 1D proton decoupled 13C NMR spectra were recorded
in CDCl3 on a Brucker AC-300 spectrometer operating at 300 MHz
and 75 MHz, respectively. Chemical shifts, d, are given in ppm rela-
tive to TMS and coupling constants, J, in Hz. The measurements
were carried out using the standard pulse-sequences. The carbon
type (methyl, methylene, methine, or quaternary) was determined
by DEPT experiments. Mass spectra were recorded on a ZQ 2000
Waters spectrometer, equipped with the positive electrospray
mode (ES+). Chemicals were commercial products of the highest
available purity and were used as supplied. Reduced catalyst 1red
was synthesized in two steps from commercially available 2-nitro-
resorcinol.[22]
Representative experimental procedure for CuII/1ox-catalyzed
aerobic oxidative cross-coupling of two primary amines
Equimolar amounts of 4-methylbenzylamine 2a (2.5 mmol) and 1-
ethylpropylamine 3a (2.5 mmol), reduced organocatalyst 1red
(0.1 mmol, 4 mol%), and copper (II) acetate (0.01 mmol, 0.4 mol%)
were mixed in methanol (10 mL) in an air atmosphere. The reaction
mixture was stirred at room temperature (258C) for six hours.
Then, an additional aliquot of 1red (0.025 mmol, 1 mol%) was intro-
duced into the reaction mixture and the reaction was stirred for
roughly four 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 the cross-coupled
imine product 4a (97%) as an almost pure product as confirmed
Scheme 2. Tandem oxidative aza Diels–Alder reaction for the synthesis of di-
hydro-4-pyridones.
1
by H and 13C NMR spectroscopy (see the Supporting Information).
Imine 4a: 1H NMR (300 MHz, CDCl3, 258C, TMS): d=0.88 (t, J=
8 Hz, 6H, 2ꢁCH3), 1.70 (m, 4H, 2ꢁCH2), 2.43 (s, 3H, CH3), 2.91 (m,
1H, CH), 7.25 (d, J=7 Hz, 1H, 2ꢁCH, Ar), 7.68 (d, J=7 Hz, 1H, 2ꢁ
CH, Ar), 8.24 ppm (s, 1H, CH=N); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=11.1 (2ꢁCH3), 21.5 (CH3), 28.9 (2ꢁCH2), 75.2 (CH), 128.1
(2ꢁCH, Ar), 129.3 (2ꢁCH, Ar), 133.8 (Cq), 140.5 (Cq), 159.4 ppm
(CH=N); MS (ES+): m/z=190 [MH+].
The above procedure is generally representative for all the prod-
ucts shown in Tables 2 and 3. Any deviations from this protocol are
specified in the footnotes of the tables.
Representative procedure for CuII/1ox-catalyzed aerobic oxida-
tive synthesis of dihydro-4-pyridones derivatives
1-Cyclopropyl-N-(4-methoxyphenyl)methanimine 7 was prepared in
situ by mixing equimolar amounts of aminomethylcyclopropane 6
(1.25 mmol) and 4-methoxyaniline 3i (1.25 mmol), reduced organo-
catalyst 1red (0.05 mmol, 4 mol%), and copper(II) acetate
(0.005 mmol, 0.4 mol%) in methanol (5 mL) under ambient condi-
tions for six hours. Then, an additional aliquot of 1red
(0.0125 mmol, 1 mol%) was introduced into the reaction mixture
and the reaction was stirred for four hours. After roughly 60% of
aminomethylcyclopropane 6 had been converted into the cross-
coupled imine product 7 (see the NMR spectrum in the Supporting
Information), 2 mL of the resulting solution (which corresponds to
roughly 0.3 mmol of 7) was removed and Danishefsky’s diene 8
(0.6 mmol, 2 equiv) was added dropwise to it over 30 min. After
stirring for 1 h at room temperature (258C), another equivalent of
Danishefsky’s diene 8 (0.3 mmol) was added dropwise over 15 min
to the reaction mixture, which was stirred for 2 h at room tempera-
ture. The reaction mixture was then quenched with HCl (2 mL,
1.0m). The product was extracted with diethyl ether and the sol-
vent was evaporated under reduced pressure. The crude material
was purified by column chromatography with dichloromethane/
Scheme 3. Proposed overall two-step mechanism for the Cu(OAc)2/1ox-medi-
ated cross-coupling of primary amines.
through a transamination process, which leads to the homo-
coupled imine intermediate, followed by dynamic transimina-
tion. This atom-economical process, which proceeds at room
temperature, under ambient air, with equimolar amounts of
each coupling partner, and tolerates diverse functional groups,
generates with unprecedented selectivity cross-coupled
imines, which have been previously shown to have broad use
in organic synthesis. The mild reaction conditions used in this
work should be particularly favorable for using unstable alkyl-
imines in situ for further reactions.
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Commun. 2014, 50, 5637–5640; g) S. Zhao, C. Liu, Y. Guo, J.-C. Xiao, Q.-
Y. Chen, J. Org. Chem. 2014, 79, 8926–8931.
ethyl acetate (4:1 v/v) as the eluent, leading to dihydro-4-pyridone
9 (45%) together with (Z)-enaminone 10 (52%).
[7] For selected recent examples, see: a) H. Huang, J. Huang, Y.-M. Liu, H.-Y.
He, Y. Cao, K.-N. Fan, Green Chem. 2012, 14, 930–934; b) C. Su, M. Acik,
K. Takai, J. Lu, S.-J. Hao, Y. Zheng, P. Wu, Q. Bao, T. Enoki, Y.-J. Chabal,
K. P. Loh, Nat. Commun. 2012, 3, 1298–1306; c) L. Liu, Z. Wang, X. Fu,
C.-H. Yan, Org. Lett. 2012, 14, 5692–5695; d) H. Wang, X. Zheng, H.
Chen, K. Yan, Z. Zhu, S. Yang, Chem. Commun. 2014, 50, 7517–7520.
[8] For a recent review, see: a) X. Lang, X. Chen, J. Zhao, Chem. Soc. Rev.
2014, 43, 473–486. See also: b) J. H. Park, K. C. Ko, E. Kim, N. Park, J. H.
Ko, D. H. Ryu, T. K. Ahn, J. Y. Lee, S. U. Son, Org. Lett. 2012, 14, 5502–
5505; c) X. Lang, W. Ma, Y. Zhao, C. Chen, H. Ji, J. Zhao, Chem. Eur. J.
2012, 18, 2624–2631; d) S. I. Naya, K. Kimura, H. Tada, ACS Catal. 2013,
3, 10–13; e) N. Li, X. Lang, W. Ma, H. Ji, C. Chen, J. Zhao, Chem.
Commun. 2013, 49, 5034–5036; f) W. Zhao, C. Liu, L. Cao, X. Yin, H. Xu,
B. Zhang, RSC Adv. 2013, 3, 22944–22948; g) X.-J. Yang, B. Chen, X.-B.
Li, L.-Q. Zheng, L.-Z. Wu, C.-H. Tung, Chem. Commun. 2014, 50, 6664–
6667; h) L. Ye, Z. Li, ChemCatChem 2014, 6, 2540–2543; i) B. Yuan, R.
Chong, B. Zhang, J. Liu, C. Li, Chem. Commun. 2014, 50, 15593–15596;
j) D. Sun, L. Ye, Z. Li, Appl. Catal. B 2015, 164, 428–432.
Dihydro-4-pyridone 9: 1H NMR (300 MHz, CDCl3, 258C, TMS): d=
0.00 (m, 2H, CH2), 0.40 (m, 2H, CH2), 1.37 (m, 1H, CH), 2.62 (dd, J=
16 Hz, J=4 Hz, 1H, CH), 2.98 (dd, J=16 Hz, J=6.7 Hz, 1H, CH),
3.24 (m, 1H, CH), 3.85 (s, 3H, CH3), 5.16 (d, J=7.6 Hz, 1H, CH), 6.93
(d, J=8.9 Hz, 2H, 2ꢁCH, Ar), 7.16 (d, J=8.9 Hz, 2H, 2ꢁCH, Ar),
7.27 ppm (d, J=7.6 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=1.7 (CH2), 5.6 (CH2), 12.1 (CH), 41.6 (CH2), 55.5 (CH3), 65.4
(CH), 99.6 (CH=), 114.6 (2ꢁCH, Ar), 125.2 (2ꢁCH, Ar), 138.6 (Cq),
150.7 (CH=), 157.8 (Cq), 191.5 ppm (Cq, C=O); MS (ES+): m/z=244
[MH+]; elemental analysis calcd (%) for C15H17NO2: C 74.07, H 6.99,
N 5.76; found C 73.96, H 7.10, N 5.74.
1
(Z)-enaminone 10: H NMR (300 MHz, CDCl3, 258C, TMS): d=2.18
(s, 3H, CH3), 3.82 (s, 3H, CH3), 5.30 (d, J=7.6 Hz, 1H, CH), 6.93 (d,
J=9.0 Hz, 2H, 2ꢁCH, Ar), 7.16 (d, J=9.0 Hz, 2H, 2ꢁCH, Ar), 7.20
(m, 1H, CH), 11.65 ppm (broad d, 1H, NH, D2O exchanged);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=29.4 (CH3), 55.6 (CH3), 96.6
(CH=), 114.9 (2ꢁCH, Ar), 117.7 (2ꢁCH, Ar), 134.0 (Cq), 144.1 (CH=),
[9] a) K. N. Tayade, M. Mishra, J. Mol. Catal. A 2014, 382, 114–125; b) A. Mo-
nopoli, P. Cotugno, F. Iannone, F. Ciminale, M. M. Dell’Anna, P. Mastrorilli,
A. Nacci, Eur. J. Org. Chem. 2014, 5925–5931.
[10] a) A. Grirrane, A. Corma, H. Garcia, J. Catal. 2009, 264, 138–144; b) X.
Qiu, C. Len, R. Luque, Y. Li, ChemSusChem 2014, 7, 1684–1688.
[11] a) S.-I. Murahashi, D. Zhang, Chem. Soc. Rev. 2008, 37, 1490–1501; b) L.
Que, Jr., W. B. Tolman, Nature 2008, 455, 333–340.
1
156.1 (Cq), 198.4 ppm (Cq, C=O). H and 13C NMR spectral data are
in agreement with those previously reported in the literature.[23]
Acknowledgements
[12] a) M. Mure, S. A. Mills, J. P. Klinman, Biochemistry 2002, 41, 9269–9278;
b) M. Mure, Acc. Chem. Res. 2004, 37, 131–139.
The authors would like to thank ADRAPHARM (Association
pour le Dꢂveloppement de la Recherche Appliquꢂe ꢃ la Phar-
macologie) for financial support of this work.
[13] For a recent perspective, see: a) M. Largeron, M.-B. Fleury, Science 2013,
339, 43–44. See also: b) A. E. Wendlandt, S. S. Stahl, Org. Lett. 2012, 14,
2850–2853; c) H. Yuan, W.-J. Yoo, H. Miyamura, S. Kobayashi, J. Am.
Chem. Soc. 2012, 134, 13970–13973; d) D. V. Jawale, E. Gravel, E. Ville-
min, N. Shah, V. Geertsen, I. N. N. Namboothiri, E. Doris, Chem. Commun.
2014, 50, 15251–15254.
Keywords: cross-coupling
· cycloaddition · homogeneous
catalysis · oxidation · primary amines
[14] M. Largeron, A. Chiaroni, M.-B. Fleury, Chem. Eur. J. 2008, 14, 996–1003.
[15] For a review, see: J. Piera, J.-E. Bꢄckvall, Angew. Chem. Int. Ed. 2008, 47,
3506–3523; Angew. Chem. 2008, 120, 3558–3576.
[16] M. Largeron, M.-B. Fleury, Angew. Chem. Int. Ed. 2012, 51, 5409–5412;
Angew. Chem. 2012, 124, 5505–5508.
[17] For selected examples, see: a) Y. Yuan, X. Li, K. Ding, Org. Lett. 2002, 4,
3309–3311; b) C. Loncaric, K. Manabe, S. Kobayashi, Chem. Commun.
2003, 574–575; c) L. Liu, S. Zhang, X. Fu, C.-H. Yan, Chem. Commun.
2011, 47, 10148–10150.
[18] F. Bellezza, A. Cipiciani, U. Costantino, F. Fringuelli, M. Orrꢆ, O. Piermatti,
F. Pizzo, Catal. Today 2010, 152, 61–65.
[19] For a recent review, see: a) M. Ciaccia, S. Di Stefano, Org. Biomol. Chem.
2015, 13, 646–654. See also: b) M. Ciaccia, R. Cacciapaglia, P. Mencarelli,
L. Mandolini, S. Di Stefano, Chem. Sci. 2013, 4, 2253–2261; c) M. Ciaccia,
S. Pilati, R. Cacciapaglia, L. Mandolini, S. Di Stefano, Org. Biomol. Chem.
2014, 12, 3282–3287.
[20] For a review, see: a) M. E. Belowich, J. F. Stoddart, Chem. Soc. Rev. 2012,
41, 2003–2024. See also: b) S. M. Landge, V. Atanassova, M. Thimmaiah,
B. Tçrçk, Tetrahedron Lett. 2007, 48, 5161–6164.
[1] For recent reviews, see: a) R. D. Patil, S. Adimurthy, Asian J. Org. Chem.
2013, 2, 726–744; b) R. J. Angelici, Catal. Sci. Technol. 2013, 3, 279–
296; c) W. Qin, S. Long, M. Panunzio, S. Biondi, Molecules 2013, 18,
12264–12289; d) B. L. Ryland, S. S. Stahl, Angew. Chem. 2014, 126,
8968–8983; Angew. Chem. Int. Ed. 2014, 53, 8824–8838.
[2] For selected recent examples, see: a) J. F. Soulꢂ, H. Miyamura, S. Kobaya-
shi, Chem. Commun. 2013, 49, 355–357; b) B. Chen, J. Li, W. Dai, L.
Wang, S. Gao, Green Chem. 2014, 16, 3328–3334; c) L. Han, P. Xing, B.
Jiang, Org. Lett. 2014, 16, 3428–3431; d) M. Guan, C. Wang, J. Zhang, Y.
Zhao, RSC Adv. 2014, 4, 48777–48782; e) M. Tamura, K. Tomishige,
Angew. Chem. Int. Ed. 2015, 54, 864–867; Angew. Chem. 2015, 127,
878–881.
[3] For selected recent examples, see: a) J. S. M. Samec, A. H. Ell, J. E. Bꢄck-
vall, Chem. Eur. J. 2005, 11, 2327–2334; b) B. Zhu, R. J. Angelici, Chem.
Commun. 2007, 2157–2159; c) A. E. Wendlandt, S. S. Stahl, J. Am. Chem.
Soc. 2014, 136, 506–512; d) A. E. Wendlandt, S. S. Stahl, J. Am. Chem.
Soc. 2014, 136, 11910–11913.
[21] S. Morales, F. G. Garcia Ruano, M. B. Cid, J. Am. Chem. Soc. 2014, 136,
1082–1089.
[4] For a recent review, see: M. T. Schꢅmperli, C. Hammond, I. Hermans,
ACS Catal. 2012, 2, 1108–1117.
[22] D. Xu, A. Chiaroni, M.-B. Fleury, M. Largeron, J. Org. Chem. 2006, 71,
6374–6381.
[5] For a recent review, see: M. Largeron, Eur. J. Org. Chem. 2013, 5225–
5235.
[23] J.-C. Zhuo, Magn. Reson. Chem. 1997, 35, 21–29.
[6] For selected recent examples, see: a) R. D. Patil, S. Adimurthy, Adv.
Synth. Catal. 2011, 353, 1695–1700; b) Z. Hu, F. M. Kerton, Org. Biomol.
Chem. 2012, 10, 1618–1624; c) R. D. Patil, S. Adimurthy, RSC Adv. 2012,
2, 5119–5122; d) B. Huang, H. Tian, S. Lin, M. Xie, X. Yu, Q. Xu, Tetrahe-
dron Lett. 2013, 54, 2861–2864; e) E. Zhang, H. Tian, S. Xu, S. Yu, Q. Xu,
Org. Lett. 2013, 15, 2704–2707; f) J. Wang, S. Lu, X. Cao, H. Gu, Chem.
Received: October 27, 2014
Published online on && &&, 0000
&
&
Chem. Eur. J. 2015, 21, 1 – 7
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Homogeneous Catalysis
M. Largeron,* M.-B. Fleury
&& – &&
A Metalloenzyme-Like Catalytic
System for the Chemoselective
Oxidative Cross-Coupling of Primary
Amines to Imines under Ambient
Conditions
Synergistic action: The cooperative
copper salt and topaquinone-like cata-
lysts lower the activation energy, ena-
bling high reactivity toward the chemo-
selective oxidative cross-coupling of pri-
mary amines to imines that neither cat-
alyst can accomplish alone.
Chem. Eur. J. 2015, 21, 1 – 7
www.chemeurj.org
7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ