Efficient Homocoupling of Aryl- and Alkenylboronic Acids in the Presence of Low Loadings of [{Pd(μ-OH)Cl(IPr)} 2 ]

Article abstract of DOI:10.1055/s-0036-1591602

NHC-palladium(II) complex [{Pd(μ-OH)Cl(IPr)} ₂ ] (IPr = bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) catalyzes the oxidative coupling of a broad spectrum of aryl- and alkenylboronic acids at loadings down to 5 ppm. At the concentration of 0.05 mol% the catalyst permits an efficient reaction under base-free conditions.

Full text of DOI:10.1055/s-0036-1591602

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
en
S. Ostrowska et al.
Letter
Synlett
Efficient Homocoupling of Aryl- and Alkenylboronic Acids in the
Presence of Low Loadings of [{Pd(μ–OH)Cl(IPr)}2]
Sylwia Ostrowskaa
Szymon Rogalskia
Jan Lorkowskia
Jędrzej Walkowiakb
Cezary Pietraszuk*a
i-Pr
i-Pr
N
H
Cl
i-Pr
O
N
i-Pr
Pd Pd
i-Pr
N
i-Pr
OH
Cl
N
i-Pr
0
0
0
0
0-
0
0
3
2-
4
1
3
0-
4
7
8
i-Pr
1
a Adam Mickiewicz University in Poznań, Faculty of Chemistry,
Umultowska 89b, 61-614 Poznań, Poland
pietrasz@amu.edu.pl
b Adam Mickiewicz University in Poznań, Centre for Advanced
Technologies, Umultowska 89c, 61-614 Poznań, Poland
typically 85–98%
typically 94–96%
Ar
or
Ar
0.05 mol%, base-free, 22 °C
0.0005 mol%, KOH, reflux
(HO)2B
R
R'
EtOH, air
R'
R = aryl or alkenyl
Dedicated to Professor Jacek Gawroński on the occasion of his
75th birthday.
Received: 23.05.2018
Accepted after revision: 09.06.2018
Published online: 10.07.2018
based catalytic systems have been described.15 As summa-
rized in a recent review,6 the known catalytic systems
require the use of relatively high loadings of the metal pre-
cursor. Only for a few systems the use of catalysts in con-
centrations below 0.1 mol% and relatively high productivity
of the catalyst expressed by TON ≥ 103 have been report-
ed.8a,e,h The use of NHC–palladium complexes as precata-
lysts did not lead to improvement in the efficiency of the
catalysts.16
Recently, we have reported high catalytic activity of pal-
ladium hydroxide dimer [{Pd(μ–OH)Cl(IPr)}2] (1) in the
Suzuki–Miyaura cross-coupling of aryl chlorides with sub-
stituted aryl- and alkenylboronic acids.17 This catalyst was
still active even when used with a loading as low as 0.1
ppm. Herein, we report the successful application of com-
plex 1 as a catalyst for the oxidative coupling of a series of
aryl- and alkenylboronic acids.
DOI: 10.1055/s-0036-1591602; Art ID: st-2018-b0503-l
Abstract NHC–palladium(II) complex [{Pd(μ–OH)Cl(IPr)}2] (IPr = bis(2,6-
diisopropylphenyl)imidazolin-2-ylidene) catalyzes the oxidative cou-
pling of a broad spectrum of aryl- and alkenylboronic acids at loadings
down to 5 ppm. At the concentration of 0.05 mol% the catalyst permits
an efficient reaction under base-free conditions.
Keywords homogeneous catalysis, palladium, NHC complexes, homo-
coupling, boronic acids
Symmetric and nonsymmetric biaryls are fundamental
building blocks in biologically active compounds1 and natu-
ral products.2 They are widely used as ligands, especially in
catalytic asymmetric synthesis.3 Synthetic methods leading
to symmetric biaryls involve the Ullmann reaction, a num-
ber of transition-metal-catalyzed coupling processes such
as the Suzuki, Negishi, Stille, and Kumada reactions, and di-
rect arylation.3,4 In recent years, significant progress has
been achieved in exploring the synthetic utility of the oxi-
dative coupling reactions.5 The oxidative coupling of organo-
boron compounds is a convenient approach to symmetrical
biaryls.6 This route is particularly useful because of the
wide commercial availability of boronic acids, their conve-
nient synthesis, stability in the presence of moisture and a
number of functional groups, and low toxicity, with respect
to other organometallics used in coupling processes.7 Homo-
coupling of boronic acids is usually catalyzed by palladium8
and copper complexes.9 Recently, gold10 and rhodium11 de-
rivatives have been found active catalysts. Moreover, palla-
dium,12 gold,13 and copper14 colloids or nanoparticles have
been reported to promote this transformation. In addition,
several types of active copper-containing catalysts, i.e.
heterogeneous, nano-sized, or organometallic framework-
Stirring the ethanolic solution of tolylboronic acid (2a)
in the presence of complex 1 resulted in the selective and
nearly quantitative formation of 4,4'-dimethyl-1,1'-biphe-
nyl within two hours (Scheme 1).
1 (0.5 mol%)
B(OH)2
EtOH, 22°C, 2 h, air
base-free
2a
3a
Scheme 1 Homocoupling of tolylboronic acid in the presence of
complex 1
The activity of complex 1 was compared with that of
complexes 4,18 519 and 620 (Figure 1), known to be catalyti-
cally active in Suzuki–Miyaura cross-coupling. Moreover,
the catalytic activity of selected palladium salts was tested.
The reactions were carried out under conditions previously
found optimal for the Suzuki–Miyaura coupling catalyzed
by complex 1.17 The results are summarized in Table 1.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
S. Ostrowska et al.
Letter
Synlett
action proceeded efficiently under base-free conditions.
The catalytic system was not sensitive to the presence of
H2O; however, the use of water as a solvent did not permit
an effective reaction because complex 1 is not water-
soluble. The highest yields were obtained for KOH from
among different bases tested. An addition of KOH permitted
the reduction of the catalyst loading to 0.0005 mol%. Re-
sults aimed at optimizing the amount of the catalyst used
are summarized in Table 3.
R
N
N
R
R
R
N
N
Cl
Cl
Cl
N
R
Cl Pd Cl
N
Pd
R
Pd
Pd
R
N
R
Cl
Cl
N
Ph
Cl
4
5
6
R = 2,6-diisopropylphenyl
Figure 1 Palladium complexes tested in homocoupling of boronic
acids
As indicated in Table 1, catalyst 1 exhibits excellent cat-
alytic activity in the reaction and permits obtaining high
yields of the products under base-free conditions. None of
the other salts and/or complexes tested showed catalytic
activity in the absence of a base. Addition of one equivalent
of KOH with respect to boronic acid permits an effective
run of the reaction in the presence of PEPPSI catalyst 4 and
chloride dimer 6. All other palladium compounds tested ex-
hibited low catalytic activity under the conditions used.
The presence of atmospheric oxygen proved to be necessary
for an efficient progress of the reaction. Homocoupling of
tolylboronic acid in the presence of catalysts 1, 4, and 6,
performed under oxygen-free conditions, did not provide
any product (Table 1, entries 6, 9, 14, respectively).
In order to optimize the reaction conditions, a number
of tests were performed. Selected results are given in Table
2.
According to the results, the reaction was effective in
alcohols as the solvent, and the highest yield was obtained
in ethanol. When 0.05 mol% of catalyst 1 was used, the re-
Table 2 Homocoupling of Tolylboronic Acid Catalyzed by Complex 1.
Optimization of the Reaction Conditionsa
Entry
1 (mol%)
Solvent
Base
Time
(h)
Yield of 3a
(%)b
1
2
0.05
MeOH
EtOH
–
–
–
–
–
–
–
2
2
92
98
75
0
0.05
3
0.05
i-PrOH
H2O
2
4
0.05
24
24
24
24
2
5
0.05
dioxane
toluene
CH2Cl2
EtOH
24
10
79
45
51
61
83
98
6
0.05
7
0.05
8
0.0005
0.0005
0.0005
0.0005
0.0005
K2CO3
9
EtOH
Cs2CO3
NaOH
TBAOH
KOH
2
10
11
12
EtOH
2
EtOH
2
EtOH
2
a Reaction conditions: catalyst 1, [base]/[ArB(OH)2] = 1:1, 22 °C, air.
b Isolated yield.
Table 1 Homocoupling of Tolylboronic Acid, the Effect of a Palladium
Precatalyst and a Basea
Complex 1 used under the base-free conditions permit-
ted obtaining a TON of 8.2 × 104 at a catalyst loading of
0.0005 mol%. However, to obtain yields exceeding 90%, the
use of 0.05 mol% of the catalyst was required. The addition
of hydroxides had a beneficial effect on the reaction yield.
Complex 1 used in the presence of excess of the base
([KOH]/[ArB(OH)2] = 1:1) showed activity at concentrations
down to 0.5 ppm and permitted a TON of 9.6 × 105. Satisfac-
tory yields needed the use of 0.0005 mol% (5 ppm) of the
catalyst.
In order to investigate the scope of the reaction, a num-
ber of tests were made with the use of a variety of arylbo-
ronic acids of different stereoelectronic properties and for a
number of selected alkenylboronic acids (Scheme 2). The
results are summarized in Figure 2. High isolated yields
were obtained for arylboronic acids containing both elec-
tron-donating and -accepting groups in the aromatic ring,
Entry
Cat.
PdCl2
Base
–
Yield of 3a (%)b
1
2
0
10
0
PdCl2
KOH
3
Pd(OAc)2
–
4
Pd(OAc)2
KOH
–
20
98
0c
0
5
1
1
4
4
4
5
5
6
6
6
6
–
7
–
8
KOH
KOH
–
92
0c
0
9
10
11
12
13
14
KOH
–
21
0
KOH
KOH
81
0c
1
R
B(OH)2
2a–u
R
3a–u
R
EtOH
a Reaction conditions: [Pd] (0.5 mol%), EtOH, [KOH]/[ArB(OH)2] = 1:1, 22 °C,
R = aryl, heteroaryl, alkenyl
24 h, air.
Scheme 2 Oxidative coupling of aryl, heteroaryl, and alkenylboronic
acids in the presence of complex 1
b Isolated yield.
c Reaction performed in a glove-box.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
S. Ostrowska et al.
Letter
Synlett
Table 3 Homocoupling of Tolylboronic Acid in the Presence of
Catalyst 1. Optimization of the Catalyst Loadinga
From among the alkenylboronic acids tested, the synthesis
of homocoupling products failed only for (Z)-prop-1-en-1-
ylboronic acid MIDA ester. Attempts to achieve an efficient
transformation through the slow-release protocol failed.
Hydrolysis of the MIDA ester led to 2,4,6-tri[(Z)-prop-1-en-
1-yl]boroxine, which did not undergo homocoupling in the
presence precatalyst 1 irrespective of the reaction condi-
tions used.
Entry 1 (mol%)
[KOH]/[Pd]
Yield of 3a
TON
(%)b
1
2
0.5
0
79
158
0.05
0
96
1920
3
0.005
0
58
1.16 × 104
1.88 × 104
8.2 × 104
2.8 × 105
1.88 × 104
1.96 × 104
1.62 × 105
1.96 × 105
4.8 × 105
9.6 × 105
4
0.005
0
94c
41c
14c
94
5
0.0005 (5 ppm)
0.00005 (0.5 ppm)
0.005
0
6
0
7
1:1
1:1
1:1
1:1
(1:1)d
(1:1)d
3a A: 99% B: 95%
3b A: 98% B: 96%
3c A: 98% B: 96%
3f A: 94% B: 93%
8
0.005
98c
81
9
0.0005 (5 ppm)
0.0005 (5 ppm)
0.00005 (0.5 ppm)
0.00005 (0.5 ppm)
Br
Br
MeO
OMe
10
11
12
98c
24
3d B: 58%
MeO
3e A: 87% B: 85%
OMe
48c
O
OMe
O
a Reaction conditions: EtOH, KOH, 22 °C, 24 h, air.
b Yield calculated on the basis of GC analysis.
c Reflux.
MeO
OMe
MeO
d [KOH]/[ArB(OH)2].
3g A: 92% B: 90%
O2N
3h A: 97% B: 95%
3i A: 93% B: 90%
for thiophenes as exemplary heteroaromatic reactants and
for naphthalene derivatives. The procedures proposed could
also be successfully used to couple alkenylboronic acids. In
the presence of complex 1, all tested reactions could be ef-
fectively carried out under base-free conditions. However,
then it was necessary to use 0.05 mol% of the catalyst. In the
presence of one equivalent of KOH (with respect to boronic
acid) it was possible to reduce the catalyst loading down to
0.0005 mol% and to achieve TONs of up to 1 × 106 for a wide
spectrum of reagents.21
Me2N
NMe2
NO2
3k D: 70%
3j C: 91%
3l A: 98% B: 96%
S
S
S
S
3o A: 91% B: 87%
3n A: 97% B: 95%
3m A: 96% B: 92%
Efficient synthesis of products such as 3j, 3k, 3p, 3q, 3t,
and 3u required higher concentrations (0.01 mol%) of the
catalyst. The reaction for obtaining 3q was slow and accom-
panied by deboronation of boronic acid that took place even
though base-free conditions were applied. The competitive
deboronation leading to diphenylacetylene involved to a
significant reduction in the reaction yield, down to 34%.
This moderate reaction yield was achieved by using 1 mol%
of catalyst 1. The synthesis of tetraene 3u was performed
with the use of the MIDA ester of dienylboronic acid.
(1E,3E)-4-phenylbuta-1,3-dienylboronic acid MIDA ester
was synthesized by a literature method.22 Unfortunately,
the attempts of selective and efficient hydrolysis of the
ester failed. In view of that, the coupling reaction was per-
formed in the presence of excess of KOH, according to the
slow-release protocol.23 Under such conditions, however, a
competitive deboronation of the generated 4-phenylbuta-
1,3-dienylboronic acid was observed. The product 3u was
obtained as a mixture of two isomers at the molar ratio 2:1,
with the total yield of 28%. The mixture was not separated.
3p F: 45%
3q G: 34%
F
F
3s A: 96% B: 94%
3r A: 95% B: 95%
3t E: 94%
3u F: 28% (based on GC)
Figure 2 Synthesis of symmetric biaryls and dienes through oxidative
coupling of aryl, heteroaryl, and alkenylboronic acids in the presence of
complex 1. Figures denote isolated yields. Reaction conditions: A 1
(0.05 mol%), 22 °C, 2 h; B 1 (0.0005 mol%), [RB(OH)2]/[KOH] = 1:1,
reflux, 6 h; C 1 (0.1 mol%), 40 °C, 6 h; D 1 (0.1 mol%); 22 °C, 24 h;
E 1 (0.1 mol%); [RB(OH)2]/[KOH] = 1:10, 22 °C, 24 h; F 1 (1 mol%);
[Pd]/[KOH] = 1:1; 22 °C, 72 h; G 1 (1 mol%); 22 °C, 24 h
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

D
S. Ostrowska et al.
Letter
Synlett
The catalytic system described here is active in atmo-
spheric air. Under oxygen-free conditions no formation of
the coupling product was observed. This clearly indicates
that in the oxidative coupling of boronic acids tested, dioxy-
gen plays the role of a terminal oxidant. The commonly
accepted mechanism of the reaction, proposed by Amatore
and Jutand,24 (Scheme 3) involves oxidation of Pd(0) com-
plex (I) to the peroxo complex (II) and its further reaction
with boronic acid leading to the formation of complex (III)
and, after hydrolysis, to σ-aryl hydroxo complex (IV). First,
the transmetalation step (from II to III), requires assistance
of an additional molecule of boronic acid which forms an
adduct (not shown in the scheme) with peroxide complex
II. Once the adduct is formed, it undergoes transmetalation
with a second molecule of arylboronic acid to generate
complex III.
the reaction of boronic acid with hydroxide complex and/or
through the reaction of potassium boronates K[(RB(OH)3]
with palladium chloride complexes.17
The key oxidative addition of an O2 molecule by an N-
heterocyclic carbene–palladium(0) complex leading to for-
mation of the palladium(II) peroxo complex has been de-
scribed in the literature.25
The above presented procedures do not permit oxida-
tive coupling of pinacol esters of boronic acids. The
observed lack of reactivity can be explained on the basis of
Denmark’s recent works revealing the structures of pre-
transmetalation intermediates.26 According to the mecha-
nism proposed by Denmark, the elusive Pd–O–B containing
intermediates, necessary to transfer the organic moiety
from boron to palladium in the transmetalation step, are
formed from boronic acid or relative boronates and the
palladium hydroxide complex. It seems that the relatively
stable pinacol esters are not able to form the crucial inter-
mediate under the mild conditions of the process we
applied. To confirm this hypothesis we demonstrated that
both vinylboronic acid pinacol ester and N-methyliminodi-
acetic acid (MIDA) vinylboronic ester do not undergo
hydrolysis in ethanol, by using one equivalent of KOH
relative to the ester at room temperature. Under the in-
1
+ 2 RB(OH)2 or
+ 2 K[RB(OH)3]
– 2 B(OH)3 or
– 2 KCl, – 2 B(OH)3
IPr
O2
R
R
[Pd]
I
IPr
Pd
R
IPr
L
O
O
R
L
Pd
II
creased concentration of KOH ([ester]/[KOH]
= 1:10;
2 RB(OH)2
RB(OH)2
EtOH/H2O = 2:1; r.t.) MIDA ester undergoes effective hydro-
lysis to vinylboronic acid. Under the same conditions no
transformation of pinacol ester was observed (see Support-
ing Information, Figure S1). Under an increased concentra-
tion of KOH, the procedures we proposed permitted effec-
tive transformation of boronic acid MIDA esters.
The high effectiveness of the reaction in the presence of
small amounts of the catalyst 1, observed for the majority
of substrates studied, can be explained by the stabilizing
effect of the NHC ligand whose presence prevents the
aggregation of Pd(0) species and prolongs the catalyst life-
time. Moreover, the NHC ligand facilitates the reductive
elimination by increasing the steric hindrance at the metal
center and oxidative addition of dioxygen.
In conclusion, we have developed a convenient and effi-
cient procedure for the oxidative coupling of aryl- and
alkenylboronic acids in the presence of the readily accessi-
ble precatalyst [{Pd(μ–OH)Cl(IPr)}2], permitting effective
syntheses of a wide spectrum of symmetric biaryls and
dienes at extremely low catalyst loadings (down to 5 ppm).
Moreover, it has been demonstrated that the reaction can
proceed efficiently under base-free conditions.
V
B(OH)3
RB(OH)2
IPr
Pd
IPr
R
L
R
Pd
L
OOB(OH)2
OH
III
IV
H2O
HOOB(OH)2
Scheme 3 Simplified mechanism of the oxidative coupling of boronic
acid. Cis–trans equilibria in palladium complexes IV and V are not
shown for clarity.
Hydroxide complex IV undergoes transmetalation with
boronic acid to form bis(σ-carbyl) complex V. Subsequent
reductive elimination results in the release of biaryl and re-
formation of the Pd(0) complex I.
The presence of the Pd(0) species is crucial for the
course of the reaction. In the system under study, genera-
tion of Pd(0) takes place as a result of interaction of the
dimeric hydroxide complex 1 with boronic acids.17 The re-
action has been proposed to occur by transmetalation fol-
lowed by reductive elimination. The lack of activity of
chloride complexes under hydroxide-free conditions results
from their inability to undergo transmetalation with
boronic acid and subsequent reduction to Pd(0). In the
presence of potassium hydroxide, both chloride complexes
and hydroxide complex 1 remain catalytically active. Under
such conditions, the transmetalation occurs as a result of
Funding Information
The research was co-financed by the National Centre for Research and
Development (NCBR), Project ORGANOMET No: PBS2/A5/40/2014,
and the National Science Centre (Poland), project UMO-
2013/11/N/ST5/01612.
)(
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

E
S. Ostrowska et al.
Letter
Synlett
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The reaction flask (10 mL) equipped with stirring bar was
charged with 4-tolylboronic acid (124 mg, 0.91 × 10-3 mol),
ethanol (96%) (2 mL), [{Pd(μ-OH)Cl(IPr)}2] (1) (5 mL, 4.55 × 10-9
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of CH2Cl2. The solution should be stored in the dark, no longer
than 3 days). The mixture was stirred in air under reflux for 6 h.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

F
S. Ostrowska et al.
Letter
Synlett
159 mg of 4,4'-dimethylbiphenyl was obtained as a white solid.
Yield = 94%. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.50 (d, J = 8.1
Hz, 4H), 7.25 (d, J = 8.1 Hz, 4H), 2.41 (s, 6H); 13C NMR: (75 MHz,
CDCl3, ppm) d: 138.3, 136.7, 129.4, 126.8, 21.1. MS (EI) m/z (%) =
182 (M+, 100), 167 (54), 152 (15).
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F