Chan-Evans-Lam Couplings with Copper Iminoarylsulfonate Complexes: Scope and Mechanism

Article abstract of DOI:10.1021/acscatal.8b01881

Copper(II) pyridyliminoarylsulfonate complexes with chloride or triflate counteranions were employed in Chan-Evans-Lam (CEL) couplings of N-nucleophiles and arylboronic acids. The complexes avoided typical side reactions in CEL couplings, and an excess of boronic acid was not required. Water was tolerated, and addition of neither base nor other additives was necessary. Primary amines, acyclic and cyclic secondary amines, anilines, aminophenol, imidazole, pyrazole, and phenyltetrazole can be quantitatively arylated at either 25 or 50 °C with 2.5 mol % of the catalyst. Reaction kinetics were investigated in detail. Kinetic and spectroscopic studies provide evidence for the formation of unproductive copper-substrate complexes. Formation of an aniline-phenylboronic acid adduct was responsible for the zero-order dependence of reaction rates on phenylboronic acid concentration. Kinetic evidence indicates that the order of reaction steps is transmetalation, nucleophile coordination, and oxidation. Couplings performed poorly with electron-deficient arylboronic acids, due to a slower Cu(II)/Cu(III) oxidation in the catalytic cycle. Photoredox catalysis partially resolved this problem, but addition of copper acetate as an external oxidant proved to be more efficient.

Full text of DOI:10.1021/acscatal.8b01881

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Article
Chan-Evans-Lam couplings with imino-arylsulfonate
copper complexes: scope and mechanism
Valérie Hardouin Duparc, Guillaume Lionel Bano, and Frank Schaper
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01881 • Publication Date (Web): 25 Jun 2018
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ACS Catalysis
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Chan-Evans-Lam couplings with imino-arylsulfonate copper com-
plexes: scope and mechanism
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Valérie Hardouin Duparc, Guillaume L. Bano, Frank Schaper*
Centre in Green Chemistry and Catalysis, Department of chemistry, Université de Montréal, C. P. 6128 Succ. CentreꢀVille,
Montréal, QC, H3T 3J7, Canada
Supporting Information Placeholder
ABSTRACT: Pyridyliminoarylsulfonate Copper(II) complexes with chloride or triflate counteranions were employed in Chanꢀ
EvansꢀLam (CEL) couplings of Nꢀnucleophiles and arylboronic acids. The complexes avoided typical side reactions in CEL couꢀ
plings and excess of boronic acid was not required. Water was tolerated and neither addition of base or other additives was necesꢀ
sary. Primary amines, acyclic and cyclic secondary amines, anilines, aminophenol, imidazole, pyrazole, and phenyl tetrazole can be
quantitatively arylated at either 25 °C or 50 °C with 2.5 mol% catalyst. Reaction kinetics were investigated in detail. Kinetic and
spectroscopic studies provide evidence for the formation of unproductive copperꢀsubstrate complexes. Formation of an anilineꢀ
phenylboronic acid adduct was responsible for zeroꢀorder dependence of reaction rates on phenylboronic acid concentration. Kinetꢀ
ic evidence indicate that the order of reaction steps is transmetallation, nucleophile coordination, followed by oxidation. Couplings
performed poorly with electronꢀdeficient arylboronic acids, due to a slower Cu(II)/Cu(III) oxidation in the catalytic cycle. Photoreꢀ
dox catalysis partially resolved this problem, but addition of copper acetate as a external oxidant proved to be more efficient.
Chan-Evans-Lam coupling, copper coordination complexes, homogenous catalysis, mechanism, C-N bond formation
moved…5, 23 when it is not beneficial, 24ꢀ26 the addition of base
INTRODUCTION
28ꢀ32
is essential…27 or unnecessary,17,
solvent dependence is
Over the last two decades, palladiumꢀcatalyzed coupling reꢀ
actions have become a staple reaction of the pharmaceutical
industry,1 to an extend that processes to remove residual pallaꢀ
dium from pharmaceutic products became an active area of
research.2 Partly due to their lower costs and higher availabilꢀ
ity, but mostly due to their significantly lower toxicity, there is
thus an ongoing effort to replace catalysis with palladiumꢀ
group metals by firstꢀrow transition metal alternatives for CꢀC,
CꢀN, or CꢀO coupling reactions. Based on earlier work by
Barton on couplings with aryl bismuth reagents,3 Chan, Evans
and Lam reported in 1998 the oxidative coupling of amines
(and other nucleophiles) with arylboronic acids by copper salts
(Scheme 1).4ꢀ6 In the following years, ChanꢀEvansꢀLam (CEL)
couplings with catalytic amounts of copper were developed
and the method proved to be applicable to a wide variety of
nucleophiles.7ꢀ15 Compared to the UllmannꢀGoldberg reaction
or BuchwaldꢀHartwig aminations catalyzed by palladium or
copper, CEL couplings proceed under much milder conditions,
often at room temperature, and are thus more attractive for
complicated and sensitive substrates. While CEL couplings
have now been successfully employed for a large variety of Nꢀ
, Oꢀ, Sꢀ, and even Cꢀnucleophiles, from the very beginning
researchers remarked the “somewhat capricious nature of this
reaction”,16 and its exceedingly high substrateꢀdependency.
Early – and even current – work on CEL couplings thus report
optimized reaction conditions which differ strongly even for
closely related substrates such as amines,17 anilines,18 teꢀ
strong, but completely empirical, and copper sources with
acetate or triflate anions work best,15, 33 with the exception of
those cases where they don’t.20, 34, 35 Only lately, more general
protocols for CEL couplings of Nꢀnucleophiles emerged. Watꢀ
son et al. reported a modified protocol with stoichiometric
amounts of copper, addition of B(OH)3 and an excess amine,
which is generally applicable to a larger variety of amines and
anilines.36 Phukan reported CEL couplings with
[Cu(DMAP)4I]I to proceed with high activities and to be likeꢀ
wise applicable to a larger variety of substrates under the same
reaction conditions.37
Scheme 1. ChanꢀEvansꢀLam coupling of Nꢀnucleophiles and
the dinuclear copperꢀboron intermediate proposed for CEL
couplings with Cu(OAc)2 (A), for previously investigated
catalysts in our group (B) and for catalysts in this work (C).
Typical catalysts in CEL couplings are simple copper salts,
in most cases Cu(OAc)2. Copper salts immobilized in resins,
zeolites or other solid supports have also been employed.32, 38ꢀ
20
trazoles,19, aminopyridines,21 and aminophenols.22 In these
optimized reaction protocols, water typically needs to be reꢀ
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The triflate complex 3 is obtained by anion exchange with
47 Coordination complexes have been used rarely, even though
1
2
3
4
5
6
7
8
the first catalytic CEL coupling by Collman employed
silver triflate (Scheme 2) and crystallizes as a coordination
polymer with triflate and sulfonate interactions between
neighboring molecules.53 3 can also be prepared directly from
the ligand precursors and Cu(OTf)2, but required 2 equiv of
the copper salt. Under these conditions 4, a polymorph of 3
with a different constitution, was obtained, in which triflate
dissociated from the coordination sphere and a dinuclear,
dicationic complex is formed in the solid state (Figure 1, Table
1). 1 is soluble only in strongly polar solvents, such as water,
DMSO or DMF and poorly soluble in methanol. The solubility
of 3 is much higher and it is readily soluble in THF, CH2Cl2 or
methanol.
49
[(tmeda)Cu(OH)]2Cl2 for the arylation of imidazoles.48,
A
tetranuclear Copper(II) carbene complex was employed for
arylations of benzimidazoles, but showed low activity with
amines or anilines.30 Copper salen complexes have been used
51
to enable imidazole couplings in water,50, and likewise a
cyclodextrinꢀbased complex, which showed good activities for
amines and anilines.31 Recently, Phukan reported
[Cu(DMAP)4I]I as a catalyst, which showed so far the highest
and most general reactivity for Nꢀnucleophiles.37
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We hypothesized that the large variety of reaction condiꢀ
tions in CEL couplings and the strong dependence of reactiviꢀ
ty on them is related to the use of simple copper salts as cataꢀ
lysts. Solvent and added base are required to solubilize and
activate the copper salt, and base and counteranion play a role
in the formation of dinuclear copperꢀboron complexes
(Scheme 1, A), as a first step in the transmetallation.36, 52 Inꢀ
corporating these features into the ligand of a coordination
complex could provide catalysts with a more general reaction
protocol and – hopefully – increased reactivities. Given that
Copper(II) tends to form squareꢀplanar or squareꢀpyramidal
complexes and that two coordination sites are required for
interaction with the substrates, we targeted tridentate ligands.
A sulfonate group was integrated in the ligand to enable a
bridging coordination to boron and to facilitate transmetallaꢀ
tion. We have previously reported sulfonatodiketimine comꢀ
plexes (Scheme 1, B), which showed indeed a more general
reactivity towards amines and anilines, but proved to be unreꢀ
active even for slightly bulky substrates.26 We then targeted
sterically less crowded pyridylimino arylsulfonate complexes
(Scheme 1, C), for which we reported a high reactivity toꢀ
wards amines, anilines, and Nꢀheterocycles in a preliminary
publication,53 and which showed some of the highest activities
in CEL couplings, in particular for challenging substrates. In
the following, we investigate the mechanism of CEL couꢀ
plings with complexes of type C and how to address remainꢀ
ing problems of reactivity.
Figure 1. Crystal structures of 2 (left) and 4 (right). Thermal
ellipsoids were drawn at the 50% probability level. Hydrogen
atoms, cocrystallized water (2) and the anion (4) were omitted for
clarity.
Table 1. Geometrical data of complexes 1-4.
1 a
3 a
2
4
CuꢀNimine
2.051(1) 2.026(1) 1.972(1), 2.023(2)
1.986(1)
1.992(1) 1.967(1) 2.045(2), 1.967(2)
2.073(1)
1.969(1) 1.929(1) 2.200(1), 1.934(1)
2.877(2)
CuꢀNpyridine
CuꢀOsulfonate
CuꢀObridging
CuꢀOH2
CuꢀOtriflate/Cl
τ
2.379(1)
2.235(1)
1.993(1)
2.307(1)
2.243(1) 2.015(1)
0.1
RESULTS AND DISCUSSION
0.5
0.5
Catalyst synthesis and structures. The chlorideꢀcoordinated
complex 1 can be prepared in a simple oneꢀpot procedure,
following previous protocols where ligand and complex are
assembled in the same reaction from commercial starting
materials (Scheme 2).54 From undried methanol, 1 crystallized
as the waterꢀcoordinated, mononuclear complex (Scheme 2).53
Recrystallization of 1 in acetonitrile afforded the homoleptic
complex 2 (Figure 1, Table 1).
a Data taken from ref. 53
Despite τꢀvalues55 indicating a coordination geometry beꢀ
tween squareꢀpyramidal and trigonalꢀbipyramidal, coordinaꢀ
tion geometries around Cu are essentially squareꢀpyramidal
and contain one ligand in the apical position (water in 1, sulꢀ
fonate in 2 and 4) with a 0.2ꢀ0.3 Å longer Cuꢀligand distance.
Complex 2 is essentially isostructural to its analogue lacking
the paraꢀmethyl substituent.56 Copperꢀligand distances are
otherwise in the range observed in complexes with very simiꢀ
lar ligands (Cuꢀimino: 2.03(3) Å, Cuꢀpyridine: 2.00(2) Å, Cuꢀ
OSO2: 1.98(6) Å based on 13 entries in the CSD).53, 54, 56ꢀ60
N
NH2
CuCl2
MeCN
N
N
S
+
Cu
Cl
–
N
N
SO3
N
S
Cu
SO3H
O
O
OH2
O
N
O
O
1
excess Cu(OTf)2
Chan-Evans-Lam couplings: general reaction conditions.
Typical for CEL couplings is the requirement for a careful
optimization of reaction conditions. Variables are the solvent
(the choice of which depends strongly on the substrate and
reaction conditions), the requirement to eliminate water (presꢀ
ence of molecular sieves), the presence of a (Lewis) base
(typically NEt3, pyridine or other Nꢀbases), potential addiꢀ
tives/ligands and the counteranion (most often acetate or triꢀ
flate). We investigated if these factors would indeed be less
important for couplings with 1. Arylation of aniline with pheꢀ
nylboronic acid was chosen as the standard reaction. Reactions
O
O
2
2+
AgOTf
N
O
S
O
Cu
N
N
O
2 OTf–
O
N
N
Cu
OTf
Cu
N
S
O
O
O
S
3
O
O
4
Scheme 2. Preparation of 2ꢀ4
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ACS Catalysis
reported, however, that too high an excess of molecular sieves
were quenched after 5 h to provide an intermediate conversion
likewise reduces activities.48 In other cases, the presence of
water was tolerated27 or even led – in the correct amounts – to
improvements in reaction yields.24ꢀ26 Last but not least, several
CEL couplings were reported in water as a solvent.31, 35, 41, 49ꢀ51
It is notable that in all cases where water was found to be
beneficial or used as a solvent, coordination complexes or
supported catalysts were employed rather than simple copper
salts. In accordance with this, addition of molecular sieves
slightly reduced yields in CEL couplings with 1, while addiꢀ
tion of 20 equiv of water (15 vol% of the solution) was well
tolerated (Table 2, entries 6+7; Fig. S1).
1
2
3
4
5
6
7
8
which is sensitive to changes in conditions. Longer reaction
times lead to full conversion (vide infra).
Solvent. Solvent dependence in CEL couplings is normally
difficult to predict, since the solvent plays an activating role in
solubilizing the copper catalyst and a deactivating role in
saturating coordination sites required for substrate coordinaꢀ
tion. An empirical order of CH2Cl2 > 1,4ꢀdioxane, THF, DMF
> EtOAc, toluene > DMSO >> MeOH,15 or 1,4ꢀdioxane,
CH2Cl2 >> DMF > EtOAc > THF > toluene > DMSO10 has
been claimed, but deviations from these are the rule. A more
predictable dependence on solvent polarity was expected for 1,
since coordination complexes typically show less pronounced
solvent interactions than simple copper salts. In fact, there is
only a small dependence on the solvent in CEL couplings with
1 (Table 2, entries 1ꢀ5), with polar solvents working slightly
better than less polar solvents. Only the use of acetonitrile was
detrimental, most likely due to blocking of the copper coordiꢀ
nation site. It is also possible that – as in recrystallizations in
acetonitrile – 1 undergoes ligand exchange to the homoleptic
complex 2. The latter is not active in CEL couplings (Table
S1, entry 1).
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Base. The requirement and role of an organic or inorganic
base in CEL couplings is likewise unclear. While addition of
base often increases yields, other couplings proceed better
under baseꢀfree conditions. The base was speculated to be
involved in the formation and activation of boroxine species,
in the activation of the nucleophile by deprotonation, and in
the formation of copper hydroxide or alkoxide species, which
allow bridging to boron or acting as a ligand for the copper
catalyst. Addition of base to arylations with 1 strongly supꢀ
pressed the observed yields (Table 2, entries 8ꢀ12)). Investigaꢀ
tion of timeꢀdependent conversion showed that this was indeed
due to a reduction of the apparent rate constant to one half and
not due to decomposition or delayed activation (Fig. S2). In
the case of NEt3, reduced activity might be related to deacꢀ
tivating coordination of the base to copper, but the strongly
suppressed activity upon addition of NaOH or Na2CO3 indiꢀ
cates that for 1 replacement of chloride by hydroxide or methꢀ
oxide is also detrimental.
Table 2. Coupling of aniline and phenylboronic acid using 1
as a catalyst a
Entry Solvent
Modification a
ꢀ
ꢀ
ꢀ
ꢀ
Yield
0%
36%
41%
67%
Counteranion. The most commonly employed catalyst in
CEL couplings is Cu(OAc)2, or more precisely Cu2(OAc)4.15
1
MeCN
Toluene
CH2Cl2
THF
2
3
63
Cu(OTf)2 typically shows similar activities.62,
Cu(NO3)2, Cu(ClO4)2, or CuSO4 are less active,15,
CuCl2,
20, 33, 62ꢀ64
4
although Stahl showed that Cu(ClO4)2 can be activated by
addition of one equiv of acetate.52 The anion dependence has
be rationalized by formation of an acetateꢀbridged dinuclear
copperꢀboron complex as an intermediate prior to transmetalꢀ
lation (A, Scheme 1).49, 52 Despite these general findings, high
activities have been observed for copper salts other than aceꢀ
tate. For example, Collman’s tmeda/CuX catalyst showed
identical activities for OTf– and Cl–,49 and coupling of hinꢀ
dered imidazoles worked best with Cu(NO3)2.34 Based on the
rate increase upon addition of methoxide to Cu(OAc)2ꢀ
catalyzed reactions, Stahl proposed that a methoxideꢀbridged
5
6
7
8
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
ꢀ
86%
62%
90%
12%
0% (12 h)
0%
52%
Molecular sieves, 4A
+ 20 equiv water
2.5 mol% NEt3
1 equiv NEt3
2.5 mol% NaOH
2.5 mol% Na2CO3
1 equiv Na2CO3
3 instead of 1
N2 atmosphere
N2 atmosphere,
100 mol% 1
1 equiv PhB(OH)3
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13
14
15
23%
99%
0% (12 h) b
45% (12 h)
species is likewise
a
possible intermediate to
transmetallation.52 Watson later found HRMSꢀevidence for the
formation of acetateꢀbridged and hydroxideꢀbridged dinuclear
species, of which the hydroxideꢀbridged complex was calcuꢀ
lated to be of lower energy.36 The influence of the anion might
thus be negated if a hydroxideꢀcontaining species is formed in
the catalytic cycle, as it is the case for Collman’s tmeda/CuX
system.48, 49
16
MeOH
98% (12 h)
a
Conditions: room temperature, air, 320 min if not othꢀ
erwise noted, 1.5 equiv. PhB(OH)2, 1.0 M aniline, 2.5
mol% 1. Equivalents refer to concentrations relative to
amine. b 1% conversion would have been expected from the
stoichiometric reaction, but was likely not detected.
For CEL couplings with 1 or 3, we proposed that coordinaꢀ
tion of phenylboronic acid to the sulfonate group precedes
transmetallation (Scheme 1, C). We would thus expect that the
nature of the anion, which is crucial if the anion acts as a
bridging ligand, has only a minor impact on reactivity. CEL
couplings with the triflate complex 3 showed, however, notaꢀ
bly higher conversions than with the chloride complex 1 (99%
vs. 86%, Table 2, entry 13). A closer investigation of the reacꢀ
tion kinetics showed that the reduced activity of 1 was due to
delayed catalyst activation, while the actual reactivities were
Water. The influence of water in CEL couplings is complex,
contradictory and undefined. Early reports of Evans indicated
that the presence of water can be detrimental due to the forꢀ
mation of phenol and diphenyl ether byproducts from the
oxidative coupling of phenylboronic acid with water.5 Isotope
labeling studies by Lam confirmed that water and not oxygen
is the source of phenol byproducts.61 Water is believed to
originate from condensation of boronic acids to boroxines and
yields increased in the presence of molecular sieves or when
23
boroxines instead of boronic acids were used.5,
Collman
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very similar with apparent firstꢀorder rate constants of kapp
=
induction period (Fig. 3). Preactivation with phenylboronic
acid, on the other hand, reduced the induction period to one
0.40(2) h–1 and 0.50(1) h–1, respectively (Fig. 2).
1
half. Finally, stirring in the presence of 20 equiv of water
reduced it to <10 min, similar to that of the triflate complex 3.
It seems thus likely that water is required to solubilize the
complex 1 in methanol. The analogous complex lacking the
2
3
4
5
6
7
8
9
100
80
60
40
20
0
paraꢀmethyl group interconverts between
a methanolꢀ
insoluble, dinuclear, chlorideꢀbridged complex and a mononuꢀ
clear, waterꢀcoordinated complex in the absence or presence
of water.60 In the absence of external water, the latter might be
slowly taken up from atmosphere or – in the presence of pheꢀ
nylboronic acid ꢀ formed during the reaction or by boroxine
formation (although we did not observe boroxines when reacꢀ
tions were followed by NMR). To avoid complications by the
long induction time of 1, further reactivity studies were – if
not otherwise mentioned – conducted with 3 as the catalyst.
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0
100
200
time [min]
300
400
500
Oxidant. CEL couplings are oxidative couplings and the
presence of an oxidant is required in the reaction. In most
cases, either air or an oxygen atmosphere is sufficient, altꢀ
hough other oxidants have been used originally.65ꢀ67 For most
CEL couplings, the accepted mechanism is the one proposed
by Stahl, in which aryl Copper(II) is oxidized by another Copꢀ
per(II) complex to aryl copper(III) prior to reductive eliminaꢀ
tion.52, 68 The oxidant is required solely to reꢀoxidize the copꢀ
per(I) complexes formed. Tromp reported successful CEL
couplings of imidazoles in the absence of oxidants and found
evidence for the formation of boranes under anaerobic condiꢀ
tions.28, 69 To the best of our knowledge, this is the only report
of successful catalytic CEL couplings in the absence of oxyꢀ
gen or external oxidant.
Figure 2. Conversionꢀtime profiles for the arylation of aniline
with PhB(OH)2 in methanol ([PhNH2] = 1.0 M, [PhB(OH)2] = 1.5
M, [Cu] = 25 mM, RT, air). Black triangles: 3, average of 4 exꢀ
periments, kapp = 0.50(1) h–1. Red circles: 1, average of 4 experiꢀ
ments, kapp = 0.40(2) h–1. For the deviations at high conversion,
see discussion of reaction kinetics.
no pre-activation
catalyst stirred for 1.5 h
1.4
catalyst + aniline stirred for 1.5 h
catalyst + phenylboronic acid stirred for 1.5 h
catalyst + 20 equiv water stirred for 1.5 h
1.2
1
Nꢀarylation of aniline with 1 under exclusion of oxygen did
not lead to any observable formation of product. When the
copper complex was added in stoichiometric amounts, 45%
conversion to product was observed under exclusion of oxyꢀ
gen (Table 2, entries 14+15). CEL couplings with 1 thus reꢀ
quire two equivalents of 1 to complete a catalytic cycle and
oxygen for the regeneration of the catalyst, following the
mechanism proposed by Stahl in this aspect.52, 68
0.8
0.6
0.4
0.2
0
Substrate reactivity. Since CEL couplings with 3 tolerate
water, various solvents, do not require addition of base or
additional ligand and since the sulfonate group rather than the
anion participates in the transmetallation step, optimization of
reaction conditions was essentially limited to choosing the
reaction time and temperature. Satisfyingly, 3 was active in
the arylation of a variety of Nꢀnucleophiles, including anilines,
amines and Nꢀheterocycles. Reactions were conducted in
undried methanol at room temperature or at 50 °C. In heated
reactions, solvent vapor seemed to impede oxygen uptake
from the atmosphere when condensers were used. Simple
stirring of heated reactions open to air led to higher apparent
conversions, but calibrated GC/MSꢀanalysis showed in some
cases a mass imbalance between the product formed at full
conversion and the starting amine, most likely due to evaporaꢀ
tion of the latter. Reactions at 50 °C were thus stirred in closed
vessels under a supply of oxygen to ensure reproducible reacꢀ
tion conditions. Chart 1 reports the result of the reactivity
study with various Nꢀnucleophiles. To best characterize subꢀ
strate reactivity, conversions were obtained from calibrated
GC/MSꢀanalysis of the quenched reaction mixtures. We have
shown in a preliminary communication that pure compounds
can be isolated after column chromatography in yields of
>85%.53
0
50
100
150
200
time [min]
Figure 3. Semiꢀlogarithmic conversionꢀtime profiles for the arylaꢀ
tion of aniline with PhB(OH)2 under various preꢀactivation condiꢀ
tions ([PhNH2] = 1.0 M, [PhB(OH)2] = 1.5 M, [Cu] = 25 mM, RT,
air). The two datapoints per time indicate conversions calculated
from appearance of diphenylamine and disappearance of aniline,
respectively.
The significantly longer induction period observed for 1 (40
min) in comparison to triflateꢀcoordinated 3 (10 min) was
puzzling, since anionꢀexchange reactions in Cu(II), d9, comꢀ
plexes would be expected to be reasonably fast. Color changes
during the reaction seem to point towards solubility problems
as the main cause of the induction period: 3 is soluble in methꢀ
anol to provide a green solution, while 1 is not, or only barely
soluble. In CEL coupling reactions, the green color of the 1 or
3 in solution is never observed, however: the reaction mixture
turns orange after the induction period and this color persists
throughout the reaction. CEL couplings with 1 were thus inꢀ
vestigated under a variety of preꢀactivation conditions to clariꢀ
fy the origin of the induction period. Preactivation of the cataꢀ
lyst for 1.5 h with or without added aniline substrate before
addition of phenylboronic acid did not notably influence the
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ACS Catalysis
1
2
3
4
5
6
7
8
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23
Chart 1. Products of CEL couplings of Nꢀnucleophiles with phenylboronic acid catalyzed by 3.
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Notably, arylation proceeded well even for substrates typiꢀ
cally reported to be difficult to arylate, such as aminoꢀ
pyridines, picolylamine and tertꢀbutyl amine. Coupling of
acyclic secondary amines, which are considered one of the
biggest challenges in CꢀN bond formations via CEL coupling,
proceeded not only well, but with very high activity. Water
was tolerated well enough that methylamine could be added as
an aqueous solution. Reduced reactivity was observed for
some substrates, mainly due to secondary reactions which will
be discussed in the next sections.
highest activity being full conversion in 15 min at room temꢀ
perature.77 Due to the complete absence of side reactions, CEL
coupling with 3 is thus possible without using excess of pheꢀ
nylboronic acid. In the presence of a stoichiometric amount of
PhB(OH)2, 98% conversion of aniline to diphenylamine was
observed after 12 h at RT (Table 2, entry 16). For the followꢀ
ing mechanistic investigations, an excess of 1.5 equiv of boꢀ
ronic acid will continued to be used, however, to exclude any
influence of side reactions on amine conversions and to ensure
the reproducibility of these results.
Substrate-independent side reactions. Typical side reactions
in CEL couplings are deboration to yield benzene and oxidaꢀ
tion or coupling with water to yield phenols or diphenyl ethers
if the former undergo CEL coupling. Homocoupling of two
arylboronic acids to provide the respective diaryl is another
common side reaction. These parasitic reactions can be comꢀ
petitive with the coupling reaction and are the main reason
why CEL couplings typically require excess arylboronic acid
or do not reach completion. Neither of these products nor
coupling to the methanol solvent have been observed in CEL
couplings with 3. Reactions in MeOD followed by NMR
showed the excess amount of phenylboronic acid still present
after 12 h of reaction. Neither NMR, nor GC/MS analysis
provided any indication for the presence of other byproducts,
although traces (<5%) of the diaryl were observed in some
reactions (Scheme 3). Even in the absence of amine nucleoꢀ
phile, but under otherwise identical conditions (1.5 M
PhB(OH)2, 2.5 mol% 3, methanol, RT/air), the only product
formed was diphenyl and even this in less than 5% (Scheme
3). In presence of triethylamine, complete conversion of pheꢀ
nylboronic acid to diphenyl occurred in 1 h (Scheme 3), still
without evidence of any other byproducts. Targeted homocouꢀ
Scheme 3. Possible parasitic reactions in CEL couplings.
Substrate poisoning. Typically, more electronꢀrich anilines
react faster in CEL couplings.18, 51, 64, 78 It was thus surprising
that with 3 electronꢀpoor anilines reacted with very comparaꢀ
ble rate constants to aniline, while electronꢀrich anilines did
not react at room temperature, but required heating (Table 3).
We had previously observed catalyst poisoning by the subꢀ
strate in CEL couplings with related sulfonateꢀdiketimine
complexes (Scheme 1, B),26 and this provides a likely explanaꢀ
tion for the observed reactivities. Competition experiments
between aniline and bromoaniline with a limiting amount of
phenylboronic acid confirmed the expected higher reactivity
pling of arylboronic acids with copper catalysts has been reꢀ
70ꢀ77
ported previously with and without external base,31,
the
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Page 6 of 18
of the more electronꢀrich aniline (Table 3). In the presence of and 750 nm showed best agreement with the reaction of two
1
2
3
4
5
6
7
8
methoxyaniline, on the other hand, arylation of both substrates
was suppressed, indicating that electronꢀrich anilines, such as
methoxyaniline, deactivate the catalyst by formation of an
inactive anilineꢀcopper complex.
additional aniline to form 3(NH2Ph)3 with equilibrium conꢀ
stants of K1 ≈ 50 M–1 and K2 ≈ 10 M–2 (Fig. 4).
tert-Butyl aniline. A different reason was responsible for the
reduced conversion with tertꢀbutyl aniline. Reaction at room
temperature led to complete conversion of tertꢀbutyl aniline
after 12 h, but the obtained product was a 1:1 mixture of the
coupling product and 4,4’ꢀdiꢀtertꢀbutylazobenzene (Scheme
4). The oxidative coupling of anilines by copper to azobenꢀ
zenes is known since the ‘50s,11, 79 but has, to the best of our
knowledge, not been reported to interfere with CEL couplings.
The mechanism of azobenzene formation most likely proceeds
via an aniline radical, generated by oxidation of aniline either
directly by Cu(II) or by a peroxocopper complex formed upon
reaction of Cu(I) with oxygen.80 Reactions under different
conditions showed that oxygen as well as PhB(OH)2 were
required for azobenzene formation (Table 4) and a Cu(I)/O2
reaction product is thus most likely responsible for generating
the aniline radical. Consequently, azobenzene formation was
strongly reduced to 8% if couplings were performed in the
presence of tetramethylpiperidine to trap oxygen radicals
(Table 4). However, the presence of a nitrogen base also supꢀ
pressed CEL coupling and conversion to product was limited
to 25%. At 50 °C formation of azobenzene could be mostly
suppressed, even without tetramethylpiperidine, in favor of the
CEL coupling product (Scheme 4).
Table 3. Coupling of paraꢀsubstituted anilines and phenylꢀ
boronic acid with 3 a
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X
Conversion (12 h)
kapp
H
F
Br
100%
94%
100%
100%
0%
0.55(1)
0.49(7)
0.36(2)
OPh
OR b
H + OMe c 0%
H + Br c
71% (X=H), 29% (X=Br)
a
Conditions: room temperature, air, 320 min if not otherꢀ
wise noted, 1.5 equiv PhB(OH)2, 1.0 M aniline, 2.5 mol% 3.
Equivalents refer to concentrations relative to amine. b R = Me,
nBu, nHex, cyclohexyl. c 1.0 M aniline, 1.0 M pꢀXꢀaniline, 1.0
equiv PhB(OH)2, 2.5 mol% 3.
Formation of an aniline adduct 3·NH2Ph was confirmed by
UV/vis spectroscopy. Upon addition of aniline to a green
methanol solution of 3, a color change to orange is observed.
An isosbestic point persists up to an aniline concentration of
25 mM, indicating a simple aniline coordination to yield the
putative 3(NH2Ph) complex. Upon further addition of aniline
up to reaction concentrations of 1.0 M, new peaks appear
which were assigned to a higher 3(NH2Ph)n complex. Simultaꢀ
neous regression of the spectral changes at 347, 450, 540, 625,
Scheme 4. CEL coupling of tertꢀbutylaniline with PhB(OH)2
1.6
0 mM
1.4
5 mM
0 mM
10 mM
14 mM
19 mM
24 mM
29 mM
33 mM
38 mM
43 mM
0.4
0.3
0.2
0.1
0
25 mM
50 mM
70 mM
100 mM
140 mM
240 mM
330 mM
430 mM
520 mM
620 mM
710 mM
810 mM
900 mM
1 M
1.2
1
K1 ≈ 50 M−1
K2 ≈ 10 M−2
N
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
N
S
Cu
OTf
O
3
O
O
0.8
0.6
0.4
0.2
0
347 nm
450 nm
625 nm
750 nm
540 nm
300
350
400
450
λ [nm]
0
0.2
0.4
0.6
0.8
1
0
0.2
0.4
0.6
0.8
1
300
400
500
600
700
800
900
1000
c(Aniline) [M]
c(Aniline) [M]
λ (nm)
Figure 4. Left: UV/vis titration of 3 (58 µM) in MeOH with aniline. The inset shows the isosbestic point obtained until 25 mM aniline.
Middle: Absorption at different wavelengths vs aniline concentration. The lines indicate the results of the simultaneous nonꢀlinear regresꢀ
sion presuming reaction with 2 aniline in the second equilibrium. Right: Concentration of 3 and its aniline adducts at different aniline
concentrations, calculated from K1 = 50 M–1 and K2 = 10 M–2.
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1
ACS Catalysis
Table 4. Oxidation of tertꢀbutyl aniline catalyzed by 3 a
2
3
4
5
6
Yield
azobenzene b
66%
0%
0%
Temperature PhB(OH)2 Conditions
RT
1.5 equiv
1.5 equiv
0 equiv
Air
N2
RT
7
RT
O2
8
9
50 °C
50 °C
RT
0 equiv.
1.5 equiv
1.5 equiv
O2
0%
O2
10%
Scheme 6. CEL coupling of βꢀhydroxyamines with
Air c
8% c
PhB(OH)2
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a
Conditions: MeOH, [tBuC6H4NH2] = 1.0 M, 12 h, 2.5 mol%
b
Double arylation. Since 1 and 3 were active in CEL couꢀ
plings of amines and anilines under the same reaction condiꢀ
tions, the question of chemoselectivity arises, i. e. if the reacꢀ
tion is complicated by double arylation. In fact, methylamine
can be doubly arylated at prolonged reaction times and with
2.5 equiv PhB(OH)2 present (Scheme 7). The same product
was obtained by arylation of Nꢀmethylaniline (Chart 1). In the
presence of 1.5 equiv PhB(OH)2, selective and quantitative
monoarylation was observed after one hour. If the reaction is
continued over night, a 1:1 mixture of PhN(H)Me and
Ph2NMe was obtained. (Scheme 7). No double arylation was
observed in any other reaction. Diphenylamine or Nꢀ
octylaniline, when reacted independently, could not be further
arylated (Chart 1). Reactions of aniline or octylamine with 2.5
equiv of PhB(OH)2 consequently yielded selective conversion
to the monoarylation products, even at 50 °C and upon addiꢀ
tion of water to reproduce the reaction conditions with meꢀ
thylamine, where an aqueous solution of the amine was used
(Table S1, entries 2ꢀ9). CEL couplings with 3 are thus highly
selective for monoarylation.
3. Based on percentage of aniline which reacted to azobenzene.
Molar ratios of coupling product to azobenzene were 1:1 at RT
and 20:1 at 50 °C. c In the presence of 0.5 equiv tetramethylpiperꢀ
idine.
Benzylamine. Arylations of benzylamine likewise suffered
from oxidative side reactions, in this case the formation of Nꢀ
benzylidene benzylamine in an equimolar amount with the
desired coupling product (Scheme 5). The side product is most
likely the consequence of amine oxidation to the imine, folꢀ
lowed by hydrolysis and condensation with benzylamine. The
rateꢀdetermining step in aerobic copperꢀcatalyzed amine oxiꢀ
dations is considered to be the abstraction of an αꢀH atom to
form an amine radical.11 The latter might explain while this
side reaction was only observed for benzyl amine. Amine
oxidation was avoided at 50 °C and only coupling product was
observed.
Scheme 5. CEL coupling of benzylaniline with PhB(OH)2
Ammonia. While an aqueous solution of methylamine reactꢀ
ed fast, aqueous solutions of ammonia were unreactive. From
the unusual blue color of the reaction mixture and the fact that
Scheme 7. CEL coupling of methylamine with PhB(OH)2
no
diphenyl
was produced, catalyst decomposiꢀ
Mechanism of CEL couplings with 1 and 3. The kinetics of
CEL couplings with 3 were investigated for the Nꢀarylation of
aniline. Calibration of the GCꢀMS detector response and the
use of internal standard allowed the determination of absolute
quantities of unreacted aniline and the diphenylamine product.
Both methods provided essentially identical conversion valꢀ
ues, indicating that no aniline was lost in secondary reactions
or due to evaporation (Fig. 5). After a short induction period
of approx. 10 min, the reaction followed pseudoꢀfirst order
kinetics. Conversions above approx. 80% were consistently
higher than expected on the basis of a pseudoꢀfirstꢀorder rate
law (Fig. 5, solid line). Kinetics with 1 showed the same beꢀ
havior (Fig. S3). A possible explanation for this deviation is
formation of an inactive, anilineꢀcoordinated complex as disꢀ
cussed above. In the concentration profiles calculated from the
equilibrium constants determined in UV/visꢀtitrations of 3
with aniline, the concentration of the active LCuX species
sharply increases at aniline concentrations below 0.2 M (Fig.
4), in good agreement with the observed increase in activity
above 80% conversion (Fig. 5). If catalyst poisoning by subꢀ
strate is taken into account, agreement with the observed conꢀ
tion/deactivation is most likely responsible for this lack of
reactivity.
Aminophenols and aminopyridines. CEL coupling of amines
able of chelating coordination was reported to be difficult.22
Using 3, 4ꢀpyridyl amine, 4ꢀhydroxyaniline and 2ꢀ
picolylamine were coupled readily at 50 °C, although
picolylamine was the only alkyl amine substrate which reꢀ
quired heating. 2ꢀPyridylamine reacted sluggishly and not to
completion. 2ꢀHydroxyaniline and ethanolamine could no be
coupled. In both of the latter cases, analysis of the reaction
mixture showed the presence of arylated (5a, 6a) and nonꢀ
arylated boronic esters (5b, 6b, Scheme 6). In the presence of
3 equiv of PhB(OH)3, reactions with ethanolamine provided
only the arylated boronic ester 6a as the single observed prodꢀ
uct. Ester formation thus leads to deactivation of phenylꢀ
boronic acid, rather than of the amine. Reactions with 2ꢀ
hydroxyaniline, however, did not proceed to full arylation
even under excess of phenylboronic acid.
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ACS Catalysis
versions improved notably (Fig. 5, dashed line). It should be
Page 8 of 18
100
80
60
40
20
0
noted that the value for K1 = 1 Mꢀ1 obtained in nonꢀlinear
regression of the kinetic data was one magnitude lower than
the value determined via UV/vis spectroscopy. If the coordinaꢀ
tion of two further aniline to yield [LCu(NH2Ph)3]X (K2) is
included in the fitting of the kinetic data, the value for K2
refined to nearly zero. Inclusion of inhibition by substrate thus
agrees with the kinetic data, but quantitative values differ
significantly from those determined independently. This is not
surprising, given that we neglected the presence of any other
Lewis acids and bases in the reaction mixture.
1
2
3
4
5
6
7
8
1
0
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59
60
0
60
120
time [min]
180
240
300
100
80
0
120
240
360
480
600
time [min]
Figure 6. Conversion vs time profile for the Nꢀarylation of aniline
under different reactant concentrations (MeOH, RT, 1.0 M aniꢀ
line) Squares, 1.5 M PhB(OH)2, 2.5 mol% 3, average of 4 experꢀ
iments; red circles, 3.0 M PhB(OH)2, 2.5 mol% 3, 2 experiments;
brown, hollow circles: 1.0 M PhB(OH)2, 2.5 mol% 3; diamonds,
1.5 M PhB(OH)2, 5.0 mol% 3; triangles, 1.5 M PhB(OH)2, 1.0
mol% 3, 2 experiments. The inset shows the linearized ln (c0/c)
plot.
60
4
3
40
2
1
20
0
0
100
200
300
time [min]
0
0
100
200
300
400
500
time [min]
Table 5. Apparent FirstꢀOrder Rate Constants for the Nꢀ
Arylation of Aniline with 3. a
Figure 5. Conversion vs time profile for the Nꢀarylation of aniꢀ
line. Four independent reactions under identical conditions are
shown (MeOH, RT, 1.0 M aniline, 1.5 equiv PhB(OH)2, 2.5
mol% 3). Filled symbols: conversion determined from remaining
aniline. Hollow symbols: conversion determined from diphenyl
amine product. The solid, black line is calculated from the pseuꢀ
doꢀfirstꢀorder rate constant kapp = 0.50(1) hꢀ1, determined from all
datapoints in the range of 30ꢀ140 min. The blue, dashed line is the
bestꢀfit conversion trace with a pseudoꢀfirstꢀorder rate constant
kapp = 0.82 hꢀ1 and an equilibrium constant of K1 = 1 Mꢀ1 for the
coordination of aniline to 3. The inset shows the linearized ln
(c0/c) plot.
Catalyst
[Catalyst] [PhB(OH)2] kapp
0.025 M
0.025 M
0.025 M
0.010 M
0.050 M
0.025 M
0.025 M
1.0 M
1.5 M
3.0 M
1.5 M
1.5 M
1.5 M
1.5 M
0.46(2) h–1
0.50(2) h–1 b
0.65(1) h–1 c
0.28(1) h–1 c
0.73(2) h–1
0.40(2) h–1
0.15(1) h–1
3
3
3
3
3
1
The pseudoꢀfirstꢀorder rate constant was essentially indeꢀ
pendent from phenylboronic acid concentration. Tripling the
phenylboronic acid concentration from 1.0 to 3.0 equiv led
only to a small increase in the pseudoꢀfirstꢀorder rate constant
of approx. 40% (Fig. 6, Table 5). Stahl had observed for the
arylation of methanol that the reaction displayed saturation
kinetics in boronic acid concentration.52 The small increase of
kapp indicates a similar situation here, i. e. that transmetallation
is not the rateꢀdetermining step.
1/[NEt4]Cl
a
Conditions: 1.0 M Aniline, 1.5 M PhB(OH)2, 2.5 mol% cataꢀ
b
lyst, MeOH, RT, air. Rate constant determined from datapoints
of product appearance and aniline disappearance in 4 independent
c
experiments. Rate constant determined from datapoints of 2
independent experiments.
Arylation of aniline at 1.0 or 5.0 mol% of catalyst loading
followed similar kinetics (Fig. 6, Table 5). The apparent rate
constants and the initial rates of the reaction indicate a halfꢀ
order dependence on catalyst concentration (Fig. S4). A halfꢀ
order dependence is typically associated with associaꢀ
tion/dissociation equilibria and 3 shows indeed bridging sulꢀ
fonate coordination in the solid state. However, in the presꢀ
ence of water 1 forms solvated, mononuclear complexes in the
solid state and both complexes show very similar UV/vis
spectra (Fig. S5 and S6).53 It is thus unlikely that 3 would be
present as a sulfonateꢀbridged dimer in undried methanol
solution. An alternative explication for a halfꢀorder dependꢀ
ence on catalyst concentration would be formation of an acꢀ
tive, cationic species by dissociation of the anion (Scheme 8).
In the presence of such an equilibrium, the concentration of
8
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ACS Catalysis
the active, cationic species would be dependent on anion conꢀ
perfluoroaryl complex81 and Tilley’s mixedꢀvalence µꢀaryl
complex,82 the few isolated organoCopper(II) aryl complexes
stabilize the aryl group as part of a rigid macrocyclic ligand.83ꢀ
1
2
3
4
5
6
7
8
centration. Indeed, addition of an equimolar amount of
[NEt4]Cl to CEL couplings with 1 reduced the apparent rate
constant to half its value (Table 5, Fig. S7). A similar anion
dissociation equilibrium has been proposed by Stahl for the
arylation of methanol with Cu(OAc)2, where halfꢀorder deꢀ
pendence on catalyst concentration and deactivation by addiꢀ
tional anion has likewise been observed.52
90
Accumulation of the catalyst in the Cu(II) aryl species C
would lead to extensive aryl homocoupling. The unstabilized
Cu(III) aryl species D, on the other hand, will undergo rapid
reductive elimination.91 In the absence of amine this would
lead to arylation and thus destruction of the catalyst or to
arylation of solvent, both of which is not observed. D is thus
likewise an improbable catalyst resting state.
9
Alternatively, saturation of a preꢀequilibrium would lead to
zeroꢀorderꢀdependence on phenylboronic acid concentration.
In this case, the catalyst resting state would be the dinuclear
copperꢀboron complex B and transmetallation can remain the
rateꢀdetermining transition state. Dinuclear copperꢀboron
complexes have been proposed as intermediates in couplings
with Cu(OAc)2 by Collman and Stahl.49, 52 Stahl found EPRꢀ
evidence for the formation of an adduct between phenylꢀ
boronic acid and copper acetate, which he proposed as the
catalyst resting state. Watson later found massꢀspectroscopic
evidence for the presence of bridged species in the catalytic
cycle.36 However, UV/vis titrations of solutions containing 3
with phenylboronic acid up to a concentration of 1.1 M, did
not show notable changes of the absorption spectrum (Fig. 7).
While this does not disprove the formation of a dinculear
3·boronic acid adduct (Scheme 9, B) in small equilibrium
amounts, there is no indication that the latter can be the major
catalyst species present in the reaction mixture.
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58
59
60
Scheme 8. Anion dissociation equilibrium for 3
CEL couplings with copper iminosulfonates thus follow the
mechanism proposed by Stahl (Scheme 9):52 Formation of the
active catalyst requires displacement of the anion, most likely
by solvent. Transmetallation occurs from a dinuclear CuꢀBꢀ
complex B to form the copperꢀaryl complex C. Oxidation by
another complex A to the Cu(III) complex D is followed (or
preceded) by coordination of the amine substrate, which then
leads to product formation by reductive elimination. The cataꢀ
lytic cycle is closed by reꢀoxidation of the Cu(I) complexes E
by oxygen. Modifications consists in our proposal that the
sulfonate group and not hydroxide or the anion is bridging to
boron in B (in agreement with the observations above) and the
existence of the offꢀcycle, anilineꢀcoordinated complex F,
which was indicated by UV/vis and kinetic data. Substrate
inhibition, i. e. F being offꢀcycle, also supports that
transmetallation precedes interaction with the nucleophile in
the catalytic cycle. If transmetallation would occur after aniꢀ
line coordination, there is no reason why complex F should be
unfavorable. (The alternative scenario, that aniline coordinates
before transmetallation and that the offꢀcycle intermediate F
contains more than one aniline cannot be excluded, but agrees
less with the kinetic data.)
0 mM
7.5 mM
38 mM
50
75 mM
112 mM
150 mM
40
225 mM
340 mM
490 mM
675 mM
1.1 M
30
20
10
0
550
600
650
700
750
800
850
900
950
1000
λ [nm]
λ [nm]
Figure 7. UV/vis spectra of 3 in methanol upon addition of pheꢀ
nylboronic acid. The slight increase in ε is due to phenylboronic
acid.
In the absence of a plausible mechanism which would acꢀ
commodate a fast transmetallation step, we considered possiꢀ
bilities which would provide an apparent zeroꢀorder dependꢀ
ence on the phenylboronic acid concentration despite slow
transmetallation. Dependence on aniline concentration can be
firstꢀorder, even if interaction with the aniline takes place after
transmetallation as long as the latter is reversible. This is not
unlikely, if transmetallation occurs in a dinuclear intermediate
such as B. Should transmetallation remain the highest activaꢀ
tion barrier, the rate law is expected to be:
Scheme 9. First proposal of catalytic cycle for CEL couplings
with 3
The proposed mechanism is, however, inconsistent with the
observed rateꢀlaw. The (nearꢀ) independence of the reaction
rate from phenylboronic acid concentration and its firstꢀorder
dependence on aniline concentration indicate that the catalyst
resting state is located after transmetallation, but before reacꢀ
tion with the aniline. Neither C nor D are stable species, howꢀ
ever. With the exception of Warren’s isolation of a Cu(II)ꢀ
ꢄ.ꢅ
ꢂ
ꢃꢂ
ꢃ
ꢀ = ꢁ PhB(OH)2 PhNH2 ꢂLCuXꢃ
(equation 1)
9
ACS Paragon Plus Environment

ACS Catalysis
To explain the apparent independence of the rate law from
phenylboronic acid concentration, we propose that aniline is
involved in a Lewis acidꢀLewis base adduct equilibrium with
phenylboronic acid, similar to aniline coordination to 3.
Page 10 of 18
0.8
0.6
0.4
0.2
0
1
2
3
4
5
6
7
8
HO OH
HO
OH
NH2
B
B
KAB
H2N
3 eq, 2.5 mol%
1.5 eq, 2.5 mol%
1.5 eq, 5 mol%
1.5 equiv, 1 mol%
+
9
10
11
12
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43
44
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48
49
50
51
52
53
54
55
56
57
58
59
60
Incorporation of this equilibrium in rate law (1), provides,
1.0 equiv, 2.5 mol%
ꢆꢂ
ꢃꢂ
ꢃꢄ.ꢅ
0
100
200
Time [min]
300
ꢁꢂPhNH2ꢃ PhB(OH)2 LCuX
1 + ꢂPhB(OH)2ꢃꢇꢈꢉ
(equation 2)
ꢀ =
Figure 9. Conversion vs time profiles for the Nꢀarylation of aniꢀ
line under different reactant concentrations (MeOH, RT, 1.0 M
where [PhNH2]t is the total concentration of unreacted aniline
aniline). Solid lines are the simulated conversions based on
ꢄ.ꢅ
ꢂ
ꢃꢂ
ꢃ
ꢀ = ꢁ PhB(OH)2 PhNH2 ꢂLCuXꢃ
under consideration of
ꢂ
ꢃ
(see supp. information). For PhB(OH)2 ꢇꢈꢉ ≫ 1, the rate law
aniline coordination to phenylboronic acid. KAB and k refined to
bestꢀfit values of k = 0.4 M–1.5min–1 and KAB = 5 M–1 (see supp.
information).
becomes independent from [PhB(OH)2].
The existence of anilineꢀphenylboronic acid adducts was
investigated by NMR spectroscopy in MeOD. An equimolar
solution of phenylboronic acid and aniline showed signals
displaced from the positions of the pure compounds, indicative
of interaction of the two species in solution. A reliable deterꢀ
mination of the equilibrium constant was not possible, howevꢀ
er, since saturation of the equilibrium was barely occurring
even at a 12 M concentration of one compound. At these high
concentrations it is not possible to distinguish between the
effect of the coordination equilibrium or changes due to the
solvent composition. Nevertheless, from the concentrationꢀ
dependent shifts between 1 M and 12 M concentration, a value
of KAB ≈ 1 M–1 was estimated (Fig. 8).
The observed reaction kinetics are well reproduced using
rate law (1) and equilibrium KAB (Fig. 9). Due to the overparꢀ
ametrization of the problem, anilineꢀcoordination to 3 (equiꢀ
libria K1 and K2) were ignored and only datapoints below 80%
conversion were employed in the kinetic fit (c.f. Fig. 5). Free
refinement of both parameters provided k = 0.4 M–1.5min–1 and
KAB = 5 M–1, in reasonable agreement with the value of KAB
=
1 M–1 estimated from NMR investigations of the equilibrium
(c. f. Fig. 8). Since the apparent rate law is nearly independent
from phenylboronic acid concentration, KAB and k are strongly
correlated and nearly identical fits can be obtained in the range
of KAB = 1 – 10 M–1 (supp. information). Since the kinetic
model also ignores the formation of B(OH)3 and Ph2NH (or
assumes that their formation cancels each other out), values
obtained from the kinetic fit should only be considered appar-
ent equilibrium or kinetic values of a strongly simplified modꢀ
el. More important than quantitative values, the good agreeꢀ
ment with the kinetic data in Fig. 9 shows that apparent saturaꢀ
tion behavior in phenylboronic acid concentration is well
explained by formation of an anilineꢀphenylboronic acid adꢀ
duct and does not need to involve fast transmetallation or
saturation of a preꢀequilibrium.
7.1
7.34
7.32
7.08
7.3
7.28
7.06
6.72
7.26
7.38
7.36
6.7
7.34
7.32
6.68
4.88
7.3
4.84
4.8
7.76
7.68
7.6
Based on the above, we now propose the following adapted
mechanism for CEL couplings with 3 (Scheme 10): the reꢀ
versible transmetallation from the dinuclear complex B is rateꢀ
determining and yields the Cu(II)ꢀaryl complex C. Warren
recently reported a Cu(II)ꢀperfluorophenyl complex, which
undergoes oxidation to Cu(III) and reductive elimination when
reacted with a nucleophile.81 It seems thus more likely that
coordination of the amine (D) occurs before oxidation. Amine
coordination is in competition with the backꢀreaction of the
transmetallation CꢀB. Product formation thus depends on
both steps and is dependent on amine concentration, even if
reaction with amine occurs after the rateꢀdetermining step. If
phenylboronic acid is present in excess, any enhancement in
the transmetallation reaction by increased boronic acid conꢀ
centration is counterbalanced by a reduction in the concentraꢀ
tion in free amine due to the Lewis acidꢀLewis base complex
formed. Due to its aryl substituent and the coordinated amine,
complex D is significantly more electronꢀrich and can be
4.76
4.72
7.52
0
3
6
9
c(boronic acid) [M]
12
0
3
6
c(aniline) [M]
9
12
Figure 8. Displacement of chemical shifts in the NMR spectra of
aniline upon addition of phenylboronic acid (left) or of phenylꢀ
boronic acid upon addition of aniline (right). The solid line repreꢀ
sents the theoretical displacement assuming an equilibrium conꢀ
stant of KAB ≈ 1 M–1.
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ACS Catalysis
ent aryl from deboration side reactions. More important, howꢀ
oxidized by the original Copper(II) species A to form the
1
2
3
4
5
6
7
8
copper(III) complex E.
ever, was the notable amount of homocoupling. While homoꢀ
coupling normally is only observed in trace amounts, the
diaryl was the main product in these reactions.
If transmetallation is slow, either Cu(II) complex A, amineꢀ
adduct G, or the Cu(I) complexes F might be catalyst resting
states. We did not observe any accumulation of Cu(I) species
when the reaction was followed by NMR, but they might be
obscured by remaining paramagnetic Cu(II). The color of the
reaction mixture, however argues in favor of species G as the
resting state: a methanol solution of 3, i. e. species A, is green.
Under reaction conditions, the green catalyst powder dissolves
to provide an orange solution, which is reminiscent of the
color of the amine adduct observed in UV/vis titrations with
aniline. For Cu(I) species, we would expect them to be reꢀ
oxidized at the end of the reaction, but the orange color reꢀ
mains stable for hours after the reaction reached completeness.
While G is thus the most likely resting state (probably as an
adduct with the product at the end of the reaction), we could
not obtain any evidence for such as species in HRMS spectra
of the reaction mixture.
The formation of diaryl species indicated that transmetallaꢀ
tion is unlikely to be the problematic step. The lack of reacꢀ
tivity with electronꢀdeficient boronic acid reagents probably
stems from a slower oxidation to the Cu(III) species E
(Scheme 10) Since the Copper(II) aryl species C or D would
be more difficult to oxidize with more electronꢀdeficient aryl
substituents, CꢀC homocoupling from C now becomes comꢀ
petitive.11 Oxidation to E would be facilitated by more nucleꢀ
ophilic amines. Reaction with nꢀoctylamine indeed provided
the coupling product in modest yields (Table 6). Similarly, we
attempted to increase the nucleophilicity of aniline by addition
of triethylamine, but without effect. This is consistent with the
mechanistic proposal that deprotonation occurs after oxidation
(Scheme 10). Addition of boric acid was proposed by Watson
to be beneficial, in particular in the reoxidation of Cu(I) speꢀ
cies.36 Reaction conditions following Watson’s protocol, i. e. 1
equiv B(OH)3 and excess amine, which were beneficial for
Cu(OAc)2, strongly reduced conversions in couplings with
catalytic amounts of 3 (Table S1, entries 10ꢀ13). Addition of
substoichiometric amounts of boronic acid, however, inꢀ
creased the yield of couplings with paraꢀfluorophenylboronic
acid, but did not exceed 50% conversion (Table 6).
9
10
11
12
13
14
15
16
17
18
19
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
Photoredox catalysis. Lightꢀinduced electronic transitions,
in particular chargeꢀtransfer transitions, can be considered
intramolecular redox reactions and in recent years photocataꢀ
lytic reactions have proved very useful in promoting otherwise
difficult redox chemistry.93, 94 We thus investigated if irradiaꢀ
tion by light would facilitate the oxidation to Cu(III) species
E. CEL couplings of aniline with paraꢀfluorophenylboronic
acid were conducted under irradiation with white, green (525
nm) or blue (452 nm) light (Table 7). While irradiation with
white or green light was not effective, irradiation with blue
light afforded the coupled product in moderate yields. Heating
to 35 °C or 50 °C did not notably improve conversions.
Scheme 10. Final catalytic cycle for CEL couplings with 3
C-O and C-S couplings. The absence of coupling to methaꢀ
nol solvent and the tolerance of water already indicated that 1
and 3 are not highly reactive towards Oꢀnucleophiles. Atꢀ
tempts of CEL couplings to phenol either in dichloromethane
or methanol required the addition of base, either because this
role is fulfilled by substrate in CEL couplings of amines and
anilines, or because deprotonation is required to increase the
nucleophilicity of phenol. However, even under these condiꢀ
tions reactions with phenols were sluggish at best and thiols
did not react at all. This chemoselectivity of 3 was also indiꢀ
cated by the selective arylation of aminophenols (vide supra).
While 3 outperforms near all catalyst systems in the coupling
of Nꢀnucleophiles, even simple copper salts show better reacꢀ
tivity towards weaker nucleophiles such as phenols. Hydroxyꢀ
and thiol substituents should thus be considered tolerated
functional groups rather than potential reaction sites, and we
did not further attempt to optimize reaction conditions for CꢀO
or CꢀS couplings.
Table 6. CEL couplings of aniline with electronꢀdeficient
phenylboronic acids catalyzed by 3. a
X
OEt
NO2 PhNH2
RNH2
PhNH2
Conditions a
RT, air
RT, air
conversion
100%
0%
I
I
PhNH2
PhNH2
RT, air or O2
50 °C, O2
0%
0%
I
nOctNH2 RT, air
30%
4%
10%
0%
0%
33%
47%
F
F
I
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
RT, O2
50 °C, O2
RT, air, 10 mol% NEt3
RT, air, 10 mol% NEt3
RT, air, 2.5 mol% B(OH)3
RT, air, 10 mol% B(OH)3
Electron-deficient boronic acid reagents. CEL couplings of
aniline with paraꢀethoxyphenylboronic acid, catalyzed by 3,
proceeded smoothly with an activity 4 times higher than that
observed with phenylboronic acid (Fig. S8). Electronꢀdeficient
I
F
F
F
boronic acids, on the other hand, are typically more difficult to
92
couple.52,
Indeed, couplings with paraꢀiodophenylboronic
50 °C, O2, 10 mol% B(OH)3 50%
acid did not yield any coupling product after 12 h at room
temperature or at 50 °C. Paraꢀfluorophenylboronic acid reactꢀ
ed likewise very sluggishly with less than 10% conversion
(Table 6). For the first time, we noticed formation of the parꢀ
a 1.0 M RNH2, 1.5 M ArB(OH)2, 2.5 mol% 3, MeOH, 12 h.
Table 7. Coupling of aniline or RR’NH and paraꢀ
fluorophenylboronic acid with 3 under photoredox conditions
11
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ACS Catalysis
Page 12 of 18
plete conversion to the coupling product under photocatalytic
1
2
3
4
5
6
7
8
conditions, while methoxyaniline and imidazole, which reꢀ
quired heating in the reaction with phenylboronic acid, did not
show any reactivity with paraꢀfluorophenylboronic acid, even
under heating and irradiation (Table 7). Paraꢀ
nitrophenylboronic acid remained unreactive. While photoreꢀ
dox catalysis thus improved conversions and further supported
that oxidation to Cu(III) became the reaction’s bottleneck, it
did not provide a generally applicable solution for electronꢀ
deficient phenylboronic acids.
Light
source
ꢀ
white
green
blue
blue
blue
blue
ꢀ
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
T, time
Conditions a
conversion
20 °C, 12 h
20 °C, 12 h
20 °C, 12 h
20 °C, 12 h
35 °C, 12 h
50 °C, 8 h
50 °C, 8 h
35 °C, 12 h 1 mol% PC1
35 °C, 12 h 1 mol% PC1
35 °C, 12 h 1 mol% PC1, O2
35 °C, 12 h 1 mol% PC2
50 °C, 12 h 1 mol% PC1
no reaction
no reaction
no reaction
50%
69%
50%
54%
no reaction
59%
50%
50%
9
Chemical oxidation. Addition of stoichiometric amounts of
external oxidants, such as 4ꢀphenylpyridineꢀoxide (PPO),65ꢀ67
tBu2O2, or TEMPO,65, 66 did not lead to product formation in
the coupling of paraꢀfluorophenylboronic acid with aniline.
Curiously, in the presence of oxidants the main product was
the deborated product instead of the diaryl. When the same
oxidants were used in CEL couplings with phenylboronic acid,
these reactions did not improve either (Table S1, entries 14ꢀ
17). In the case of PPO, coupling was in fact suppressed. In
agreement with Stahl’s mechanistic proposal, an external
oxidant thus does not participate directly in the Cu(II)/Cu(III)
oxidation and is only required to reꢀoxidize the Cu(I) species
formed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O2
59%
54%
60%
50%
20 °C, 8 h
20 °C, 8 h
50 °C, 8 h
2.5 mol% B(OH)3
10 mol% B(OH)3
2.5 mol% B(OH)3
50 °C, 12 h 2.5 mol% B(OH)3, O2 100%
20 °C, 12 h RR’NH = nHexNH2
20 °C, 12 h RR’NH = nOctNH2
20 °C, 12 h RR’NH = (nBu)2NH
20 °C, 8 h
50 °C, 12 h RR’NH = Imidazole,
2.5 mol% B(OH)3
100%
100%
no reaction
no reaction
no reaction
We thus attempted to encourage the formation of the Cu(III)
with a catalytic amount of a copper-based oxidant. Cyclic
voltammograms of Cu(OAc)2 and 3 are difficult to interpret
due to the irreversibility of the Cu(II)/Cu(III) oxidation step
and complications due to copper deposition on the cathode
with Cu(OAc)2, but they qualitatively provide that coordinaꢀ
tion of the iminoꢀarylsulfonate ligand lowers the reduction
potential for oxidation and reduction steps in 3 (Fig. S9). We
thus conducted couplings with 3 in the presence of 2.5 mol%
of Cu(OAc)2 as oxidation aid. Under these conditions aniline
as well as octylamine could be coupled quantitatively with
paraꢀfluorophenylboronic acid at room temperature. In fact,
the reaction was complete in 3 h. Surprisingly, Cu(OAc)2 itself
is reactive under these conditions, but unlikely to be the active
species in the 3/Cu(OAc)2 system: its activity in the coupling
of aniline with paraꢀfluorophenylboronic acid was only half of
that of 3/Cu(OAc)2 (Table 8). In addition, couplings with
Cu(OAc)2 alone showed induction periods of 30 – 110 min
(Fig. 10), while the 3/Cu(OAc)2 system showed the same 10
min induction period observed in couplings with 3 alone.
These differences were even more pronounced in coupling of
aniline with phenylboronic acid: while 3/Cu(OAc)2 coupled
aniline and phenylboronic acid with a rate constant similar to
that of 3 alone (Tables 5, 8) and with short induction periods,
couplings with Cu(OAc)2 were an order of magnitude slower,
induction periods were above 1 h and the reaction was incomꢀ
plete even after 12 h (Table 8, Fig. 10). Despite the surprisingꢀ
ly high activity of Cu(OAc)2 in couplings with fluorophenylꢀ
boronic acid, the active catalyst is thus 3. Copper acetate acts
as an oxidation aid in reactions with electronꢀdeficient arylꢀ
boronic acids, while it does barely increase rate constants for
phenylboronic acid.
RR’NH = Imidazole
blue
50 °C, 12 h O2NC6H4B(OH)2,
no reaction
2.5 mol% B(OH)3
a 1.0 M aniline or RR’NH, 1.5 M ArB(OH)2, 2.5 mol% 3.
The UV/vis spectrum of 3 shows a chargeꢀtransfer transition
centered at 337 nm and a d-d transition at 730 nm (Fig. S5 and
S6). If the methyl group in the paraꢀposition of the arylꢀ
sulfonate in 1 or 3 is replaced by hydrogen, the chargeꢀtransfer
transition is displaced slightly (approx. 10 nm) hypsochromic.
This would agree with an assignment as a ligandꢀtoꢀmetal
chargeꢀtransfer transition. For photoredox catalysis, 3 seem to
require irradiation of the LMCT band. Since an LMCT transiꢀ
tion increases the electron density at the metal center in the
excited state, it is unlikely that excitation directly enables
reductive elimination from the excited state. Irradiation thus
seems to facilitate the oxidation of D by A, but from the availꢀ
able data it is impossible to judge whether this occurs through
oxidative quenching of an excited copper aryl species D or by
reductive quenching of a photoexcited oxidant A (Scheme 10).
Kobayashi reported photoredox catalysis of CEL couplings
using the typical Cu(OAc)2 catalyst and an Iridium photocataꢀ
lyst,95 to the best of our knowledge the only other report of
photocatalytic CEL coupling. We briefly investigated if elecꢀ
tron transfer from dedicated photocatalysts is more efficient
than direct excitation of 3, but addition of 1 mol% of either
[Ir(ppy)2(bipy)][PF6], PC1, or [Ru(bipy)3][PF6]2 , PC2 (see
exp. section), did not show any remarkable improvement
(Table 7). It has to be noted that the performance of Kobaꢀ
yashi’s PC1/Cu(OAc)2 system showed a strong solvent deꢀ
pendence, which we did not optimize. The results presented
here should thus not be considered a limitation of the reported
PC1/Cu(OAc)2 system.
Table 8. CEL couplings of aniline with electronꢀdeficient
phenylboronic acids catalyzed by 3/Cu(OAc)2. a
Addition of boric acid again improved reaction yields and at
50 °C and in the presence of 2.5 mol% B(OH)3, we observed
quantitative CEL coupling between aniline and fluorophenylꢀ
boronic acid. The scope of the photocatalytic reaction was
investigated briefly. Substrate reactivity is similar to catalysis
without irradiation: hexylamine and octylamine showed comꢀ
X
RNH2
Conditions a
kobs [h–1] conversion
F
nOctNH2
RT
100% (2 h)
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ACS Catalysis
I
F
I
H
F
nOctNH2
aniline
aniline
aniline
RT
RT
RT
RT
100% (2 h)
On the down side, the limited access to the metal center and
its reduced Lewis acidity, which are the likely reason for the
lack of typical side reactions, also limited reactivity towards
weaker nucleophiles such as phenols or thiols.96 While we
believe that wellꢀdefined coordination complexes can also
provide better performance for other substrate classes, these
would require a different ligand framework than used in this
work.
1.10(8)
0.43(3)
100%
97%
100%
0%
1
2
3
4
5
6
7
8
imidazole 50°C, O2
NO2 nOctNH2
RT
0%
0.60(1),
0.64(1)
F
aniline
aniline
Cu(OAc)2 only
95%, 99% b
62%, 66% b
Mechanistic studies with 1 and 3 largely confirmed the genꢀ
eral reaction mechanism established by Collman, Stahl and
Watson for CEL couplings.36, 48, 49, 52, 68 In addition to this, we
propose that formation of nucleophileꢀboronic acid adducts
might be responsible for saturation behavior in boronic acid
concentrations. Dinuclear copperꢀboron species are likely
present only in small concentrations, even if required as inꢀ
termediates to transmetallation. Based on our observations
herein, the series of steps in the catalytic cycle is likely to be
transmetallation – nucleophile coordination – oxidation –
reductive elimination for CEL couplings with 1 and 3.
Collman proposed nucleophile coordination prior to
transmetallation for [(tmeda)Cu(OH)]2Cl2,48, 49 and it is possiꢀ
ble that the order of these two steps differ dependent on the
Lewis acidity and the steric saturation of the copper complex
employed. While deprotonation is required for product forꢀ
mation even with good nucleophiles such as amines (in no
case we observed quaternisation of tertiary amines or pyriꢀ
dines), its actual position in the catalytic cycle remains unclear
and might depend on the nucleophile employed.
H
Cu(OAc)2 only 0.06(1)
a
b
9
1.0 M RNH2, 1.5 M ArB(OH)2, 2.5 mol% 3, MeOH, 12 h.
Two experiments.
10
11
12
13
14
15
16
17
18
19
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
X = F, 2.5 mol% 3 / 2.5 mol% Cu(OAc)2
X = F, 2.5 mol% Cu(OAc)2
X = H, 2.5 mol% 3 / 2.5 mol% Cu(OAc)2
X = H, 2.5 mol% Cu(OAc)2
100
80
60
40
20
0
0
CEL couplings have been praised for their reactivity under
mild conditions, but criticized for their unpredictability. Placꢀ
ing the copper catalyst in a wellꢀdefined ligand environment
can clearly overcome these limitations.
100
200
time [min]
300
400
Figure 10. Conversion vs time profile for the Nꢀarylation of
aniline with 3/Cu(OAc)2 or Cu(OAc)2 only. solid squares:
3/Cu(OAc)2, FC6H4B(OH)2; hollow squares: Cu(OAc)2,
FC6H4B(OH)2, two independent reactions with different induction
periods shown; solid diamonds: 3/Cu(OAc)2, PhB(OH)2; hollow
diamonds: Cu(OAc)2, PhB(OH)2. (MeOH, RT, 1.0 M aniline, 1.5
equiv ArB(OH)2). Solid lines are the simulated conversions calcuꢀ
lated from the rate constants and induction periods determined by
linear regression (Table 8, Fig. S10).
EXPERIMENTAL SECTION
General. Phenylboronic acid was purified by washing with diꢀ
chloromethane until the filtrate stayed colorless. All other chemicals
were purchased from common commercial suppliers and used without
further purification. Elemental analyses were performed by the Laꢀ
boratoire d’analyse élémentaire (Université de Montreal). UV/vis
spectra were recorded on a Cary Series UVꢀVisꢀNIR spectrophotomeꢀ
ter from Agilent Technologie. GCꢀMS spectra were recorded on a
Agilent Technologie GC/MS.
While addition of copper acetate gratifyingly solved the botꢀ
tleneck of slow oxidation to Cu(III) for amines and anilines,
the protocol was unfortunately not generally applicable. Imidꢀ
azoles, which required heating for coupling with phenylꢀ
boronic acid, did not couple to electronꢀpoor phenylboronic
acids even under heating. Likewise, paraꢀnitrophenylboronic
acid could not be coupled even with the reactive nꢀoctylamine.
LCuCl(H2O), 1. To a hot solution (60 °C) of 2ꢀaminoꢀ5ꢀ
methylbenzenesulfonic acid (187 mg, 1.0 mmol) in water (5 mL) and
methanol (10 mL) was added 2ꢀpyridinecarboxaldehye (95 µL, 1.0
mmol). The mixture was stirred for one hour, then copper chloride
hydrate (205 mg, 1.1 mmol) was added, resulting in a green solution.
Heating was stopped and the solution was stirred another hour. Slow
evaporation of the solvent afforded green Xꢀray quality crystals (321
mg, 82%).
Anal. Calcd. for C13H13ClCuN2O4S : C, 39.80; H, 3.34; N, 7.14; S,
8.17. Found: C, 40.09; H, 3.37; N, 3.37; S, 8.47. UVꢀvis (DMSO,
1ꢁ10–2 M or 1.49ꢁ10–4 M) [λmax, nm (ε, M–1ꢁcm–1)] : 338 (97 000), 800
(500).
CONCLUSIONS
Use of 1 and 3 as catalysts in ChanꢀEvansꢀLam couplings
avoided common side reactions such as deboration or homoꢀ
coupling. As a consequence, excess phenylboronic acid is not
required and reactions typically run to quantitative conversion
to product. Incorporation of the functionalities commonly
achieved by choice of solvent, base and counterꢀanion into the
ligand system avoided the need for an extensive optimization
of reaction conditions and provided a general protocol for the
arylation of amines, anilines and Nꢀheterocycles, which inꢀ
cludes sterically difficult substrates such as tert-butylamine
and dibutylamine. The activity of 3 is among the highest reꢀ
ported for CEL couplings of these class of substrates. In fact,
nꢀoctylamine and tert-butylamine can be arylated in less than
1 h using 0.5 mol% of catalyst at room temperature.
{LCu(OTf)}n, 3. Chloride complex 1 (390 mg, 1.0 mmol) was disꢀ
solved in dry THF (5 mL) under nitrogen atmosphere to give a green
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solution. Silver triflate (328 mg, 1.1 mmol) was added. After one hour
galvanostat interfaced to a PC on which was installed the ECꢀlab
of reaction at ambient temperature, a precipitate appeared and the
color of the solution intensified. Filtration through a syringe filter and
slow evaporation of the green filtrate under N2, afforded green Xꢀray
quality crystals (236 mg, 54%).
Anal. Calcd. for C14H11CuF3N2O6S2 : C, 34.46; H, 2.27; N, 5.74; S,
13.14. Found: C, 34.10; H, 2.59; N, 5.26; S, 12.61. UVꢀvis (DMSO,
1.2ꢁ10–2 M or 3.35ꢁ10–4 M) [λmax, nm (ε, M–1ꢁcm–1)] : 338 (62 000),
730 (470).
software. The working electrode was a glassy carbon electrode (3mm
diameter) which was polished with 0.05 µm alumina paste before
each sample. The counter electrode was a Pt wire and the pseudoꢀ
reference electrode was a silver wire (Ag/AgCl). The supporting
electrolyte used for analysis was tetrabutylammonium perchlorate at
0.1 M in solution. The analyte concentration was about 1 mM and
tetrabutylammonium hexafluorophosphate (TBAPF6) was used as
supporting electrolyte at 0.10 M. Cyclic voltammograms were obꢀ
tained at scan rates of 100 mV/s.
X-ray diffraction studies. Crystal for Xꢀray diffraction were proꢀ
duced from synthesis as described above. Diffraction data were colꢀ
lected on a Bruker Venture METALJET diffractometer (Ga
Kα radiation).97 Data reduction was performed with SAINT,98 absorpꢀ
tion corrections with SADABS.99 Structures were solved by dualꢀ
space refinement (SHELXT).100 All nonꢀhydrogen atoms were refined
anisotropic using fullꢀmatrix leastꢀsquares on F2 and hydrogen atoms
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[(LCu)2](OTf)2, 4. To a hot solution (60 °C) of water (5 mL) and
methanol (10 mL) containing 2ꢀaminoꢀ5ꢀmethylbenzenesulfonic acid
(187 mg, 1.0 mmol) was added 2ꢀpyridinecarboxaldehye (95 µL, 1.0
mmol). The mixture was stirred for one hour at 60 °C, then copper
triflate (724 mg, 2.0 mmol) was added. Heating was stopped and the
solution was stirred another hour. After filtration, slow evaporation of
the solvent provided green Xꢀray quality crystals (195 mg, 40%).
Anal. Calcd. for C14H9CuF3N2O5S2 : C, 33.24; H, 2.59; N, 5.54; S,
12.67. Found: C, 33.24; H, 2.57; N, 5.10; S, 13.44. UVꢀvis (DMSO,
1.2ꢁ10–2 M or 3.35ꢁ10–4 M) [λmax, nm (ε, M–1ꢁcm–1)] : 328 (19 000),
727 (430).
L2Cu, 2. Recrystallization of complex 1 in a mixture of water
and acetonitrile from 50 °C to RT provided to the homoleptic comꢀ
plex.
Anal. Calcd. for C14H11CuF3N2O6S2 : C, 39.80; H, 3.34; N, 7.14; S,
8.17. Found: C, 40.09; H, 3.37; N, 7.37; S, 8.47. UVꢀvis (DMSO,
1.2ꢁ10–2 M or 3.35ꢁ10–4 M) [λmax, nm (ε, M–1ꢁcm–1)] : 322 (23 000),
793 (810).
General procedure for Chan-Evans-Lam couplings. To a soluꢀ
tion of amine or aniline (1.0 mmol) and phenylboronic acid (1.5
mmol) in methanol (1 mL) was added catalyst 1 or 2 (0.025 mmol).
Trimethoxybenzene was added as internal standard. The reaction was
stirred open to air at ambient temperature or at 50 °C under O2 atmosꢀ
phere. For kinetic experiments, 20 µL aliquots were taken, diluted in
ethyl acetate and analyzed by GCꢀMS. After the desired reaction time,
the reaction was quenched with 0.5 mL of a saturated aqueous soluꢀ
tion of ammonium chloride. The organic layer was extracted and
filtered through a short silica plug to remove remaining copper comꢀ
plex. Products and sideꢀproducts were identified by the MSꢀ and
NMRꢀspectrum from comparison to literature. Conversion was typiꢀ
cally analysed by GCꢀMS. Quantitative concentrations were deterꢀ
mined by comparison to trimethoxybenzene standard. Calibration
factors between starting materials, products, sideꢀproducts and triꢀ
methoxybenzene were determined from simultaneous NMR and GCꢀ
MS analysis or by analysis of solutions prepared from isolated or
commercially available products.
Photoredox catalysis. Following otherwise the general procedure,
20 mL headspace vials were used. For blue (λ = 452 nm, FWHM =
150 nm) and green light radiation (λ = 525 nm, FWHM = 170 nm),
the vials were placed on a panel constituted of 90 x 1 W LED in a
thermostatic bath with a PolyꢀScience controller set to 20 °C or 50 °C.
For white light (λ = 445 and 552 nm, FWHM = 350 nm), a 10 W
LED in a thermostatic bath with a AꢀNova controller set to 20 °C or
50 °C was used. For reactions with additional photocatalyst,
[Ir(ppy)2(bipy)][PF6] (8 mg, 0.01 mmol) or [Ru(bipy)3][PF6]2 (9 mg,
0.01 mmol) were added.
refined with fixed isotropic
U
using
a
riding model
(SHELXL97).101 Further experimental details can be found in Table 9
and the supporting information (CIF).
Table 9. Experimental details of Xꢀray diffraction studies
2
4
Formula
C26H24CuN4O7S2 C14H13CuF3N2O7S2
Mw (g/mol); F(000)
T (K); wavelength
Crystal System
Space Group
Unit Cell: a (Å)
b (Å)
632.5; 2600
100; 1.34190
Orthorhombic
Pbca
17.7588(4)
13.9390(3)
20.7682(4)
90
505.92; 510
150; 1.34190
Triclinic
Pꢀ1
7.9814(3)
11.0894(4)
11.1020(4)
96.4610(10)
100.1760(10)
110.0070(10)
892.77(6)
c (Å)
α
β
γ
(°)
(°)
(°)
90
90
V (Å3)
5140.96(19)
8; 1.639
5.89; multiꢀscan
Z; dcalcd. (g/cm3)
(mm–1); Abs. Corr.
Extinction coefficient
(°); completeness
2; 1.882
8.50; multiꢀscan
ꢀ
ꢀ
0.120(3)
3.7ꢀ60.7; 0.997
66841; 0.023
5895; 0.051
5566; 0.033
0.0894; 1.05
0.64
7.2ꢀ121.3; 1.000
21646; 0.023
4095; 0.037
4073; 0.036
0.0933; 1.18
0.45
θ
Collected reflections; Rσ
Unique reflections; Rint
Observ. reflections; R1(F)
wR(F2) (all data); GoF(F2)
Residual electron density
ASSOCIATED CONTENT
Supporting Information
Additional tables and figures. Details of calculations. Details of
crystallographic studies (CIF). The Supporting Information is
available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
* Email: Frank.Schaper@umontreal.ca
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Funding was supplied by the NSERC discovery program
(RGPINꢀ2016ꢀ04953) and the Centre for Green Chemistry and
Catalysis (FQRNT). We thank Dr. Thierry Maris for support with
Cyclic voltammetry. Electrochemical measurements were carried
out in dry methanol at RT with a BioLogicꢀSP50 potentiostatꢀ
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ACS Catalysis
20. Liu, C.ꢀY.; Li, Y.; Ding, J.ꢀY.; Dong, D.ꢀW.; Han, F.ꢀS., The
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D. Zargarian for access to GC/MS, and T. Audrey and Prof. G.
Hanan for help with CV measurements. C. Sauvée, H. Frédon,
and A. Thouvenin contributed during their internships to these
results.
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