Chan-Evans-Lam C?N Coupling Promoted by a Dinuclear Positively Charged Cu(II) Complex. Catalytic Performance and Some Evidence for the Mechanism of CEL Reaction Obviating Cu(III)/Cu(I) Catalytic Cycle

Article abstract of DOI:10.1002/cctc.202000212

In the present study, we report the synthesis of a series of copper(II) complexes with a wide range of ligands and their testing in the copper catalyzed Chan-Evans-Lam (CEL) coupling of aniline and phenylboronic acid. The efficiency of the coupling was directly connected with the ease of the reduction of Cu(II) to Cu(I) of the complexes. The most efficient catalyst was derived from 4-t-butyl-2,5-bis[(quinolinylimino)methyl]phenolate and two Cu(II) ions. Depending on the counter-anion nature and the concentration of the reaction mixture, the reaction can be directed to predominant C?N-bond formation. Forty-three derivatives of diphenylamine were prepared under the optimized conditions. The proposed mechanism of the catalysis was based on the reduction potential of a series of complexes, molecular weight measurements of the catalytic complex in MeOH and the kinetic studies of aniline and phenylboronic acid coupling. In addition, an ¹H NMR experiment in a sealed NMR tube, without external oxygen supply available, proved that no complete Cu(II) to Cu(I) conversion was observed under the condition, ruling out the usually accepted mechanism of the C?N coupling, which included the oxygenation of the intermediately formed Cu(I) complexes after the key step of C?N conversion had already been completed. Instead, a mechanism was proposed, involving an oxygen molecule coordinated to two copper ions in the key C?N bond formation without any detectable conversion of the Cu(II) complexes to Cu(I).

Full text of DOI:10.1002/cctc.202000212

Accepted Article
Title: Chan-Evans-Lam C-N Coupling Promoted by a Dinuclear Cu(II)
Complex. Catalytic Performance and Some Evidence for the
Mechanism of CEL Reaction Obviating Cu(III)/Cu(I) Cycle.
Authors: Yuri Belokon, Nikolay V. Akatyev, Mikhail M. Il’in, Mikhail
M. Il’in, Svetlana M. Peregudova, Alexander S. Peregudov,
Anastasiya G. Buyanovskaya, Kirill R. Kudryavtsev,
Alexander S. Dubovik, Valerij Y. Grinberg, Victor N. Orlov,
Alexander A. Pavlov, Valentin V. Novikov, and Ilya O. Volkov
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.202000212
Link to VoR: http://dx.doi.org/10.1002/cctc.202000212
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10.1002/cctc.202000212
ChemCatChem
Chan-Evans-Lam C-N Coupling Promoted by a Dinuclear
Positively Charged Cu(II) Complex. Catalytic Performance and
Some Evidence for the Mechanism of CEL Reaction Obviating
Cu(III)/Cu(I) Catalytic Cycle.
Nikolay Akatyev[a], Mikhail Il’in[a], Mikhail Il’in(Jr.)[a], Svetlana Peregudova[a], Alexander Peregudov[a],
Anastasiya Buyanovskaya[a], Kirill Kudryavtsev[b], Alexander Dubovik[a,c], Valerij Grinberg[a], Victor
Orlov[d], Alexander Pavlov[a], Valentin Novikov[a] , Ilya Volkov[a] and Yuri Belokon’[a]*
_______________________________________________________________________________
[a]
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov St. 28, 119991 Moscow, Russian Federation,
yubel@ineos.ac.ru
[b]
D. I. Mendeleyev University of Chemical Technology of Russia, Miusskaya sq. 19, 125047 Moscow, Russian Federation
N.M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Kosygin St. 4, 119334 Moscow, Russian Federation
M.V. Lomonosov Moscow State University, A.N. Belozersky Institute of Physico-Chemical Biology, Leninskie Gory, 1/40, 119991 Moscow, Russian
[c]
[d]
Federation
Abstract: In the present study, we report the synthesis of a series
of copper(II) complexes with a wide range of ligands and their
testing in the copper catalysed Chan-Evans-Lam (CEL) coupling of
aniline and phenylboronic acid. The efficiency of the coupling was
directly connected with the ease of the reduction of Cu(II) to Cu(I) of
the complexes. The most efficient catalyst was derived from 4-t-
butyl-2,5-bis[(quinolinylimino)methyl]phenolate and two Cu(II) ions.
Depending on the counter-anion nature and the concentration of the
reaction mixture, the reaction can be directed to predominant C-N-
bond formation. Forty-three derivatives of diphenylamine were
prepared under the optimized conditions. The proposed mechanism
of the catalysis was based on the reduction potential of a series of
complexes, molecular weight measurements of the catalytic
complex in MeOH and the kinetic studies of aniline and
phenylboronic acid coupling. In addition, an 1H NMR experiment in a
sealed NMR tube, without external oxygen supply available, proved
that no complete Cu(II) to Cu(I) conversion was observed under the
condition, ruling out the usually accepted mechanism of the C-N
coupling, which included the oxygenation of the intermediately
formed Cu(I) complexes after the key step of C-N conversion had
already been completed. Instead, a mechanism was proposed,
involving an oxygen molecule coordinated to two copper ions in the
key C-N bond formation without any detectable conversion of the
Cu(II) complexes to Cu(I).
critically important in numerous commercial chemical
processes.[18] There are several reports for three-component,[19]
tandem CEL-type reactions[20] and heterocycles synthesis.[21]
Elegant CEL couplings catalysed by MOF’s,[22] COF’s,[23]
copper-exchanged zeolites[24] and electrochemical means[25]
were also reported.
Thus, the CEL reaction has greatly advanced the carbon–
heteroatom cross-coupling chemistry and has become
a
powerful synthetic tool, made even more attractive by the mild
conditions required, in comparison to the Ullmann-Goldberg or
Buchwald Hartwig aminations catalysed by palladium or
copper(II).
Scheme 1. The Chan-Evans-Lam (CEL)-reaction of C-N coupling
However, the main reaction is usually accompanied by
certain undesirable side reactions, including: deboronation (to
yield benzene derivatives); oxidative hydroxylation (to yield
phenols); homocoupling of two boronic acid species (to yield
diaryls); competitive addition of solvent (MeOH) (to yield anisole
derivatives); and formation of diaryl ethers via oxidative
couplings of two boronic acids (Scheme 2).
Introduction
Copper-catalysed reactions are widely used in modern
organic synthesis including natural product synthesis[1,2] and
pharmaceuticals design.[3] As copper is an inexpensive, earth-
abundant, relatively non-toxic metal,[4,5] its application in
catalysis attracts ever-increasing attention of the chemical
community for the construction of important organic molecules
via formation of carbon–carbon and carbon–heteroatom
bonds.[6] In particular, the discovery of an experimentally simple
and convenient copper(II)-promoted C-N and C-O bond
formation protocols by the oxidative Chan-Evans-Lam (CEL)
coupling reaction (Scheme 1)[7–9] has, since 1998, opened new
horizons in the field, especially important for the pharmaceutical
industry.[10] Initially, the reaction represents a condensation of
boronic acids and amino- or oxygen-based nucleophiles in the
presence of oxidants and catalysts of oxidation, being
predominantly copper salts. Air is routinely used for the reaction
as an oxidant. The CEL coupling later was elaborated to allow
C-N,[11–13] C-O,[14] C-S,[15] C-Se,[16] C-P[17] bond formation via
copper(II)-catalyzed pathways of arylboronic acids with a wide
range of nucleophiles, including sensitive substrates, which is
Scheme 2. Side reactions in CEL coupling
Although there is a series of papers dedicated to the
elucidation of details of the reaction, a significant stumbling
block for the development of the catalytic systems is poor
understanding of the mechanism of CEL reactions. The
generally held view of the catalytic cycle includes the redox
Cu(III)/Cu(I) couple as the main driving force of the oxidative
conversions. Scheme 3 illustrates this point, as was recently
discussed by Stahl,[26] Schaper[27] and Watson.[28] According to
the mechanism, one Cu(II) ion oxidizes another ion into the
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10.1002/cctc.202000212
ChemCatChem
Cu(III) version, at which both components of the coupling are
coordinated. The reductive elimination yielded the product and
another Cu(I) complex. Both Cu(I) complexes are then oxidized
by air to yield the initial Cu(II) catalyst.
a - aniline (TR = 2.803 min), b - phenylboronic acid (TR = 3.583 min), c - phenol (TR = 4.140
min), d - anisole (TR = 6.912 min), e - benzene (TR = 7.323 min), f - diphenylamine (TR
11.355 min), g - diphenyloxide (TR = 15.433 min), h - biphenyl (TR = 15.855 min).
=
Eluent: MeCN : (buffer рН=2,5 (Et3N + H3PO4)) = 60 : 40 (v/v)
λ = 210,8 nm
Column Reprosil-PurC18-AQ 5 μm (250 x 4 mm)
Chromatograph: Agilent 1100 with diode matrix
Figure 1. HPLC chromatogram of a model mixture of reagents, and main and
possible side products of the reaction of aniline and phenylboronic acid under
the conditions of the Chan-Evans-Lam coupling.
Our literature review indicated the predominant use of
copper(II) acetate (up to 1.5 eq. to substrate) for the CEL
couplings in the earlier works.[9,29,30] To test the analytical
procedure, a model reaction was performed using catalytic
amounts of the Cu(OAc)2 H2O. Initially, MeOH was chosen as
the solvent of choice, as it is easy to purify and remove and it is
good for solving anilines and arylboronic acids. The HPLC
chromatogram of the reaction mixture of aniline and
phenylboronic acid in the presence of Cu(OAc)2 H2O (10 mol%)
after the complete conversion of phenylboronic acid is depicted
in Figure 2.
Scheme 3. Generally accepted concept of CEL coupling mechanism, as
illustrated by the case of diphenylamine synthesis.
The postulated mechanism hinted at high importance of
redox potentials of the complexes and the decisive role of the
ligands in promoting CEL reactions.
In this work, we set ourselves the task of studying the CEL
coupling of anilines and phenylboronic acids promoted by a
series of closely related complexes, differing in their oxidative
and reductive potentials. In addition, as the reaction involves
two copper ions in the oxidative/reductive stages, we attempted
to prepare ligands capable of encompassing two copper(II) ions
and test the possible variations in CEL activity, coming from
putting the two metal ions together in the same complex. The
best precatalyst derived from 2,6-diformyl-4-tert-butylphenol and
2
equivalents of 8-aminoquinoline, and 2 equivalents of
Cu(OAc)2 was used to elaborate an efficient catalytic protocol
for CEL generation of diphenylamines. Molecular weight
measurements in MeOH and certain kinetic trials pointed
towards the likely structure of the real catalytic particle.
Additionally, some insights into the mechanism of the reaction
were derived from 1H NMR experiments on the reaction mixture
devoid of air supply.
Reaction conditions: aniline 0.1 mmol, phenylboronic acid 1.5 eq., MeOH (1
ml), RT, air.
Figure 2. HPLC chromatogram of a real reaction mixture of aniline and
phenylboronic acid (molar ratio 1/1.5) promoted by Cu(OAc)2 H2O (10 mol%)
as the catalyst after the complete conversion of phenylboronic acid (144 h)
Results and discussion.
After complete conversion of the initial phenylboronic acid,
the side product of the competitive addition of MeOH – anisole –
was found to be the main product of the CEL reaction (52%)
under the standard conditions. The yield of the desired product
Analytic methods. First, we turned our attention to
analytical methods allowing us to quantitatively assess the
ratios of all formed products and the conversion of the initial
reagents in the model reaction. The procedure should have
facilitated the detection of easily volatile components of the
reaction. HPLC was found to be the most suitable method for
the point, permitting the quantitative assessment of anisole and
benzene formation (Fig. 1). Such a combination facilitated good
separation of all the components of the reaction mixture.
Furthermore, we have successfully used this method to
determine the product yields and employed the procedure for
the kinetic studies.
1
– diphenylamine – was only 42% (determined by H NMR and
the isolated yield was 40%, from 1 mmol scale experiment).
Another side reaction was 7% of phenol formation. Furthermore,
some unreacted aniline (56%) was also present. From this point
forward, the rate of conversion of phenylboronic acid was taken
as the CEL reaction rate, since in all cases, it was consumed
first. The kinetics of the conversion of phenylboronic acid and
the formation of the main and side products indicated that all
these processes occurred in parallel (Fig. 3).
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10.1002/cctc.202000212
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Figure 4. The set of catalysts employed in the work.
Unexpectedly, catalyst 4 – derived from a Schiff base of (R)-
valinol and salicylaldehyde was an exception, as the conversion
of the acid was already 95% complete after 12 h (run 7).
The first representatives of NNO ligand-derived catalysts
were 5a-c. The ligand was easily prepared by the condensation
Figure 3. Kinetics of the conversion of phenylboronic acid (a) and the
formation of the main and side products (b) in the reaction mixture of aniline
and phenylboronic acid with Cu(OAc)2 H2O (10 mol%) as the catalyst.
of
substituted
salicylaldehyde
with
8-aminoquinoline.
The choice of catalysts. Among numerous possible
structures of ligands, a simple variation of Schiff bases based
on salicylaldehyde was chosen to approach the solution of the
postulated problem. The ligands were easily prepared, and
many of them already described in the literature earlier, the
denticities of the ligands were easily controlled, and the overall
charges of the resulting complexes were simply regulated. In
addition, the ligands are strongly coordinated to the metal ions,
ensuring the complexes are stable under the reaction
conditions.
The set of tested complexes are presented in Figure 4. The
chosen test reaction was the coupling of aniline and
phenylboronic acid, run at an ambient temperature in air for 24
h. The results of the experiments are presented in Table 1. As
can be seen from the data, another simple catalysts, CuCl2 and
Cu(OTf)2, were much more reactive than Cu(OAc)2. Even after 1
h, the initial boronic acid was completely consumed (Table 1,
entries 2, 3). In both cases, the major product was PhOMe (45%
and 47%, respectively), whereas the amount of Ph2NH was
diminished to 8% and 17% with the appearance of all other by-
products with yields up to 26%.
Complexes 5a-c had very low catalytic reactivities (runs 8-10)
and low selectivity.
Condensation of 2,6-diformyl-4-tert-butylphenol with
2
equivalents of 8-aminoquinoline led to pentadentate NNNNO
ligand potentially capable of forming binuclear complexes with
Cu(II) ions. The corresponding dinuclear complex derived from
the analogues ligand and Ni(II) ions was well characterized by
its X-ray analysis data.[31]
By the reaction with the
corresponding copper(II) salts, complexes 6a-c were prepared.
For the comparison reasons the mononuclear analogue 6d (Fig.
4) was prepared by the reaction of the ligand with one
equivalent of Cu(II) ion.
The complexes 6a-c displayed much greater catalytic
reactivity (runs 11-13) than the mononuclear analogue 6d (run
14). The counter-anion affected the selectivity of the reaction,
with 6b promoting mainly the biphenyl formation (run 12), and
6a predominantly leading to the target CEL C-N construction
(run 11). Thus, the selectivity pattern of CuX2 catalysis (runs 1
and 2) repeated itself in 6a and 6b. At the same time, complex
6c has not demonstrated any selectivity (run 13).
All the complexes derived from ONNO, and ONO-type
ligands (complexes 1-3) displayed low catalytic reactivities (runs
4-6) with the phenylboronic acid conversion in the range of only
11-21%.
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10.1002/cctc.202000212
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Table 1. The CEL reaction catalysed by a series of Cu(II) complexes.
Run
Cat.
Cat.
mol%
Reaction
time, h
Conversion of
PhB(OH)2, %
Yield, %[a]
Ph2NH[b]
[b]
PhOH[b]
PhOCH3
PhH[b]
Ph2NH[c]
Ph2O[b]
Ph-Ph[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Cu(OAc)2 H2O
CuCl2 2H2O
Cu(OTf)2
10
10
10
10
10
10
10
10
10
10
5
24
1
1
50
96
98
21
11
15
95
7
4
12
15
2
1
2
11
3
0
2
4
31
45
47
8
2
3
28
2
1
0
6
7
1
2
2
9
0
5
0
6
0
16
3
15
5
11
3
2
5
34
1
2
3
42
3
23
8
17
4
3
7
42
4
3
4
52
4
0
2
3
1
0
0
5
0
0
0
2
0
0
0
26
15
6
4
3
8
1
0
5
8
40
8
1
2
3
4
5a
5b
5c
6a
6b
6c
6d
24
24
24
12
24
24
24
24
24
24
24
8
12
98
85
82
9
2
36
34
30
4
5
5
10
8
10
2
18
traces
26
traces
traces
traces
Reaction conditions: aniline 0.1 mmol, phenylboronic acid 1.5 eq., MeOH (1 ml), RT, air. [a] - determined by HPLC, [b] – relative to PhB(OH)2, [c] - relative to
PhNH2
The kinetics of product formation promoted by 6a are shown
in Figure 5.
and aniline in the catalytic cycle could be the main reason for
the appearance of the side product.
The choice of solvents and the reaction conditions. The
use of bulky alcohols or aprotic solvents seemed to be method
by which to avoid the formation of the side products and
increase the yield of the target diphenylamine. The results of the
model reaction promoted by 6a in different solvents are
summarized in Table 2.
The coupling in t-BuOH was selective, with C-N-bond
formation being the predominant reaction. Unfortunately, the
conversion of the boronic acid was only 19% for 24 h (Table 2,
run 1). The use of benzene and CH2Cl2 led to even less efficient
system (runs 2 and 3). The catalysis in THF was more
competent (48% conversion, run 4), but the selectivity of the
reaction was significantly diminished, with the phenol formation
increased. The use of MeCN inhibited the coupling almost
completely (run 5), hinting at likely competitive coordination of
the solvent to the active centre of the copper catalysts. Better
results were achieved if DMF was employed (run 6). The
selectivity of the reaction was significant with the C-N bond
formation prevalent in the mixture. Bubbling of air (CO2
removed) resulted in a sharp increase in the yield of the
accompanying phenol, and the C-N bond formation was
subjected to only limited influence (runs 6 and 7). The addition
of Hünig’s base (DIPEA) under the standard conditions led to
the dominant formation of phenol (up to 48%, run 8). The
addition of an inorganic base (K2CO3) suppressed the catalytic
performance (run 9). Higher temperatures of the reaction led to
complete loss of the reaction selectivity (run 10).
The performance of the coupling in MeOH was much better
than in other solvents (run 11), but the addition of a base led to
the predominant formation of biphenyl (run 12). Using a mixture
of solvents (run 13) led to a loss of selectivity.
Water as a solvent almost completely inhibited the reaction
(run 14).
Evidently, MeOH was the solvent of choice for the reaction.
The straightforward way to eliminate the side reaction of PhOMe
formation would be the relative increase in the concentration of
aniline in the reaction mixture relative to that of MeOH.
Figure 5. Kinetics of the conversion of phenylboronic acid (a) and the
formation of the main and side products (b) in the CEL reaction catalysed by
6a (5 mol%) at an ambient temperature for 24h.
As can be seen from the data summarized in Table 1 and
Figures 3 and 5, the main side reaction observed in the process
was the anisole formation. Evidently, the competition of MeOH
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10.1002/cctc.202000212
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Table 2. Solvent scope in the model CEL reaction catalysed by complex 6a (5 mol%) for 24h.
Run
Solvent
Conversion of
PhB(OH)2, %
Yield, %[a]
Ph2NH[b]
[b]
PhOH[b]
PhOCH3
PhH[b]
Ph2NH[c]
Ph2O[b]
Ph-Ph[b]
1
2
3
t-BuOH
CH2Cl2
C6H6
THF
CH3CN
DMF
DMF
DMF
19
13
16
48
5
28
41
68
11
55
98
80
68
10
4
1
7
12
1
2
14
48
6
18
4
8
15
7
-
-
-
-
-
-
-
-
-
0
1
-
13
10
9
14
3
19
21
15
3
13
42
5
18
14
12
20
5
26
30
22
4
18
52
7
29
2
0
0
0
2
0
0
1
1
0
0
2
1
0
0
2
1
0
12
1
traces
traces
traces
traces
19
4
8
0
7
5
4
2
5
6
9
4
2
5
6.
7[d]
8[e]
9[f]
10[g]
11[h]
12[f]
13
14
DMF
DMF
MeOH
-
36
17
12
-
8
40
17
0
MeOH
DMF/MeOH = 1:1(v/v)
H2O
20
1
Reaction conditions: aniline 0.1 mmol, phenylboronic acid 1.5 eq., solvent (1 ml), RT, air. [a] - Determined by HPLC, [b] – relative to PhB(OH)2, [c] - relative to
PhNH2, [d] - air (CO2 removed) bubbled through the reaction mixture. [e] - Hünig’s base (DIPEA) was added (1 eq. related to the catalyst). [f] - K2CO3 0.075 mmol
(0.5 eq to PhB(OH)2) was added, [g] - 50oC, 6h, h Data from Table 1, run 11 were installed
To verify the assumption, the model reaction was conducted
at much higher concentrations of the reagents, using one-tenth
of the MeOH solvent volume, thereby reducing the amount of
competing MeOH nucleophile and raising the concentration of
the reaction components without changing of their molar ratios.
Simultaneously, the counter-anion impact using 6a-c as
catalysts was assessed (Table 4, runs 1-4)). In addition, catalyst
4 was tested under the conditions (Table 3, run 6).
As shown in Table 3, the concept has been experimentally
confirmed. The coupling promoted by 6a gave the target product
in 96% yield (Table 3, run 1).
Table 3. The CEL reaction catalysed by 6a-c concentrated solution.
Run
Cat.
Conversion of
PhB(OH)2, %
Yield, %[a]
Ph2NH[b]
[b]
PhOH[b]
PhOCH3
PhH[b]
Ph2NH[c]
Ph2O[b]
Ph-Ph[b]
1
2
6a
6b
6c
6a
6a
4
80
70
88
55
51
20
6
12
8
4
<5
<5
10
0
20
6
<5
<5
0
0
21
0
0
0
64
18
34
45
40
10
96 ± 4
26
51
59 ± 3
48
12
0
0
0
0
0
0
0
40
5
traces
0
0
3
4d
5e
6e
Reaction conditions: aniline 0.1 mmol, phenylboronic acid 1.5 eq., MeOH (0.1 ml), RT, air, cat. 5 mol%, stirring. [a] - determined by HPLC, [b] – relative to
PhB(OH)2 [c] – relative to PhNH2, [d]- aniline 0.1 mmol, phenylboronic acid 0.1 mmol (1.0 eq.), MeOH (0.1 ml), RT, air, cat. 5mol%, [e] - The reaction was run for
1 h.
The effect of the counter-anion on the catalytic activities and
selectivity of 6a-c was also significant (Table 3, entries 1-3).The
general tendencies were the same as in the dilute solution with
chloride ion substitution of acetate, leading to greater
percentage of biphenyl in the reaction mixture (Table 3, run 2).
The introduction of triflate anion led to greater quantities of
“parasitic” products (run 3).
If the reaction was carried out with a molar ratio of the
reagents 1 : 1 instead of 1.5/1, the main product yield was
reduced to 59% without selectivity loss (run 4).
In situ, synthesized 6a give only 77% of C-N-coupling
product. Complex 6a showed excellent results only after its
isolation and purification (see Fig. S8).
Changing the amount of catalyst under the conditions
showed that 5 mol% of 6a were the optimal amount to achieve
the best yields of C-N coupling products (see Fig. S9).
Another efficient catalyst 4 (Table 1, run 7) was also tested
under the conditions. The comparision of the data of Table 3
(runs 5 and 6) testified that 6a was much more active than 4
under the conditions.
The substrate scope. The substrate scope was explored
under the conditions summarized in Table 3, run 1 (Scheme 4).
All product characteristics were in full accordance with the
data supported in the extant literature (see S20).
Generally, the protocol featured moderate to good yields of
the coupling products in the case of alkyl-substituted substrates,
including both boronic acids and anilines (7a, 7c, 7d, 7n, 7q,
7al, 7aj). Even such sterically burdened amine as o,o’-
diisopropylaniline gave an observable 35% yield of 7aa. The
introduction of the –I type of substituents to both anilines and
phenylboronic acid led to a significant decrease of the yields
(7e, 7f, 7g, 7i, 7j, 7k, 7l, 7m, 7p, 7x, 7z, 7w, 7y, 7ag, 7af, 7ah).
It looks as if the introduction of even +I substituents to the
aniline substrate paired with unsubstituted phenylboronic acid
diminished the product yields (compare 7d and 7d’, 7q and
7q’). However, if the boronic acid moiety was modified with a +I
group also, the yield was greatly improved (7aj). Any
heterocyclic derivatives proved to be incompetent substrates
(7t, 7u, 7v, 7ab, 7ae). The rationalization of the substituent
influence on the catalytic performance was additionally
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10.1002/cctc.202000212
ChemCatChem
sophisticated by the known ability of MeO- substituted boronic
acids to form associates.[32–34] Aliphatic amines were bad
substrates for the reaction, with only 17 - 18% chemical yields of
7al and 7am.
Reaction conditions: aniline (0.1 mmol), arylboronic acid 1.5 eq, RT, air, 24h, MeOH (0.1 ml) , 6a 5 mol%. Products yields were determined by 1H NMR using
p-dinitrobenzene as the internal standard (CDCl3, δ 8.45 s, 4H). Isolated yields are given in parenthesis. [a] - determined by 19F NMR using perfluorobenzene
(C6F6) as internal standard (CDCl3, δ -161.75 s, 6F), n/o – no product observed.
Scheme 4. Substrate scope in CEL coupling catalysed by complex 6a.
A large-scale (0.5-1 g) synthesis of 7a and 7q yielded 94%
and 82% of the isolated products, respectively (see S30).
porphyrins,[36]
bearing
C–Cu(III)
bonds,
azacalix[1]arene[3]pyridines, ionized amides,[37] substituted
oxamates[38] or perfluorinated ligands.[39] An example of C-N
bond formation involving aryl-Cu(III)-complexes was published
by Stahl.[40] Moreover, aryl - Cu(III) species were proposed by
Hartwig[41] in the reaction of α-arylation of enolates, in Hurtley-
type coupling by Ribas[42] and invoked by Ma in his review as
the most likely mechanistic scheme.[43] The formation of
copper(III) - hydroxide unit through ligand structural variation
was described by Tolman.[44] Recent advances in the field of
The reaction mechanism. Although increasing numbers of
studies presume a Cu(I)/Cu(III) catalytic cycle in the CEL
reactions (Scheme 1),[35] the limited stability of most Cu(III)
complexes with the routine ligands makes their direct detection
difficult. Whereas Cu(I) and Cu(II) complexes are the most
common species in chemistry, the number of well-defined
organometallic copper(III) complexes is very restricted. The
Cu(III) species are stabilized by very strong ligands, such as
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10.1002/cctc.202000212
ChemCatChem
Cu(III)-species and their role in catalytic applications were
reviewed by Sanford,[45] Lumb[46] and Ribas.[47]
To ascertain if the dimer was the real precatalyst in the
reaction, kinetic studies of the coupling had to be undertaken
with the substrates taken in concentrations presented in Table 3.
However, the theme of the intermediate Cu(III) formation in
copper ion catalyzed reactions invoked some scepticism. For
example, recently, Gurjar et al suggested Cu(II)/Cu(I) instead of
Cu(III)/Cu(I) catalytic cycle in the reaction of phenyl chloride with
aniline leading to the C-N-bond formation. The conclusion was
drawn on the basis of theoretical (density functional theory)
calculations and supported by in situ 1H NMR spectroscopy,
UV vis spectroscopy, Fourier transform infrared spectroscopy,
and cyclic voltammetry studies.[48]
Naturally, the performance of the series of our catalysts
should be linked to the oxidation/reduction potentials of the Cu
catalysts. Using the method of cyclic voltammetry (CVA), the
electrochemical properties of the synthesized complexes and
copper(II) salts were investigated. The experimental data is
summarized in Table S1.
The data indicated that the value of the oxidation potential
was not correlated with the catalytic performance of the
complexes. Had the Cu(III) formation stage been present as the
key step in the CEL reaction, 2-5 would become more active
than 6, which was not the case (Table 1).
On the other hand, the ease of the complex reduction (Cu(II)
to Cu(I)) roughly corresponded to the catalytic performance of
the complexes. The most easily reduced complexes, CuCl2, 6a
and 6b (Table S1) were the most reactive (Table 1). Additionally,
MeOH was the best solvent for the reaction (Table 2, run 11)
may be because of its reductive properties.
Still the reduction and the oxidation potentials of the initial
pure complexes have only indirect link with the catalytic
reactivity of the complexes. Evidently, in the reaction mixture the
pure initial complex (precatalyst) undergoes conversion into the
real catalyst with the strongly donating groups coordinated with
the metal ion (such as Ph – moieties alcoholate ions, amide ions
and so forth) making the real reduction and oxidation potential
of the complexes changed drastically. In addition, the
protonation of the ligand strongly basic alcoholate group of 4 in
MeOH could make its metal centre more susceptible to
reduction which might explain the high reactivity of 4 (Table 1,
run 7).
Reaction was carried out from 0.75 mmol (1.5 eq) of PhB(OH)2, 0.5 mmol of
PhNH2, 5 mol% 6a in 0.5 ml of MeOH. After 5, 10, 20 and 30 minutes
respectively 0.1 ml aliquots were taken, catalyst was removed by general
procedure as given in experimental section. Product yields were determined
by 1H NMR.
Figure 6. Plot of 6a (5% mol) promoted formation of diphenylamine (yield vs
time). The conditions are those of Table 3.
In order for the kinetic experiments at the earlier stages of
the reaction were valid, the absence of some induction periods
had to be confirmed. Fig.6 shows that the reaction had no
sizable induction period within 30 minutes interval.
The kinetic experiments with different amounts of 6a were
run as follows. After 30 minutes, the reaction was stopped, the
catalyst removed and the yields of the diphenylamine were
estimated by 1H NMR with an internal standard (p-
dinitrobenzene).
Additionally, the potentials of reduction had no correlation
with the selectivity of the CEL reactions. The substitution of
acetate ion for chloride in 6 (conversion of 6a to 6b) led to the
switch of the selectivity of the reaction. The biphenyl formation
was the predominant product (40%) in case of 6b catalysis
(Table 1, run 12). The yield of diphenylamine in this case
decreased to 2%. The pattern was generally retained under the
optimized conditions of Table 3 (runs 1 and 2). Since there are
no other differences in reaction parameters, this unexpected
change should be associated exclusively with the nature of the
counter-anions. It is likely that the underlying reason for this
behaviour lies in the relative coordination abilities of acetate and
chloride ions. The ability may well be important, as the
comparison of runs 2 and 3 indicates.
To estimate what kind of complex derived from 6a was the
initial material for the precatalyst formation, the determination of
the apparent molecular weight of 6a was undertaken in a
methanol solution using the sedimentation equilibrium method.
The results showed that even in a diluted solution (0.14 mM), 6a
was predominantly present as a dimeric unit (78%) with the
equilibrium constant equal to 1.6 x 105 M-1. Hence, under the
optimal reaction conditions (concentration of 6a is 5.3×10 M),
the amount of the dimer constituted 99% of the total 6a present
in solution (see p.S31).
Reaction was carried out in four runs for 30 min by general procedure as
given in experimental section with 1.0, 2.5, 5.0 and 10.0 mol% of 6a
respectively. Product yields were determined by 1H NMR.
Figure 7. Logarithmic approximation of the product yield [C] to amount of [6a].
The logarithmic dependences of the initial rates versus the
amount of the catalyst are displayed in Fig.7. The slope was
found to be 0.2 and clearly showed that the dimer had to
dissociate before the reaction could take place. The monomer,
2
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10.1002/cctc.202000212
ChemCatChem
in its turn, had to undergo dissociation of acetate to generate a
vacant site on the copper centers.
If the Cu(III)/Cu(I) couple were the real intermediate in the
reaction sequence and the oxygenation of the generated Cu(I)
intermediate occurred after the final stage of the C-N bond
formation, then, without any oxidant present, all the Cu(II) had to
convert to Cu(I). Consequently, the 1H NMR spectra of the
reaction mixture would display a narrowed line width of the
substrates and the products as compared with the initial set of
the broadened resonances due to the initial high concentration
of paramagnetic Cu(II) ions. The event would have been
inevitable had the paramagnetic Cu(II) ions been converted to
Cu(I) ions in the absence of air or any other oxidants.
Figure 9. The variation in time of 1H NMR spectra of a mixture of aniline
(0.2M) and phenylboronic acid 1.5 eq., 0.3M (the conditions of run 11, Table
1) in CD3OD with the addition of 6a (10 mol%) devoid of air supply. The major
product was benzene and the formation of Ph-Ph, Ph2NH and PhOH
observed as minor side products.
The accompanying variation of 11B NMR spectra of the
reaction mixture (Fig. S10) indicated that another single boron-
containing compound was finally formed from the initial boronic
acid. The process went parallel to the benzene formation (Fig.
S11).
The data proved that under oxygen shortage conditions the
target oxidative reaction of C-N bond formation was inhibited
and instead protodeboronation side reaction predominated.
Although some amount of biphenyl and diphenylamine
appeared in the spectra after 24 h, the broadening of the
substrate proton resonances and their position remained the
same (Fig. 9), hinting at the concentration of Cu(II) ions still
being the same in solution, although, according to the accepted
mechanism, the copper ions had to be in Cu(I) forms had the
first catalytic cycles taken place and all the oxygen oxidant been
consumed (Scheme 3).
In addition, the UV/Vis spectra of the reaction mixture
without free supply of oxygen (Fig. 9) displayed undiminished
absorption at 415-450 nm (d-d transition) as expected for Cu(II)
complexes (Fig. S7). The absorption maximum shifted to shorter
wave length as could be expected in case of coordinating
stronger ligands such as MeO – anions (vide infra). Had the
oxidation state of the copper ions been changed to +1, the
absorption maximum in the region of d-d transition would have
been changed and even disappear.
Additionally, the X-ray photoelectron spectra of 6a testified
that there were no Cu(I) admixtures in the sample (Fig S12).
The paramagnetically shifted 1H NMR signals of the initial
complex (Fig. S1 and S2) were compared with those recorded
in the reaction mixture (devoid of air supply) within the time
intervals of Fig. 9. The spectra showed that the characteristic
paramagnetically shifted signals of aromatic protons of 6a at the
range from 13 to 22 ppm remained constant during the catalytic
24 hours cycle (Fig. 10). There is the antiferromagnetic nature
of the exchange electronic interaction between the two
copper(II) ions in the dinuclear complex 6a (Fig. S3). Had there
been the conversion of even one Cu(II) ion to Cu(I) within the
dinuclear catalyst, the antiferromagnetic interaction would have
disappeared and the proton signals shifted and broadened.
Consequently, the electronic structure of the complex 6a (the
oxidation state +2 of the copper ions) remained constant in the
catalytic experiments under the short oxygen supply.
Figure 8. Variation of 1H NMR spectra of the mixture of aniline (0.2M) and
phenylboronic acid (1.5 eq, 0.3M) in CD3OD with addition of different amounts
of 6a.
Fig. 8 displays the experimentally observed variations of the
1H NMR spectra of the mixture of the initial substrates in
CD3OD, following the consecutive addition of 1-10% mol of
paramagnetic 6a (Fig. S1). The NMR tube was sealed, but the
remaining air was not removed. Expectedly, the substrate
resonances were broadened. In particular, the coordination of
aniline to the copper ions led to broadening and shifting of m-H
signals to weaker fields and o-/p-H signals to stronger fields.
Coordination of phenylboronic acid to copper was weaker than
that of aniline and takes place without any chemical shifts of the
former. The results are depicted in Fig. 8. As the experiments
were of particular importance for the understanding of the
mechanistic details of CEL reaction it was conducted repeatedly
4 times and each time with different samples of 6a prepared
from different samples of the initial Schiff base. Every
experiment had the same pattern of resonance changes.
Figure 9 illustrates the observed resonance shifts in the
sealed tube after 2-24 hours staying at the ambient
temperature. After 2 h, the chemical shifts of the broadened
aniline resonances returned to their position, corresponding to
1% of 6a added (Figs. 8 and 9). Still, there were only traces of
the final product resonances detected in the spectra (Fig. 9).
Most likely, the observation could be traced to a slow formation
of another set of complexes originated from 6a and the
substrates as the UV/VIS spectra evolutions indicated (Fig. S7).
The predominant formation of benzene was detected by 1H
NMR within the time interval (7.33 ppm, Fig. 9) and HPLC (yield
of, at least, 50%, Fig. S11) after 24 hour interval.
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10.1002/cctc.202000212
ChemCatChem
Finally, we have conducted two stoichiometric experiment
with 1/1/1.5 mol ratio of 6a/aniline/boronic acid. One was run
under Ar and another under air and both conducted for two
hours.The real ratio of Cu(II)/aniline was 2/1. Thus, the Cu(II)
ions of 6a at the beginning of the experiment were present in a
large excess over the forming diphenylamine. Under the
conditions the amount of the concomitant formation of Cu(I)
would be small relative to the remaining Cu(II) ions and,
consequently, the loss of the oxidative properties of the catalyst
would be negligible. Thus no oxygen would be needed to
restore the catalytic performance of 6a, as postulated by
Cu(III)/Cu(I) cycle, at the early stage of the conversion. Had the
accepted Cu(III)/Cu(I) mechanism been applicable in our case,
the experiments under air and Ar would have given similar
results. In fact, after two hours the “Ar” experiment produced 8-
10% of diphenylamine whereas “air” experiment gave 25-30%
yield. No other products were found in the reaction mixture.
Even that small amount of diphenylamine in the “Ar” experiment
might be formed because some oxygen was still present in the
reaction vessel. Evidently, the presence of oxygen was needed
to trigger the C-N bond formation and the oxidant seems to be
present in the transition state of the reaction.
Figure 10. 1H NMR spectra recorded at room temperature (paramagnetic
range) in methanol-d4 solutions of pure complex 6a (A) and 6a (B) with the
substrates added. The experiment was the same as in Fig. 9. The variations
of the spectra (runs C-F) were recorded at the same time intervals as those of
Fig. 9. The characteristic paramagnetic signals of aromatic protons of 6a are
marked.
Based on the experimental and literature data, the
hypothetical mechanism of the Chan-Evans-Lam reaction
catalysed by the dinuclear copper(II) complex 6a was proposed
(Scheme 5).
The results support our contention that no large quantities of
copper(I) were formed under the reaction condition with air
supply excluded.
Scheme 5. Proposed mechanism of CEL coupling catalysed by dinuclear copper(II) complex 6a.
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10.1002/cctc.202000212
ChemCatChem
At the first stage of the reaction, an aniline molecule
coordinates with monomeric particle derived from the
competing reaction of C-C formation predominant (Table 3, run
2). In case of weakly basic but bidentate triflate counter-anion
the anisole formation was the main reaction with more acidic
than aniline MeOH becoming much more competitive relative to
aniline (Table 3, run 3). The failure of 6a to promote the reaction
with strongly basic amines can be traced to the formation of
inactive off-cycle complex with the two coordination sites of 6a
occupied by the amine molecules. The inhibition of the CEL
reaction by the nucleophilic anilines (compare the yields of 7a,
7d’ and 7q’, Scheme 3) could also be linked to the same cause.
The analogous mechanism was earlier suggested by Shaper
and supported by competition experiments in the paper on CEL
reaction promoted by his sulfnato-diketimine copper(II)
complexes.[11]
The next steps include the same type of oxidative and
coordination steps, with the exception of peroxide being the
oxidizing species instead of the initial oxygen molecule,
producing diphenylamine. The resulting coordinated hydroxyl
ions interact with AcOB(OH)2, producing B(OH)3, and the
acetate ions effectively regenerating the initial catalyst.
a
predominantly dimeric form of 6a (Stage A, Scheme 5). Then a
molecule of phenylboronic acid becomes decomposed by an
acetate ion of 6a with the formation of acetylboronic derivative
AcOB(OH)2 and the simultaneous coordination of the free
phenyl anion to one of the two neighbouring copper(II) ions, or
both ions (transmetallation step B). This type of coordination
was recently shown to exist in similar dinuclear Cu(II)/Cu(I)
complexes[49]. The stage may be responsible for the narrowing
of the aniline proton signals in the 1H NMR spectra after 2 hours
(Fig. 9) as less Cu(II) sites become available for the aniline
coordination. Among different types of equilibrated complexes
the complex B with the two substrates situated in close
proximity to each other could be formed. This type of
conversions may be responsible for the observed changes in
the UV/VIS spectra of the reaction mixture depicted in Fig.S7.
In presence of MeOH the aniline substrate may become
substituted by a MeOH molecule (complex C) and then the
intramolecular protonation of the neighbouring Ph moiety leads
directly to C6H6 formation. Without oxygen present or with
oxygen supply curtailed, the benzene formation becomes the
predominant side reaction, as Fig 9 and Fig. S11 testify.
Conclusion.
When the oxygen supply is restored, an oxygen molecule
coordinates at the apical positions of the copper complexes.
Further electron transfers coupled with a proton transfer from
the aniline moiety to the coordinated oxygen molecule leads to
the formation of the final diphenylamine and coordinated
monoanion of hydroperoxide. The mechanistic scheme
rationalizes the formation of anisole (PhOMe) in dilute solutions
as forming from the intermediate C by the same mechanism.
Expectedly, the formation of both biphenylamine and anisole is
suppressed without oxygen presence (Fig. S11). Highly likely,
that the side parasitic biphenyl formation occurs also at this
stage. With limited oxygen supply the reaction is also
suppressed (Fig.S11). The complex derived from 6a with both
coordinated sites occupied by the Ph moieties may be the initial
starting intermediate. The formation of the intermediate is
promoted by K2CO3 (Table 2, run 12) as should be expected
with the transmetallation reaction promoted by bases.
Whatever the intimate mechanism of the C-N bond
formation is operating in reality, its general outline can be
presented as the nucleophilic substitution of the
Cu(II)L(OOH)[50] leaving group at the phenyl moiety by the
anilide ion. In other words, the oxygen molecule presence in the
transition state of the C-N bond formation is prerequisite for its
success.
The key role of the acetate ions in the target C-N coupling
can be traced to its basic nature and bidentate properties
realized in the aniline deprotonation step followed by the
protonation of the coordinated oxygen with the formed acetic
acid. Aniline cannot compete with the acetate as the base as
the pKa of the conjugated acid is 6.05 in MeOH whereas acetic
acid has pKa 9.52 in the solvent.[51] In addition, the local
concentration of the acetate near the Cu(II) ions could be much
greater than that of aniline. The reason for that is the negative
charge of the acetate that makes its association with the
positively charged complex much greater than that of aniline.
Complex 6b with monodentate Cl counter-anions, lacking basic
properties of the acetate ion, made the target reaction of C-N
formation slow. In addition, Cl – ion coordinates to Cu(II) ion
Monitoring the catalytic performance of differently ligated
mono- and dinuclear copper(II) complexes in a model CEL
reaction showed that neutral complexes bearing strong
negatively charged ligands had no necessary catalytic activity.
However, NNNNO-ligated dinuclear copper(II) complex, formed
from a Schiff base of 2,6-diformyl-4-tert-butylphenol and 8-
aminoquinoline as ligand and AcO– as the counter-anions (6a),
gave the highest yield in a model reaction of aniline and
phenylboronic acid coupling. Methanol was found to be the
solvent of choice, but at dilute solutions became a competitor in
the coupling reaction. The importance of counter-anions was
found, and switching from bidentate and the basic acetate ion to
the chloride ion almost completely changed the reaction
selectivity from predominant C-N to C-C coupling.
Special NMR experiments showed that in case of oxygen
supply cancelled under standard 6a promoted CEL coupling
conditions, no detectable formation of Cu(I) complexes were
observed. The oxidation state of copper was still +2 even after
significant phenylboronic acid conversions had taken place. The
result contradicted the generally accepted mechanism of the
reaction, involving the Cu(III)/Cu(I) pair with the oxidant involved
after the key C-N bond formation. The accepted mechanism
predicted the full conversion of the Cu(II) to Cu(I) ion without an
oxidant present after the first catalytic cycle. A mechanism
including the Cu(II)/Cu(II) pair was suggested as an alternative
for, at least, dimeric Cu(II) complexes.
The synthetic application of the new catalytic system was
suggested with 43 examples of substituted boronic acids and
aniline tested with the chemical yields ranging from 8% to 98%.
Keywords: Homogeneous catalysis • reaction mechanism • the
Chan-Evans-Lam reaction • dinuclear copper(II) complexes • C-
N-bond selectivity
ASSOCIATE CONTENT
Supporting Information
The Supporting Information is available free of charge. The
material includes some figures, experimental procedures and
spectra.
weaker than the acetate ion by one
- two orders of
magnitude,[52,53] whereby favouring two phenyl moiety
coordination at the neibouring Cu(II) ions of 6b. It made the
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10.1002/cctc.202000212
ChemCatChem
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10.1002/cctc.202000212
ChemCatChem
Table of Contents
The dinuclear complex derived from 8-aminoquinoline and 2,6-diformyl-4-tert-butylphenol was an efficient catalyst of CEL-coupling
reaction of phenylboronic acids and anilines. The counter-ion nature played an important role in determining the selectivity of the side
reactions. Some evidence was presented in favor of oxygen molecule present in the stage of C-N-bond formation.
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