Aerobic Oxidative Homo- and Cross-Coupling of Amines Catalyzed by Phenazine Radical Cations

Article abstract of DOI:10.1021/acs.joc.8b02345

Phenazine radical cations (PhRCs) were used for the first time as efficient metal-free catalysts for the oxidative homo- and cross-coupling of a variety of different amines. A series of functional PhRCs were prepared, characterized with X-ray diffraction, and their radical character was investigated with DFT calculations. They were tested as catalysts under neat conditions with low oxygen pressure to prepare homo- and cross-coupled aliphatic and aromatic imines in high yields. Although all synthesized phenazines were catalytically active, the highest reaction rates and the best selectivity were achieved using the 5,10-dihydro-5,10-dimethylphenazine radical cation. By means of fluorescence, UV-vis and EPR spectroscopy, a mechanism of the oxidative amine coupling, catalyzed by PhRCs, is proposed.

Full text of DOI:10.1021/acs.joc.8b02345

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Article
Aerobic Oxidative Homo- and Cross-Coupling of
Amines Catalyzed by Phenazine Radical Cations
Rok Brišar, Felix Unglaube, Dirk Hollmann, Haijun Jiao, and Esteban Mejía
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02345 • Publication Date (Web): 11 Oct 2018
Downloaded from http://pubs.acs.org on October 11, 2018
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Page 1 of 12
The Journal of Organic Chemistry
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Aerobic Oxidative Homo- and Cross-Coupling of Amines Catalyzed
by Phenazine Radical Cations
Rok Brišar,†§ Felix Unglaube,† Dirk Hollmann‡, Haijun Jiao† and Esteban Mejía†*
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†Leibniz Institute for Catalysis, Albert-Einstein-Str. 29a, 18059 Rostock, Germany; ‡ Institute of Chemistry, University of Rostock,
Albert-Einstein-Str. 3a, 18059 Rostock, Germany.
Radical ions, Oxidation, Amines, Organocatalysis, Oxygen
ABSTRACT: Phenazine radical cations (PhRC) were used for the first time as efficient metal-free catalysts for the oxidative homo- and cross
coupling of a variety of different amines. A series of functional PhRC were prepared, characterized with x-Ray diffraction and their radical
character was investigated with DFT calculations. They were tested as catalysts under neat conditions with low oxygen pressure to convert
homo and cross coupled aliphatic and aromatic imines in high yields. Although all synthesized phenazines were catalytically active, the highest
reaction rates and the best selectivity were achieved using the 5,10-Dihydro-5,10-dimethylphenazine radical cation. By means of fluorescence,
UV-VIS and EPR spectroscopy, a mechanism of the oxidative amine coupling, catalyzed by PhRC is proposed.
INTRODUCTION
acid derivatives although the amount of catalyst renders this
method relatively ineffective (Scheme 1, B).15 The radical-
mediated amine oxidation has been thoroughly investigated
using heterogeneous carbocatalysts (Scheme 1, C),16 including
graphite oxide,17 porous graphene oxide,18 nanoporous carbons
derived from MOFs,19 hierarchically porous carbon derived
from POSS,20 carbon nitride, 21 et cetera.
Imines are an important component of many relevant
biologically active heterocycles,1 latest anticancer drugs2 and
intermediates in organic transformations especially in
asymmetric synthesis.3 Most imines are prepared by catalytic
processes since these provide higher conversions, better
reaction selectivity and significantly improve economic
performance compared to non-catalytic systems. Among the
available methods, the selective aerobic oxidation of amines is a
promising approach, although it still remains a challenging task.4
Most of the effective systems are noble metal-based catalysts
We recently showed for the first time the potential of
pyrazine radical cations as oxidation catalysts in amine
homocoupling reactions (Scheme 1, C).22 As an extension of
this work, we exploited the redox chemistry of N,N’-
disubstituted-dihydrophenazines (DSP), which, upon oxidation
produce phenazine radical cations (PhRC, Scheme 1, D).23
These stable open-shell species are known as versatile one-
electron reductants and oxidants in various biochemical
processes.24 Very recently, PhRC were introduced as excellent
catalysts for atom transfer radical polymerization driven by
visibly light,25 as well as proton acceptors in the oxidative
esterification of aldehydes.26 Here, we report the use of PhRC
for the first time as highly effective and selective metal-free
catalyst for the oxidative homo- and heterocoupling of amines
under mild conditions. This homogeneous organocatalyst are
chemically stable, readily available and achieve high reaction
conversions and selectivity.
including Pd,5 or Au.2, A considerable amount of effort has
6
been put in to replace these expensive metals with cheaper
compounds containing abundant metals like Cu7 alas, not
devoid of toxicity concerns. Satisfactory selectivity towards the
cross-coupling products have so far been achieved for instance
by highly active Fe8 and Pd5 complexes Therefore it is of high
interest to replace metal-based systems by metal-free
methodologies, particularly inspired by natural principles.4c, 9 In
a pioneering effort, Stahl et al. presented a biomimetic metal-
free system using 4-tert-butyl-2-hydroxybenzoquinone
(Scheme 1, A), inspired by the Copper amine oxidase cofactors
(CuAOs).10 Later on, further bio-inspired ortho-quinone
catalysts have been successfully applied in amine oxidations.11
Further examples of CuAOs mimicry for this reaction have been
developed by the group of Largeron (Scheme 1, A), all
following a ionic transamination mechanism.12 In an elegant
Scheme 1. Exemplary metal-free systems for the oxidative
coupling of amines
approach, Carbery and co-workers developed
a Flavin-
organocatalyst cooperative system to mimic the activity of
Monoamine Oxidase B, although it is only active for the
homocoupling of benzylic amines (Scheme 1, A).13 A radical-
based approach was described by Yan and co-workers, using
azobisisobutyronitrile14 as well as Ogawa et al. using of salicylic
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corresponding 15-π-electron radical cationic state (2). This was
achieved by reaction with NOBF4 (Scheme 3). The formed NO
is bubbled off with argon, while BF4- remains in the solution as
Catalyst
R'
1
2
3
4
5
6
7
8
Ph
NH2
+
R' NH2
Ph
N
Air/O2
the counter ion to the obtained PRC (2).
A.
B.
Bioinspired organocatalysts
O
O
Cl-
OH
Once the DSPs were oxidized with NOBF4 the resulting
PhRC were characterized by electron paramagnetic resonance
spectroscopy (EPR). These measurements showed the coupling
of the unpaired electron to its molecular environment as the
hyperfine signal splitting presented exemplary in Figure 1. All
EPR spectra are presented in Figure S9. The measurements
were performed in toluene after 1 was oxidized at 300 K. All
EPR signals appear around g=2.00, which is typical for organic
radicals.28
OH
N
N
O
O
HN
NH
R
N
OH
(Stahl, 2012)
O
(Largeron, 2017)
(Carbery, 2015)
O
Radical initiators
9
OH
O
10
11
12
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N
CN
R
NC
N
(Ogawa, 2017)
(Yan, 2012)
C.
D.
(Heterogeneous) Carbocatalysts
Graphite Oxide (Fan, 2012)
Scheme 3. Oxidation of the DSP (1) with BF4NO to produce
the catalytically active PhRC (2).
Porous Graphene Oxide (Chabal, 2012)
Pyrolized MOFs (Li, 2016)
Pyrolized POSS (Wang, Mejía, 2017)
R
N
R
N
Previous work: pyrazine radical cations
BF4NO
-NO
BF4
R
R
N
N
[Ox.]
N
R
1
N
R
2
N
N
R
R
E.
This work: phenazine radical cations
R
In the case of 2a no hyperfine coupling was observed (Figure
S8), indicating a complete delocalization of the radical in the 7
π-electron system without visible coupling to a particular
element or region of the catalyst. Compare to phenazine radical
2a, the spectrum of the dimethyl substituted phenazine (2b,
Figure 1) shows a distinct hyperfine splitting (hfs) to the two
nitrogen as well as six hydrogen nuclei of the methyl groups.
R
N
N
[Ox.]
N
R
N
R
RESULTS AND DISCUSSION
Catalyst synthesis and characterization. A series of DSPs
(1) bearing different functionalities were prepared in two-steps
If an aromatic ring is added e.g. 2c-f (Figure 1) only the
hyperfine splitting to the two nitrogen ring of the pyrazine ring
were examined. The equality of the hfs indicates that the
substiution on the para position of the phenyl ring with electron
donating or electron withdrawing groups plays no major role in
25a, 27
(Scheme 2).
First, phenazine was reduced with sodium
dithionite to 5,10-dihydrophenazine (1a), which was then
functionalized through a Buchwald-Hartwig coupling reaction
to obtain the products (1b-f) in high yields. (see supporting
information for full experimental details). 1c, 1d, and 1e were
characterized by single crystal X-Ray diffraction (see figures S3,
S4 and S5 and Table S1).
the radical delocalization. In order to gain
a deeper
understanding of the nature of radical in 2, DFT calculations
were performed.
Scheme2. Synthesis of DSP precatalyst (1a-f)
H
N
N
N
NaS2O4
EtOH
N
H
1a
R
yield (%)
90
X-R
[Pd], L
a
b
H
CH3
purchased
c
d
e
f
25
45
73
82
R
N
N
R
CF3
Figure 1. EPR spectra of the PRC compounds 2b and 2f after
the oxidation with NOBF4 in toluene at 300 K and ambient
pressure. Simulation using EPRSim3229 of 2f with g=2.0043,
2xAN=6.5 G, ΔB=4 G; Simulation of 2b with g=2.0042,
2xAN=6.5 G, 6xAH=6.3 G, ΔB=6 G
O
1b-f
The DSPs (1) obtained by functionalization of 16-π-electron
phenazine contain an antiaromatic 8-π-electron core. In order
to obtain an active catalyst, 1 needs to be oxidized to its
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Using B3PW9130 density functional level of theory with the
reaction rate is limited by diffusion of the oxygen in to the
reaction mixture, being the concentration of O2 several orders
of magnitudes lower than the amine substrate.32
all-electron TZVP basis set31 (using the Gaussian 16 program
package), the neutral DSPs (1a, 1b, and 1f)as well as their
corresponding radical states, PhRCs (2a, 2b and 2f) were
computed and optimized. Their geometry, ionization potential
as well as spin density of the highest occupied molecular orbitals
(HOMO) were analyzed (see Figures S6, S6 and S8, Tables S2
and S3). Exemplarily, the optimized structure of PhRC 2b is
shown in Figure 2. From the calculations, various interesting
features were observed: 1) Upon formation of the radical, the
resulting 7 π-electron antiaromatic ring system does not
become planar (as it does not follow the Hückel’s rule), 2) the
torsion angle between the planes containing the aryl rings is
much smaller in the radical than the neutral state, indicating a
better overlapping of the orbitals, 3) the spin density is always
distributed via a delocalization over the phenanzine ring and
4)an increase of the electron density in the substituents results
in a decrease of the ionization energy, fostering the stability of
the radicals.
1
2
3
4
5
6
7
8
With the optimized reaction conditions at hand, the effect of
the phenazine substitution on the catalytic performance was
investigated. The PhRCs, which were synthesized before, were
tested as catalysts (2 a-f). As shown in the Table 1, all the
phenazines were catalytically active, although with marked
differences in their activities.
9
Me
N
10
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N
Me
Ph
NH2
2b
(1 mol%)
Ph
N
Ph
100 °C, neat
O2 (1 bar)
3a
4a
100
80
60
40
20
0
4a
3a
A
0
5
10
Time [h]
15
B
Figure 3: Concentration profiles of the oxidative coupling of
benzylamine (3a) catalyzed by a PhRC. Reaction conditions:
neat, 1mol% of 2b, 100°C, O2 (1 bar).
Table 1. Effect of the functionalization of PhRCs on its catalytic
performance.
O
Catalyst
Ph
NH2
3a
Ph
N
Ph Ph
N
H
Ph
(1 mol%)
Figure 2: Optimized structure (A) as well as the highest
occupied molecular orbital (B) of 5,10-dimethyl-5,10-
dihydrophenazine radical 2b.
+
100 °C, 16 h
neat, O2 (1 bar)
4a
5a
Entry
Catalyst
Conversion
(mol%)a
Selectivity
(mol%)b
Catalytic studies. In order to explore the activity of the
PhRC (2) as a catalyst in the oxidative coupling of amines,
several different reaction conditions were screened using benzyl
amine (3a). Interestingly, the temperature screening showed
that at temperatures below 70 °C, the conversion of the imine
dimer is negligible, while when the temperature was increased
to 100 °C, the reaction efficiency rose to almost quantitative
conversion (Figure S2, A). Even with low catalyst loading of 0.5
mol% conversion of 85 %were achieved. (Figure S2, B). If air
(instead of pure oxygen as terminal oxidant) was applied still 56
% conversion were achieved after 16 hours (with 1 mol% 2b). If
the reaction is carried out in the absence of a oxidant, no imine
product is detected.
1
2
32
99
99
84
71
56
55
54
b
96
81
97
81
90
96
98
83
2a
2b
2c
2d
2e
2f
3
4
5
6
7
8c
1b
a
Conversions were determined by GC Calculated by GC as
4a/(4a+5a)*100. c non-radical phenazine (1b) was used as a catalyst.
In order to investigate the reaction kinetics, a continuous
sampling method by GC was chosen. The results show a zero-
order kinetic dependence on the amine substrate (Figure 3).
Considering our reaction setup, it can be expected that the
The highest catalytic activity was observed for dihydro (2a)
and dimethyl (2b) functional phenazines, with conversions
reaching up to 99% (Table 1, entries 2 and 3). Although the
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phenazines functionalized with more sterically demanding
NH2
NH2
NH2
2
3
97
48
98
1
2
3
4
5
6
7
8
aromatic substituents are catalytically active, these displayed
only good to moderate conversions (2c-f, Table 1, entries 4 to
7). The ionization energy of 2c-f is lower than 2b and the
highest is found for 2a which results in an increased stability of
the radical for the diaryl substituted PhRC. This can be
correlated with the reactivity; lower radical stability is causing
higher catalytic activity. Substitution on the para position of the
functional phenyl ring by electron withdrawing (2e) or electron
donating groups (2d and 2f) seems to play only a minor role.
These observations indicate that steric hindrance; hence the
accessibility of the radical as well as the stability of the radical
determines the catalysts performance.
>99
4c
>99
99
NH2
5
6
7
99
98
97
99
99
95
9
O
10
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NH2
NH2
Cl
Interestingly, the formation of the amide side product (5a)
could be observed; it results either from the oxidation of the
benzylimine product (7),33 or as Zhang et al. showed, as the
result of oxidation of hemiaminal (see mechanistic proposal
below).34 In terms of both, activity and selectivity catalyst 2b
shows the best performance. Even in the case of the parent
phenazine (1b) conversion of 54% was achieved. (Table 1,
entry 8), pointing out the necessity of the pre-activation process
with BF4NO (Scheme 3).
F
NH2
8
9
99
99
99
99
N
S
NH2
a
b
Conversions were determined by GC. Calculated by GC as
4/(4+5)*100. c The reaction time was extended to 24 h.
To determine the versatility as tolerance towards functional
groups, the scope of reaction was investigated. Having identified
2b as the best catalyst, a series of different amines bearing
different functionalities were oxidized (Table 2). The reaction
of benzylamines with either electron donating (Table 2, entries
2-5) or electron withdrawing groups (Table 2, entries 6-9)
afforded almost quantitative conversions and excellent
selectivity in most cases. This indicates that the electronics of
the benzyl ring does not have a major impact on reaction
performance. This was verified by the kinetic investigation,
where the concentration of the para-substituted benzylamines
(-OCH3, -CH3, -H, -Cl, -F) was followed over time (Figures
S10-S14). All kinetic constants fall between 0.66-0.75 mol·L-1s-1,
indicating that the reaction rate is nearly independent of the
electronic nature of the substituent. This further confirms the
assumption that the reaction rate might not be limited by the
oxidation of the amine catalyzed by the phenazine radical
cation, but by the diffusion of the oxygen in to the reaction
mixture. Nevertheless, the amine oxidation is sensitive to
sterically demanding substrates, as in the case of (2,6-
dimethylphenyl)methanamine (Table 2, entries 3 and 4), for
which the reaction time was extended to 24 hours in order to
obtain nearly quantitative conversions.
Excellent conversions and selectivity achieved by
homocoupling of benzylamines, suggested that cross-coupling
of different amines might be possible. The combination of
benzyl amine with less readily oxidizable amines, showed
moderate selectivity towards the cross-coupling product (for
cyclohexylamine, 51%; Table 3, entry 1). The low reaction rate
might be to blame for the poor reaction selectivity. Therefore,
the oxygen pressure was increased ten-fold in order to increase
the reaction rate and so shift the reaction selectivity towards
desired product. By doing so, the reaction selectivity increased
up to 90 % of the desired cross-coupling product with
quantitative conversion (Table 3, entry 2). In all cases, the
prevailing side-product is the benzylamine homo coupling
product which is clearly caused by the high nucleophilicity of
benzylamine. Lower conversions were observed upon
increasing of the bulkiness on the substrates, obtaining for
adamantylamine and 1-naphylamine 65% and 51%, respectively
(Table 3, entries 3 and 7). Long chain aliphatic amines, namely
hexylamine and decylamine (Entry 4 and 5) gave both good
selectivity, although the conversions were rather low, perhaps
due to their low miscibility with benzylamine.
Table 3. Substrate screening for the oxidative cross-coupling of
amines catalyzed by 2b
Table 2. Substrate screening for the oxidative homo-coupling of
amines catalyzed by 2b.
2b
(1 mol%)
R'
Ph
NH2
+
R' NH2
Ph
N
100 °C, 16 h
neat, O2 (10 bar)
7
3a
(1 equiv)
6
O
(1 equiv)
2b
(1 mol%)
R
NH2
R
N
R
R
N
H
R
+
100 °C, 16 h
Substrate
(6)
Conv.
(mol%)a
Selectivity
(mol%)b
Entry
1c
Product (7)
neat, O2 (1 bar)
3
4
5
Conversion
(mol%)a
Selectivity
(mol%)b
NH2
Entry
1
Substrate (3)
76
51
N
NH2
99
98
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To further confirm the nature of the phenazine redox ability
NH2
1
2
3
4
5
6
7
8
2
3
99
65
90
to transfer the charge from pyrazine core to benzylamine, the
process was followed by UV-VIS spectroscopy, similarly as
presented above (Figure 5). 1a shows a strong absorption peak
in the rage from 250-400 nm, primary due to π-π* transitions of
the phenyl rings around pyrazine core.38 After the addition of
NOBF4 as oxidizing agent, the main adsorption band broadens
to range from 250-480 nm, while a new bands appears in the
range from 500-750 nm (strong change of color from colorless
to green). The appearance of a new band in the visible region
can be attributed to the formation of the phenazine radical
cation (2a) and its 7π-electron delocalized pyrazine core.
N
54
N
NH2
N(CH2)5CH3
N(CH2)9CH3
4
5
71
50
82
64
CH3(CH2)5NH2
CH3(CH2)9NH2
NH2
9
10
11
12
13
14
15
16
17
6
76
51
78
73
N
NH2
7
N
a
b
Conversions were determined by GC Calculated by GC as
7/(total products)*100. c 1 bar O2.
18
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Mechanistic Investigations. In order to explore the origin of
the catalytic activity of PhRCs, we investigated the amine
oxidative coupling reaction (Scheme 4) using UV-VIS and
fluorescence spectroscopy, and EPR.
The highly electron rich phenazine derivatives with their π-
conjugated pyrazine core are known to have distinctive optical
properties: many phenazine derivatives are used as fluorescent
tracers or dyes in medicinal35 and electronic applications36. A
strong fluorescence was detected in the case of diphenyl
substituted phenazine (1c). The emission spectrum of 1c in
acetonitrile showed a strong band in the range of 450-600 nm,
which disappeared almost completely upon oxidation with
NOBF4 (Figure 4). This fluorescence quenching was reported
before by Soko1owska et al. 37
Figure 4. Fluorescence spectrum of the phenazine 1c, 2c and
2c after the addition of benzylamine measured in acetonitrile at
standard conditions.
However, after the addition of one equivalent of benzylamine
to the mixture resulted in reappearance of the fluorescence
band in exactly the same position as before the oxidation. The
recovery of the fluorescence indicates that a single electron
transfer process from 2c to benzylamine takes place which
results in a partial recovery of the non-radical phenazine 1c.
Afterwards, 1c can be reoxidized (by oxygen) closing the
catalytic cycle.
Scheme 4: General scheme of phenazine (1) oxidation with
NOBF4 to its radical cation form (2) and subsequent single
electron reduction with benzylamine (3).
R
N
R
N
BF4
BF4NO
-NO
Figure 5. UV-VIS spectrum of the phenazine 1a, 2a and 2a
after the addition of benzylamine 3a measured in acetonitrile.
N
R
N
R
Interestingly, the addition of one equivalent of benzylamine is
again able to completely reverse the process back to the initial
state, which is shown by complete disappearance of absorption
bands of 2a. This result confirms that a fast recovery of the
initial catalyst state takes place, probably via single electron
transfer (SET), accompanied by the formation of the charged
bezylamine species (see proposed mechanism in Scheme 5).
1
2
SET
NH2
NH2
-
BF4
3a
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The formed hydrogen peroxide is also known
10, 15, 18, 39
In order to understand the nature of the open-shell species
others.
1
2
3
4
5
6
7
8
formed upon SET, EPR experiments were performed (Figure
6). As described above, PhRCs give two different hyperfine
splitting patterns, which depend on the substitution at the 5-
and 10- position. By the addition of benzylamine (3a) to the
PhRC (exemplary 2b and 2f) during the EPR measurement, the
hyperfine splitting lost its intensity, while at the same time the
number of lines increased to 13 or more. The complex hfs
pattern could not be simulated, however the pattern of hfs was
the same, regardless of the phenazine substitution. Thus, it is
reasonable to assume, that the same benzylamine radical species
is formed. Fukuzumi et al. showed that the radical formed is of
benzyl type (PhCH•NH2) instead of nitrogen-centered
(PhCH2NH•).39 They also proved that the benzylamine radical
may be detected by EPR spectroscopy, although it slowly decays
due to its instability. Therefore it can be assumed, that the
obtained hyperfine splitting belongs to benzyl type radical. The
hyperfine splitting presented in Figure 6 after the addition of
benzylamine shows several shoulders, which indicates that more
than one species is present in the solution. One of this species is
most probably the phenazine radical cation, which was not
completely reduced to its closed-shell form 1b or 1c.
Unfortunately, attempts to simulate these spectra were
unsuccessful; hence, the composition of this radical mixture
remains unclear.
to promote the imine formation to form amine derivatives.40
The imine intermediate 4, which was detected by GC/MS
analysis,11b can then undertake two transformation pathways.
The primary pathway involves the condensation with amine 6
to form the main product 7 and ammonia. The secondary
reaction is the hydrolysis of 4 to form benzaldehyde.41 The
coupling of benzaldehyde and another equivalent of 6 results in
the formation of hemiaminal (8), which can be either
dehydrated to yield the imine (7) or oxidized to form the amide
side product (5).34 The latter (5) is usually detected in only 1-5
mol% of the overall product.
9
10
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60
Scheme 5: Proposed reaction mechanism for phenazine
catalyzed coupling of benzylamines to imine dimers in the
presence of atmospheric oxygen.
R
O2
N
Ar
NH2
3
N
R
2
1) SET
2) Proton
abstraction
SET
O2
R
N
Ar
NH2
HOO
N
R
1
H2O2
R' NH2
H2O
6
OH
O
Ar
NH
R'
Ar
N
Ar
4
H
NH3
H2O
8
R' NH2
6
O2
NH3
H2O
O
O2
Figure 6. EPR spectra of 2f and 2b before (orange and red) and
after (black) the addition of benzylamine in toluene at 300 K.
R'
R'
Ar
N
Ar
N
Proton
transfer
H
7
5
Based on the presented fluorescence, UV-VIS and EPR
measurements of phenazine catalyzed amine oxidation and
several control experiments, a general reaction pathway is
proposed (Scheme 5). In the initial stage of the catalytic cycle,
the phenazine 1 is oxidized, by molecular oxygen dissolved on
the reaction mixture, producing the corresponding PhRC 2 and
a superoxide anion (O2•-). The concentration of oxygen in the
reaction mixture is low due to the high temperature (100 °C)
and low pressure (1 atm), therefore the re-oxidation is slow, as
indicated by the kinetic investigation. Hence, the use of pre-
oxidized phenazine (by NOBF4) results in the improvement of
reaction performance (Table 2 Entry 3 compared to Entry 8).
In the second step of the catalytic cycle, a single electron
transfer with the amine substrate 3 takes place, regenerating the
non-radical phenazine 1. The overall process is assisted by the
superoxide anion which enables the proton abstraction from 3
to produce H2O2 and benzylimine (4) as proposed by Loh and
CONCLUSION
In summary, we presented for the first time the use of
phenazine radical cations (PhRCs) as metal-free catalyst for the
aerobic oxidative homo and cross coupling of amines. The
results show, that the catalyst is not sensitive to the electronic
nature of the benzylamine substrate, therefore high reaction
conversions and selectivity could be obtained every case. In
addition to the formation of symmetric imines, we showed that
selective amine cross-coupling is also accessible. In that case it
was necessary to increase the pressure of oxygen to 10 bar.
Mechanistic investigations using spectroscopic techniques
revealed that initially a single electron transfer from the PhRC
to the amine substrate takes place, followed by the re-oxidation
of the phenazine by oxygen.
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The Journal of Organic Chemistry
The novel catalytic system presented in this work follows the
flaks. During one hour, 12,3 g (70.6 mmol)of sodium dithionite
dissolved in 100 ml water were added with a dropping funnel to
the phenanzine solution. Once the sodium dithionite was
completely added, the mixture was boiled for 2 h and stirred at
room temperature for further 15 h overnight. The resulting light
green precipitate was filtered off and washed three times with
200 ml of water. Afterwards, the light green solid was dried for
24 h under vacuum at room temperature. The title product was
obtained as a light green solid (Yield: 0,89 g, 5.3 mmol, 96 %).
1H NMR (300 MHz, DMSO-d6) δ 7.2 (s, 2H), 6.3 – 6.2 (m,
4H), 6.0 – 5.9 (m, 4H) 13C{1H} NMR (75 MHz, DMSO-d6) δ
134.2 , 120.7 , 111.8
1
2
3
4
trend of replacement of metal-based catalysts both in academia
and industry, as the need exists for the introduction of
environmentally
friendlier
catalysts
for
chemical
transformations. Since no solvents, harmful reagents or metals
are used for the oxidative coupling of amines, this process
employing PhRC as a catalyst, could potentially replace
commonly known metal-based processes in the future. Efforts
towards increasing the availability of oxygen in the reaction
mixture, and directed to a safer use of this (potentially
dangerous) gas, are currently subject of active research in our
labs.
5
6
7
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5,10-diphenyl-5,10-dihydrophenazine (1c): In a 250 ml
Schlenk flask, 1 g (5.4 mmol) of 5,10-dihydrophenazine (1a)
were mixed with 2,11 g (21.9 mmol) of NaOtBu, 103 mg (0.2
mmol) of RuPhos and 178 mg (0.2 mmol) of RuPhos
palladacycle precatalyst were dissolved in 8 ml of 1,4-Dioxane.
Upon complete dissolution, 4,5 g (22 mmol) of 4-Iodobenzene
were added. After stirring by 12 h at 110°C, the mixture was
cooled down to room temperature and 200 ml CH2Cl2 were
added to the mixture. The Mixture was washed three times with
200 ml H2O and dried over MgSO4. After filtration the mixture
was adsorbed on silica and purified by column flash
chromatography with a solvent mixture of n-hexane and ethyl
acetate (10:1). The title product was obtained as deep green
crystalline solid (Yield: 0,46 g, 1.3 mmol, 25 %). Single crystals
of X-ray quality were grown from a mixture of CH2Cl2 and n-
hexen (1:2) and after 4 days at room temperature. 1H NMR
(300 MHz, Benzene-d6) δ 7.0 (m, J = 4.2 Hz, 2H), 6.3 (m, J =
6.4 Hz, 4H), 5.9 – 5.7 (m, 4H) 13C{1H} NMR (75 MHz,
C6D6) δ 140.8, 137.2, 131.4, 128.4, 128.1, 127.7, 113.1, 30.2.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H18N2
334,1465; Found 334,1461.
EXPERIMENTAL PART
General Information
All reactions were performed under Schlenk, air/moisture-
free conditions. All solvents were dried, degassed and stored in
septum-sealed flasks over molecular sieves under Argon
atmosphere. Solvents for catalyst preparation were distilled over
Na, CaH2 or molecular sieves following standardized
procedures. All chemicals were purchased from commercial
sources (unless stated otherwise). Most of chemicals were used
without further purification. The purity of purchased products
was confirmed by either NMR spectroscopy or GC/MS
analysis. All NMR spectra were recorded in CDCl3 or Toluene-
D8 using Bruker Avance 300 spectrometer with QNP probe
head (1H: 300 MHz, 13C: 75 MHz) or Bruker Avance 400
spectrometer (1H: 400 MHz, 13C: 100 MHz). The calibration of
the spectra were carried out on referenced with residual solvent
shifts and were reported as parts per million (ppm) relative to
SiMe4. Multiplicities are abbreviated as follows: singlet (s),
doublet (d), triplet (t), quartet (q), doublet-doublet (dd),
doublet-triplet (dt), quintet (quint), sextet (sext), septet (sept),
multiplet (m), and broad (br). Samples were generally
measured at room temperature (297 K). Deuterated solvents
were degassed and distilled if necessary. ESI-TOF spectra were
obtained on Waters Q-TOF micro mass spectrometer. The
samples were dissolved in Methanol-Water (9:1) mixture with
5,10-di(4-toluoyl)-5,10-dihydrophenazine
(1d):
Following the same procedure as for 1c, using 0,5 g (2.7 mmol)
of 5,10-dihydrophenazine (1a), 1,08 g (11.2 mmol) of NaOtBu,
48 mg (0.1 mmol) of RuPhos and 93 mg (0.1 mmol) of RuPhos
palladacycle precatalyst and 2,4 g (11 mmol) of 4-Iodotoluene.
The title compound was obtained as a green crystalline solid
(Yield: 0,46 g, 1.3 mmol, 45 %). Single crystals of X-ray quality
were obtained as follows: to a supersaturated solution of
purified 1d in benzene, diethylether was added until the solid
was completely dissolved. The solvents were allowed to
evaporate through a thin cannula until crystals appeared. 1H-
NMR (300 MHz, Benzene-d6): δ 7.1 (m, 4H), 7.0 (m, 4H), 6.3
(m, 4H), 5.9 (m, 4H), 2.1 (s, 1H) 13C{1H} NMR (75 MHz,
Benzene-d6): δ 138.2 , 137.8 , 137.4 , 132.2 , 131.4 , 121.4 ,
113.1 , 21.1 HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C26H21N2 362,1778; Found 362,1778.
0.1
% HCOOH to achieve sufficient ionization. All
chromatograms were obtained on GC analysis was performed
on Hewlett-Packard 6890 Series. Samples were dissolved in
tetrahydrofuran (THF) and sampled in to the GC column.
GC/MS analysis was performed on Agilent 6890/5973 GC-MS
or on Agilent 7890/5977 GC-MS. Samples were dissolved in
tetrahydrofuran (THF).
The 5,10-dihydrophenazine (1a) was prepared following the
procedure reported by Zheng et al.27c The aromatic
functionalized phenazines (1c-f) were prepared via Buchwald-
Hartwig coupling following the procedure reported by Theriot
et al.25a The active radical cation catalysts (2) were obtained by
oxidation via addition of
nitrosonium tetrafluoroborate in acetonitrile at room
temperature.
5,10-di(4-trifluoromethylphenyl)-5,10-
dihydrophenazine (1e): Following the same procedure as for
1c, using 0,5 g (2.7 mmol) of 5,10-dihydrophenazine (1a), 1,14
g (11.9 mmol) of NaOtBu, 50 mg (0.1 mmol) of RuPhos and
87 mg (0.1 mmol) of RuPhos palladacycle precatalyst and 2,5 g
(11.1 mmol) of 4-bromobenzotrifluoride. The title compound
was obtained as a yellow-green crystalline solid (Yield: 0,95 g, 2
mmol, 73%).Single crystals of X-ray quality were obtained as
a stoichiometric amount of
Catalyst Preparation
5,10-dihydrophenazine (1a:) Phenazine (1g, 5.5 mmol)
was dissolved in 20 ml boiling ethanol in a 500 ml three neck-
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follows: to a supersaturated solution of purified 1e in benzene,
diethylether was added until the solid was completely dissolved.
The solvents were allowed to evaporate through a thin cannula
until crystals appeared. 1H-NMR: (300 MHz, Benzene-d6): δ
7.3 (q, J =7.1 Hz, 4H), 7.0 (s, 4H), 6.3 (s, 4H), 5.7 (s, 4H), 19F
NMR (282 MHz, Benzene-d6): δ -62.2
mixture from pentane and ethyl acetate (10:1). The desired
product was yellowish oil (519 mg; 2.3 mmol) 95 %. H NMR
(300 MHz, Chloroform-d) δ 8.5 (s, 1H), 7.8 (d, J = 8.1 Hz,
2H), 7.4 – 7.3 (m, 8H), 4.9 (s, 1H), 2.5 (s, 4H), 2.5 (s, 4H);
13C{1H} NMR (75 MHz, CDCl3) δ = 161.8, 141.1, 136.5,
133.8, 129.5, 128.4, 64.9, 21.7, 21.3.
1
1
2
3
4
5
6
7
8
5,10-di(4-methoxyphenyl)-5,10-dihydrophenazine (1f):
Following the same procedure as for 1c, using 0,5 g (2.7 mmol)
of 5,10-dihydrophenazine (1a), 0,92 g (8.2 mmol) of KOtBu,
24 mg (0.1 mmol) of Pd(OAc)2 and 17 mg (0.084 mmol) of
P(tBu)3 and 1,21 g (5.2 mmol) of 4-Iodoanisole Product was
purified by flash chromatography column with a solvent mixture
of n-hexan and Ethyl acetate (20:1). The title compound was
obtained as a yellow crystalline solid (Yield: 0,89 g, 2.5 mmol,
82 %).1H NMR (300 MHz, Chloroform-d): δ 7.9 – 7.7 (m,
3H), 7.4 – 7.3 (m, 4H), 7.1 – 7.0 (m, 4H), 6.2 – 6.1 (m, 4H),
3.3 (s, 6H) 13C{1H} NMR (75 MHz, Chloroform-d): δ 143.7,
138.3, 130.7, 129.8, 127.9, 116.5, 114.4, 55.5 HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C26H22N2O2 394,1676; Found
394,1675.
(E)-N-(2,6-dimethylbenzyl)-1-(2,6-
dimethylphenyl)methanimine (4c):22 Following the general
procedure, using 5,10-dimethyl-5,10-dihydrophenazine (10.5
mg, 0.005 mmol) and (2,6-dimethylphenyl)methanamine (700
mg, 5.1 mmol). The pure product was obtained by flash column
chromatography on silica gel using a mixture from pentane and
ethyl acetate (10:1). The desired product was yellowish oil (307
mg; 1.2 mmol) 48 %. 1H NMR (300 MHz, Chloroform-d) δ 8.4
(d, J = 1.8 Hz, 0H), 7.1 – 6.9 (m, 1H), 4.8 (d, J = 1.8 Hz, 0H),
2.3 (s, 1H), 2.3 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ =
160.9, 137.5, 137.1, 134.8, 134.5, 128.7, 128.4, 128.3, 127.4,
58.9, 20.5, 19.9.
9
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-N-(4-methoxybenzyl)-1-(4-
methoxyphenyl)methanimine (4d):44Following the general
procedure, using 5,10-dimethyl-5,10-dihydrophenazine (10.5
mg, 0.005 mmol) and (4-methoxyphenyl)methanamine (700
mg, 5.1 mmol). The pure product was obtained by flash column
chromatography on silica gel using a mixture from pentane and
ethyl acetate (10:1). The desired product was yellowish oil (638
mg; 2.5 mmol) 98 %. 1H NMR (300 MHz, Chloroform-d) δ 8.3
(s,1H), 7.7 (d, 2H, J = 8.3 Hz), 7.2 (d, 2H, J = 8.2 Hz), 6.8-7.1
(m, 4H), 4.7 (s, 2H) 3.8 (s, 3H), 3.8 (s, 2H); 13C{1H} NMR
(75 MHz, CDCl3) δ 161.9, 161.1, 158.4, 131.1 129.3, 129.1,
114.1, 113.9, 64.3, 55.1, 54. 1
Oxidative coupling of amines
General procedure: In a Schlenk tube, 5 mmol of substrate
were added to 0,05 mmol of catalyst (1 mol%) with a syringe.
The solution was flushed tree times with oxygen. A balloon with
oxygen was attached to the Schlenk valve. The reaction mixture
was stirred for 15 h at 100°C in an oil bath. The experiments at a
10 bar of O2 were carried out in a 12ml glass vial placed inside a
Parr stainless steel autoclave. This autoclave was flushed tree
times with oxygen with at a pressure of 10 bar. The reaction
mixture was stirred for 15 h at 100°C in an oil bath. An
optimization of the reaction parameter (temperature and
catalyst concentration) was carried out and the optimal values
(Figure S1) were used in all the experiments, unless otherwise
noted.
(E)-N-(4-chlorobenzyl)-1-(4-
chlorophenyl)methanimine (4e):44 Following the general
procedure, using 5,10-dimethyl-5,10-dihydrophenazine (10.5
mg, 0.005 mmol) and (4-chlorophenyl)methanamine (700 mg,
4.9 mmol). The pure product was obtained by flash column
chromatography on silica gel using a mixture from pentane and
ethyl acetate (10:1). The desired product was yellowish oil (625
mg; 2:4 mmol) 97 %. 1H NMR (300 MHz, Chloroform-d) δ 8.1
(s, 1H), 7.5 (d, J = 8.5 Hz, 3H), 7.2 (d, J = 8.5 Hz, 3H), 7.1 (q, J
= 8.6 Hz, 6H), 4.6 (s, 0H); 13C{1H} NMR (75 MHz, CDCl3) δ
= 160.9, 137.7, 136.9, 134.5, 132.8, 129.6, 129.4, 129.0, 128.7,
64.1.
Gas chromatography: GC analysis was performed on
Hewlett-Packard 6890 Series. Samples were dissolved in
tetrahydrofuran (THF) and sampled in to the GC column. The
chromatogram peak area ratios of the product and internal
standard anisole (Ap/As) were used for calibration. The GC-
yields are calculated with the calibration curve with anisole as an
internal standard.
(E)-N-benzyl-1-phenylmethanimine (4a):42 Following the
general procedure, using 5,10-dimethyl-5,10-dihydrophenazine
(10.5 mg, 0.005 mmol) and phenylmethanamine (500 mg, 4.7
mmol). The pure product was obtained by flash column
chromatography on silica gel using a mixture from pentane and
ethyl acetate (10:1). The desired product was yellowish oil (444
mg; 2.2 mmol) 97 %. 1H NMR (300 MHz, Chloroform-d) δ 8.3
(s, 1H), 7.8 – 7.6 (m, 4H), 7.4 – 7.0 (m, 16H), 4.7 (d, J = 1.5
Hz, 4H).; 13C{1H} NMR (75 MHz, CDCl3) δ = 162.2, 139.5,
136.3, 131.0, 128.8, 128.7, 128.5, 128.2, 127.2, 65.2.
(E)-N-(4-fluorobenzyl)-1-(4-fluorophenyl)methanimine
(4f):44 Following the general procedure, using 5,10-dimethyl-
5,10-dihydrophenazine (10.5 mg, 0.005 mmol) and (4-
fluorophenyl)methanamine (600 mg, 4.7 mmol). The pure
product was obtained by flash column chromatography on silica
gel using a mixture from pentane and ethyl acetate (10:1). The
desired product was yellowish oil (500 mg; 2.1 mmol) 92 %. 1H
NMR (300 MHz, Chloroform-d) δ 8.4 (s, 1H), 7.8 (m, 2H), 7.3
(m, 2H), 7.1 (d, 2H), 4.8 (s, 1H); 13C{1H} NMR (75 MHz,
CDCl3) δ = 160.6, 130.3, 130.2, 129.6, 129.5, 115.9, 115.6, 115.
5, 115.2, 64.1.
(E)-N-(4-methylbenzyl)-1-(p-tolyl)methanimine (4b):43
Following the general procedure, using 5,10-dimethyl-5,10-
dihydrophenazine (10.5 mg, 0.005 mmol) and p-
tolylmethanamine (600 mg, 4.9 mmol). The pure product was
obtained by flash column chromatography on silica gel using a
(E)-1-(pyridin-3-yl)-N-(pyridin-3-
ylmethyl)methanimine (4g):22 Following the general
procedure, using 5,10-dimethyl-5,10-dihydrophenazine (10.5
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The Journal of Organic Chemistry
mg, 0.005 mmol) and pyridin-3-ylmethanamine (550 mg, 5 product was obtained by flash column chromatography on silica
1
2
3
4
5
6
7
8
mmol). The pure product was obtained by flash column
chromatography on silica gel using a mixture from pentane and
ethyl acetate (10:1). The desired product was yellowish oil (483
mg; 2.5 mmol) 98 %. 1H NMR (300 MHz, Chloroform-d) δ 8.8
(s, 1H), 8.5 – 8.4 (m, 1H), 8.4 (m, 1H), 8.3 (s, 0H), 8.0 (dt, J =
7.9, 2.0 Hz, 1H), 7.5 (dt, J = 7.8, 1.9 Hz, 0H), 7.2 (m, 1H), 4.7
(s, 1H), 13C{1H} NMR (75 MHz, CDCl3) δ = 159.7, 151.5,
150.0, 149.0, 148.3, 135.5, 134.6, 134.4, 131.2, 123.6, 123.4,
62.2.
gel using a mixture from pentane and ethyl acetate (10:1). The
desired product was yellowish oil (613 mg; 2.5 mmol) 50%.
The GC/MS (electronic ionization) spectra match with the
desired product (see Supporting Information).
(E)-N,1-diphenylmethanimine (7e):47-48 Following the
general procedure, using 5,10-dimethyl-5,10-dihydrophenazine
(5,25 mg, 0.0025 mmol), phenylmethanamine (270 mg, 2.5
mmol) and aniline (230 mg, 2.5 mmol). The pure product was
obtained by flash column chromatography on silica gel using a
mixture from pentane and ethyl acetate (10:1). The desired
product was yellowish oil (688 mg; 3.8 mmol) 76 %. The
obtained spectra match those previously reported1H NMR
(300 MHz, Chloroform-d) δ 8.47 (s, 1H), 8.0 – 7.9 (m, 2H),
7.51 – 7.47 (m, 3H), 7.4 – 7.4 (m, 2H), 7.3 – 7.2 (m, 4H).
13C{1H} NMR (75 MHz, CDCl3) δ 160.6, 152.2, 136.35,
131.5, 129.3, 129.0, 128.9, 126.1, 123.0, 121.0.
9
10
11
12
13
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15
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17
18
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20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-1-(thiophen-2-yl)-N-(thiophen-2-
ylmethyl)methanimine (4h):44 Following the general
procedure, using 5,10-dimethyl-5,10-dihydrophenazine (10.5
mg, 0.005 mmol) and thiophen-2-ylmethanamine (600 mg, 5.3
mmol). The pure product was obtained by flash column
chromatography on silica gel using a mixture from pentane and
ethyl acetate (10:1). The desired product was yellowish oil (538
mg; 2.6 mmol) 98 %. 1H NMR (300 MHz, Chloroform-d) δ 8.2
(d, J = 1.2 Hz, 1H), 7.2 (m, 1H), 7.1 (dd, J = 3.7, 1.2 Hz, 1H),
7.0 (m, 1H), 7.0 (m, 1H), 6.9 (m, 1H), 6.8 (m, 1H), 4.7 (s,
1H); 13C{1H} NMR (75 MHz, CDCl3) δ = 155.2, 151.0, 147.6,
141.8, 141.4, 148.3, 135.0, 131.0, 127.2, 126.5, 126.4, 124.6,
123.4, 58.3.
(E)-N-(naphthalen-1-yl)-1-phenylmethanimine (7f):47, 49
Following the general procedure, using 5,10-dimethyl-5,10-
dihydrophenazine
(5,25
mg,
0.0025
mmol),
phenylmethanamine (270 mg, 2.5 mmol) and naphthalen-1-
amine (360 mg, 2.5 mmol). The pure product was obtained by
flash column chromatography on silica gel using a mixture from
pentane and ethyl acetate (10:1). The desired product was
yellowish oil (577 mg; 2.5 mmol) 51 %.Obtained spectra match
(E)-N-cyclohexyl-1-phenylmethanimine
Following the general procedure, using 5,10-dimethyl-5,10-
dihydrophenazine (5,25 mg, 0.0025 mmol),
(7a):45
1
those previously reported H NMR (300 MHz, Chloroform-d)
phenylmethanamine (270 mg, 2.5 mmol) and cyclohexanamine
(240 mg, 2.5 mmol). The pure product was obtained by flash
column chromatography on silica gel using a mixture from
pentane and ethyl acetate (10:1). The desired product was
yellowish oil (926 mg; 49 mmol) 99 %. The GC/MS (electronic
ionization) spectra match with the desired product (see
Supporting Information).
δ 8.8 (s, 1H), 8.7 – 8.6 (m, 1H), 8.31 – 8.24 (m, 2H), 8.14 –
8.09 (m, 1H), 7.98 (dtd, J = 8.3, 1.0, 0.4 Hz, 1H), 7.80 – 7.7 (m,
6H), 7.31 (dd, J = 7.3, 1.1 Hz, 1H). 13C{1H} NMR (75 MHz,
CDCl3) δ 160.4, 149.4, 136.5, 134.0, 131.5, 129.1, 128.9, 127.7,
126.5, 126.2, 125.9, 125.8, 124.1, 112.8.
ASSOCIATED CONTENT
Supporting Information. Complete description of the experimental
procedures of catalysts preparation and catalysis. Characterization data
of the catalysts and reaction products including: 1H and 13C NMR
spectra, and GC-MS analysis, single crystal X-ray diffraction,
computational (DFT) details. Mechanistic investigations including:
descriptions of the kinetic experiments, UV-Vis and fluorescence
spectra and EPR measurements.
(E)-N-(-adamantan-1-yl)-1-phenylmethanimine (7b):46
Following the general procedure, using 5,10-dimethyl-5,10-
dihydrophenazine
(5,25
mg,
0.0025
mmol),
phenylmethanamine (270 mg, 2.5 mmol) and adamantan-1-
amine (380 mg, 2.5 mmol). The pure product was obtained by
flash column chromatography on silica gel using a mixture from
pentane and ethyl acetate (10:1). The desired product was
yellowish oil (29 mg; 3,3 mmol) 65 %. The GC/MS (electronic
ionization) spectra match with the desired product (see
Supporting Information).
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
(E)-N-hexyl-1-phenylmethanimine (7c):45 Following the
general procedure, using 5,10-dimethyl-5,10-dihydrophenazine
(5,25 mg, 0.0025 mmol), hexan-1-amine (250 mg, 2.5 mmol)
and cyclohexanamine (240 mg, 2.5 mmol). The pure product
was obtained by flash column chromatography on silica gel
using a mixture from pentane and ethyl acetate (10:1). The
desired product was yellowish oil (671 mg; 3.5 mmol) 71 %.
The GC/MS (electronic ionization) spectra match with the
desired product (see Supporting Information).
(E)-N-decyl-1-phenylmethanimine (7d):47 Following the
general procedure, using 5,10-dimethyl-5,10-dihydrophenazine
(5,25 mg, 0.0025 mmol), phenylmethanamine (270 mg, 2.5
mmol) and decan-1-amine (390 mg, 2.5 mmol). The pure
Corresponding Author
* Esteban.Mejia@Catalysis.de (E.M.)
Present Addresses
§ National Institute of Chemistry, Hajdrijova 19, 1001 Ljubljana,
Slovenia.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We would like to thank Dr. Anke Spannenberg for the X-Ray
diffraction measurements. The financial support from Henkel AG
(R.B.) is gratefully acknowledged.
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14.
Liu, L.; Wang, Z.; Fu, X.; Yan, C.-H., Azobisisobutyronitrile
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