An Active Palladium Colloidal Catalyst for the Selective Oxidative Heterocoupling of (Hetero)Aryl Boronic Acids

Article abstract of DOI:10.1002/asia.201800358

A highly selective oxidative heterocoupling protocol for (hetero)aryl boronic acids with an active palladium colloidal catalyst was developed. The judicious choice of electronically different aryl boronic acids made possible such couplings under mild conditions, with air as oxidant, while embracing a wide substrate scope. This successful approach further allowed the development of a unique one-pot sequential oxidative heterocoupling/Suzuki–Miyaura cross-coupling tandem process for accessing substituted terphenyls.

Full text of DOI:10.1002/asia.201800358

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: An Active Palladium Colloidal Catalyst for the Selective Oxidative
Heterocoupling of (Hetero)Aryl Boronic Acids
Authors: anant kapdi, Vaibhav Sable, Karan Maindan, Shatrughn
Bhilare, Nicolas Chrysochos, and Carola Schulzke
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Asian J. 10.1002/asia.201800358
Link to VoR: http://dx.doi.org/10.1002/asia.201800358
A Journal of
A sister journal of Angewandte Chemie
and Chemistry – A European Journal

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
An Active Palladium Colloidal Catalyst for the Selective Oxidative
Heterocoupling of (Hetero)Aryl Boronic Acids
Vaibhav Sablea, Karan Maindana, Shatrughn Bhilarea, Nicolas Chrysochosb, Carola Schulzkeb, Anant
R. Kapdia,*
Abstract: A highly selective oxidative heterocoupling protocol for
(hetero)aryl boronic acids with an active palladium colloidal catalyst
was developed. The judicious choice of electronically-different aryl
boronic acids made possible such couplings under mild conditions,
with air as oxidant while embracing a wide substrate scope. This
successful approach further allowed the development of a unique
one-pot sequential oxidative heterocoupling/Suzuki-Miyaura cross-
coupling tandem porocess for accessing substtituted terphenyls.
In recent years, C–H bond functionalization7 of un-
functionalized (hetero)arenes has provided researchers with a
potential cleaner alternative to the coupling processes.
Although, selectivity for the desired bi(hetero)aryls was found
unsatisfying.8 A synthetically attractive strategy for the
construction of the bi(hetero)aryl structural motif should,
hence, become available via the selective coupling of
differently substituted organometallic reagents. These would
be most preferably aryl-boron reagents due to their mildness,
stability, ease of handling and economically attractive
availability.
1. Introduction
In literature, an extensive number of examples has appeared
for the homocoupling of arylboronic acids or arylboron
reagents to yield symmetrical biaryls under oxidative coupling
conditions using various metal catalysts.9-12 These include
reports from our group of such protocols with palladium-
based catalyst systems.13 To specifically target the
heterocoupling between different arylboron reagents while
shutting down the normally preferred homocoupling reactions
is an interesting synthetic challenge, which has been met by
the judicious choice of electronically distinguishable
substrates. Such a strategy, however, has its own limitations,
which is evident from the very few examples having featured
in the past decade. Amongst these are the notable examples of
Cahiez and co-workers14 for the oxidative heterocoupling of
Bi(hetero)aryls1 are important structural motifs found
extensively in a wide variety of drugs, agrochemicals, OLEDs
and many more. Valsartan,2a Boscalid,2b Losartan,2c
Telmisartan2d are some of the many examples of
bi(hetero)aryl based commercially successful molecules
(Figure 1). Bio-active bi(hetero)aryls with promising
antifungal properties have further been isolated from plant
sources providing additional evidence of their significant
importance. The installation of C–C bonds for the synthesis of
unsymmetrical bi(hetero)aryls was achieved in the past via
various cross-coupling3 reactions such as Suzuki-Miyaura,4
Stille5 and Negishi6 types between aryl halides and different
organometallic reagents. However, obstacles in economically
obtaining the coupling partners either due to the cost involved
or the tedious preparation procedures limit their application.
two different Grignard reagents15 Zinc reagents16, gold(I)-
,
catalyzed heterocouplings of different alkynes reported by Shi
and co-workers17 as well as the copper-catalysed
heterocouplings of unsymmetrical alkynes by Lei18 and Yin19.
The only report to date for the heterocoupling of different
arylboronic reagents was recently published by our research
group20 (as preliminary results with a limited number of
examples) to highlight the potential of active palladium
colloids for providing selective coupled products. With the
aim to demonstrate the full potential of such active palladium
colloids for the oxidative heterocoupling of different
arylboronic acids, we present herein a comprehensive study.
2. Results and Discussion
Figure 1: Drugs and Agrochemicals containing biaryl structural motif.
The importance of developing an efficient synthetic procedure
for bi(hetero)aryls beyond conventional methods not only
challenges researchers but also allows them to explore
different and unique substrate combinations. The success
related to these types of explorations necessarily depends on
the nature of the catalyst employed and the selectivity
exhibited towards the respective process. In comparison to
commonly employed homogeneous or heterogeneous
catalysts, nano or colloidal metal catalysts are ever more
clearly evidencing enhanced reactivity and selectivity.21
[a]
Mr. Vaibhav Sable, Mr. Karan Maindan, Mr. Shatrughn Bhilare, Dr.
Anant R. Kapdi
Department of Chemistry
Institute of Chemical Technology
Nathalal Parekh road, Matunga, Mumbai-400019, India
E-mail: ar.kapdi@ictmumbai.edu.in
Mr. Nicolas Chrysochos, Prof. Carola Schulzke
Institut fur Biochemie
Ernst-Moritz-Arndt Universitat Greifswald
D-17487, Greifswald, Germany
[b]
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
Several factors such as surface composition and surface
stabilization of the nanoparticles/colloidal particles,
morphology of the nanoparticles as well as their sizes are key
and the complete characterization of the synthesized
palladium colloidal catalyst was possible by utilizing
techniques such as TEM, HRTEM, XRD, XPS, EDS and
contributors to their unparalleled reactivity.22 Fine tuning EXAFS.20 In the same report, preliminary results for the
these factors should allow the development of superior, more
heterocoupling of two different arylboronic acids were
efficient catalytic technologies for C–C bond formation disclosed (with a limited number of examples) which we have
processes. One contribution to the development of novel C–C now explored in further detail and with a much broader
bond forming technologies using active palladium colloidal
catalysts from our group was published recently covering the
efficient homocoupling of arylboronic acids.20 The isolation
substrate scope (see Scheme 1).
Scheme 1: Synthetic procedure for active palladium colloids synthesis.
At first the conditions for the heterocoupling of arylboronic
acids were optimized by varying the respective parameters
including the screening of different catalyst systems for
comparison (Table 1). The optimization studies were
Employing molecular oxygen (O2 balloon) resulted in similar
selectivity as with air as oxidant (entry 22). Therefore, the
studies were continued with the abundantly available air as
oxidant. A rather significant improvement of the selective
performed with 3-nitrophenylboronic acid and 4- heterocoupling of boronic acids was finally achieved by
methyoxyphenylboronic acid (1.0 equiv. each) as model increasing the concentration of the more reactive arylboronic
substrates in air, as abundantly available oxidant, and with an acid from 1.0 equivalents to 1.5 equivalents (entry 28) in
equimolar amount of base (K2CO3). Without the addition of ACN/H2O as solvent (exhibiting higher selectivity than other
any metal catalyst or catalyst precursor the reaction failed to solvents: see entries 30-37).
proceed. Pd(OAc)2 as a ligand-free system provided only the
homocoupling of 4-methyoxyphenylboronic acid (entries 1 &
2). The addition of phosphines as activating ligands
accelerated the formation of the homocoupled product with
To summarise the optimization results, palladium colloids
obtained from a more expensive palladium(II) precursor
provide much better selectivity for heterocoupling reaction
although, Hermann-Beller palladacycle on its own does not
similar results as obtained for the employment of the provide promising yield of the heterocoupled product. Its
Hermann-Beller palladacycle or nano-ferrite. However, degradation to the active palladium colloids allowed the
employing the synthesized palladium colloids resulted in an possibility of getting better selectivity for heterocoupling as
improved selectivity for the cross-coupled product (although
still in lower concentration than the competing homocoupled
product- entry 6).
compared to the employment of Pd(OAc)2 (under ligand-free
conditions) or Pd/C (entry 5). This could also be attributed to
the presence of 6 Pd atoms together forming the colloidal
Next, the needed base was optimized revealing K2CO3 to be catalyst supported on carbon surface (confirmed by EXAFS
the most suitable one with highest selectivity for the cross- studies)20 with a Pd-Pd bond present that would provide us the
coupled product (entry 10). Temperature studies suggested 70 unique reactivity observed in heterocoupling of boronic acids.
oC as most suitable temperature with regard to selectivity
(entry 15). Further increases in yields of the cross-coupled
product were observed with raising the reaction time to 48 hrs
(entry 20). To assess the influence of the (potentially added)
oxidant on the coupling process, TBHP or Ag2O were
employed with both increasing the yields of the unwanted
homocoupled products (entry 23 and 25 respectively).
3. Heterocoupling vs Homocoupling
The unprecedented selectivity obtained with the colloidal
catalytic system for the heterocoupling of unsymmetrical
boronic acids could help open up new avenues for the
synthesis of molecules of synthetic relevance. To obtain
further insight into the selective nature of the coupling process
it was decided to monitor the catalytic reaction’ progress with
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
a Gas Chromatograph-Mass Spectrometer (GCMS) in the
presence of an internal standard (dodecane). At regular
intervals, samples were withdrawn from the catalytic reaction
between 3-nitrophenyl boronic acid and 4-methoxyphenyl
boronic acid under the given set of conditions. For the initial
13 hrs, samples were injected every hour followed by a 24 hr
and 48 hr sample providing enough data points for the
assessment. An induction period extending up to 3 hrs could
be observed as shown in Figure 2. The catalytic reaction was
found to proceed in the forward direction with a steady
consumption of the limiting 3-nitrophenyl boronic acid.
Table 1: Optimisation studies.a
Entry
Catalyst
Oxidant
Base
Solvent
Temp oC
Time
2a
2aꞌꞌ
Catalyst Screeninga,b
1.
2.
-
Air
Air
K2CO3
K2CO3
ACN/H2O (1:1)
ACN/H2O (1:1)
70
70
24
24
0
0
0
0
Pd(OAc)2 (1.0 mol%)
3.
4.
5.
6.
7.
8.
Pd(OAc)2/PPh3
Pd(OAc)2/P(o-Tol)3
Pd/C (5%/Wt) (10 mg)
Pd Colloids (10 mg, 0.32 mol%)
Nano Fe2O3 (10 mg)
Air
Air
Air
Air
Air
Air
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
ACN/H2O (1:1)
ACN/H2O (1:1)
ACN/H2O (1:1)
ACN/H2O (1:1)
ACN/H2O (1:1)
ACN/H2O (1:1)
70
70
70
70
70
70
24
24
24
24
24
24
0
15
5
30
10
20
0
10
35
20
20
15
H-B complex (1.0 mol%)
Base Studya,b
9.
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Air
Air
Air
Air
Na2CO3
ACN/H2O (1:1)
ACN/H2O (1:1)
ACN/H2O (1:1)
ACN/H2O (1:1)
70
70
70
70
24
24
24
24
0
30
10
0
0
10.
11.
12.
K2CO3
20
30
10
Cs2CO3
N(C2H5)3
Temperature Studya,b
13.
14.
15.
16.
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Air
Air
Air
Air
K2CO3
K2CO3
K2CO3
K2CO3
ACN/H2O (1:1)
30
50
24
24
24
24
0
0
ACN/H2O (1:1)
ACN/H2O (1:1)
ACN/H2O (1:1)
15
30
10
20
20
55
70
100
Reaction Duration Studya,b
17.
18.
19.
20.
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Air
Air
Air
Air
K2CO3
K2CO3
K2CO3
K2CO3
ACN/H2O (1:1)
70
70
70
70
12
24
36
48
10
30
35
55
10
20
25
10
ACN/H2O (1:1)
ACN/H2O (1:1)
ACN/H2O (1:1)
Oxidant Screeninga,b
21.
22.
23.
24.
25.
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
N2
O2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
ACN/H2O (1:1)
70
70
70
70
70
48
48
48
48
48
0
0
ACN/H2O (1:1)
ACN/H2O (1:1)
ACN/H2O (1:1)
ACN/H2O (1:1)
50
10
55
25
20
35
10
15
TBHP
Air
Ag2O
Equivalent of Boronic Acid 1b Screeningb
26.
27.
28.
Pd Colloids (10 mg, 0.32 mol%)a
Pd Colloids (10 mg, 0.32 mol%)c
Air
Air
Air
K2CO3
K2CO3
K2CO3
ACN/H2O (1:1)
ACN/H2O(1:1)
ACN/H2O (1:1)
70
70
70
48
48
48
55
65
81
10
10
5
Pd Colloids (10 mg, 0.32
mol%)d
29.
Pd Colloids (10 mg, 0.32 mol%)e
Air
K2CO3
ACN/H2O (1:1)
70
48
70
5
Solvent Studyb,d
K2CO3
30.
31.
32.
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Air
Air
Air
ACN /H2O (1:1)
MEOH
70
70
70
48
48
48
81
0
5
0
0
K2CO3
K2CO3
EtOH
0
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
33.
34.
35.
36.
Pd Colloids (10 mg, 0.32 mol%)
Air
Air
Air
Air
K2CO3
K2CO3
K2CO3
K2CO3
DMF
H2O
70
70
70
70
48
48
48
48
30
41
35
50
10
40
45
10
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
Pd Colloids (10 mg, 0.32 mol%)
DMSO
Toluene
a1.0 mmol of 1a and 1.0 mmol of 1b; bIsolated yields; c1.0 mmol of 1a and 1.3 mmol of 1b; d 1.0 mmol of 1a and 1.5 mmol of 1b; e1.0 mmol of 1a
and 2.0 mmol of 1b.
100
80
87.91
60
40
20
0
1
2
3
4
5
6.42
6
7
8
9
10
5.3
11
12
13
Nitrobenzene
Cross product
Homo nitro
24
48
Time (Hrs)
Figure 2: Heterocoupling reactions vs. homo-coupling products monitored by Gas Chromatographic – Mass Spectrometric (GCMS) analysis of
the catalytic reaction (dodecane used as an internal standard).
Besides the formation of the heterocoupled product (4- the reaction solvent) in the reaction plays a crucial role
methoxy-3-nitrobiphenyl), homocoupled product (3,3ꞌ- regarding the final outcome.
dinitrobiphenyl) as well as hydrodeborylation (nitrobenzene)
Recent reports by Watson and co-workers as part of their
was also observed, although the concentration of these developing a chemoselective boronic ester synthesis protocol
competing processes is restricted (<10% in both the cases).
The homocoupling of the activated arylboronic acid coupling
partner was not considered as it would commonly provide
higher amounts of homocoupling due to it being in excess.
The recorded results further strengthen our claim for the
selective oxidative heterocoupling of electronically distinct
boronic acids utilizing the active colloidal catalyst
suggests the addition of smaller quantities of water (5.0
equivalents) to have beneficial effects for the speciation of the
boron species.26a,b The actual observed chemoselectivity was
attributed partly to the quantity of water added. Similar
observations were also reported by our group for the
homocoupling of arylboronic acids catalyzed by
a
cyclopalladated complex in commercial grade THF solvent
wherein the presence of adventitious amounts of water (ppm
quantities of water as analysed by Karl Fischer titration) was
found to be crucial.13 Computational models are also now
available discussing the promotional role of water in
heterogeneous catalysis (as relevant for the work reported
herein).27 Water can thus positively influence catalytic
processes including selectivities either in its molecular state or
by its dissociation into hydroxyl (OH/OH-) and hydrogen
(H/H+) species on the catalyst’s surface.
4. Effect of Water on Heterocoupling
The beneficial role of water in catalytic processes, especially
regarding the Suzuki-Miyaura cross-couplings and other
related reactions has been well explored in the literature.23
The presence of water could have both accelerating as well as
decelerating effects on the rate of catalytic reactions. It
depends on the concentration of water which process
dominates.24 The employment of neat water as reaction
solvent has also found major applications in many cases.25
However, in certain synthetically relevant processes the
concentration of water (adventitious amounts, e.g. as part of
To investigate the role of water in the promotion of the
heterocoupling reactions of arylboronic acids (3-nitrophenyl
boronic acid and 4-methoxyphenyl boronic acid) as well as to
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
possibly improve the selectivity even further, we decided to
vary the concentration of water in the catalytic reactions
(relative to acetonitrile as co-solvent) again onitoring the
reactions’ progress by GCMS (with dodecane as the internal
standard). As shown in Figure 3, it was observed that
process while promoting the heterocoupling reaction. The
most promising results for the conversion of the arylboronic
acids to the corresponding heterocoupled products were
obtained for or close to approximately equal mixtures, i.e.
50% ACN:H2O (85% heterocoupled vs 5% homocoupled) and
employing either of the solvents (ACN or H2O) as sole 60%
ACN:H2O
(79%
heterocoupled
vs
6%
reaction medium (i.e. 100%) led to the rapid conversion of the
arylboronic acids to their respective homocoupled products
along with a competing proportion of heterocoupling. A
steady increase of the concentration of water (0 to 90%)
brought about a significant reduction in the homocoupling
homocoupled).Working at the optimum proportion of water
(ACN:H2O, 1:1) is therefore significantly promoting the
heterocoupling over the competing homocoupling pathway for
arylboronic acids.
% HeteroProduct
% Nitro Homo
100
80
85
60
40
20
68
79
51
43
54
25
62
61
54
45
0
100% ACN
Solvent Concentration ACN/H2O (v/v)
100% H2O
Figure 3: Effect of water content in the reaction medium on the promotion of heterocoupling vs. homocoupling reactions of arylboronic acids.
effective in providing the desired heterocoupled product. Also
5. Substrate Scope
a variety of electron-rich boronic acids were employed to
provide in most cases good to high yields of the cross-coupled
products, thus highlighting the high potential of this coupling
protocol.
As shown in Scheme 2, it was established that there is ample
scope for the heterocoupling of aryl boronic acid with the
developed catalytic system. Next the attention was turned to
the heterocoupling of polyaromatic systems such as naphthyl,
anthracenyl and phenanthrenyl boronic acids. These substrates
in most cases are less reactive than more simple arylboronic
With a highly selective and efficient protocol for the
heterocoupling of two arylboronic acids in hand, we decided
to explore the generality of the synthetic procedure by varying
the electronics on the boronic acids to further promote the
formation of the cross-coupled products. Note that the yields
provided are specifically for the cross-coupled products
(yields of homocouplings of the limiting arylboronic acid are
provided in the supporting information). The catalytic process
performed particularly well when the electron-poor aryl
boronic acid was added first to the catalyst ACN/H2O solvent acids while exhibiting a certain amount of steric hindrance
system and to the obtained catalytic solution was then slowly
added the second electron-rich aryl boronic acid (in a slight
that could hamper the success of the developed catalytic
process (Scheme 3). In general it was observed that the
excess of 1.3 Equiv.). The resultant mixture was then stirred at catalytic activity was lower regarding the desired cross-
70oC for 48 hours providing competitive yields of the cross- coupled products which were still obtained in decent yields,
coupled products. In this regards, the employment of 3- or 4- though. The employment of naphthyl or phenanthrenyl
nitrophenyl, 4-chlorophenyl and 4-fluorophenyl boronic acids
boronic acids as coupling partners with other aryl boronic
as the electron-poor boronic acid coupling partners were acids gave appreciable yields of the cross-coupled products
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
while the sterically even more challenging anthracene boronic
hydrodeborylated anthracene). Notably, it was also possible to
acid gave lower yields of the cross-coupled product (here successfully employ triphenylamine boronic acid as well as
homocoupling of the aryl boronic acid was also observed but pyrene boronic acid as coupling partners.
in smaller quantities along with large amount of
a
Scheme 2: Heterocoupling of different aryl boronic acids to provide simple biphenyls.
The synthesized cross-coupled products thus obtained were
characterized by various analytical techniques, while in some
cases the crystalline nature of the products allowed their
structural confirmation by single crystal X-ray analysis
(Figure 4). 2l crystallised in the orthorhombic space group
bridges the carbamate moiety and the adjacent phenyl ring.
The nitrogen bound hydrogen was found and refined freely. It
is involved in hydrogen bonding with O1 (H1N…O1, 2.28 Å).
Here the interaction is of intermolecular nature. In addition an
intermolecular halogen hydrogen bond is found between the
Pbca with eight molecules in the unit cell as mentioned, chlorine atom (Cl1) and another hydrogen atom of C2, 2.902
though not discussed, previously.28 The carbamate moiety is
Å. The torsion angle between the two phenyl rings is 34.6°. In
involved in hydrogen bonding both intra- and contrast to the next two structures co-planarity of the phenyl
intermolecularly. The carbonyl oxygen atom (O1) has
intramolecular hydrogen bonding contacts to two carbon
bound hydrogen atoms of the tBu group (C2, C3) and to one
carbon bound hydrogen atom of the methylene (C6) which
rings is not dominant in the crystal lattice, which is more
strongly determined by the various hydrogen bonding
interactions.
Scheme 3: Heterocoupling of different aryl boronic acids to provide polyaromatic biaryls.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
3f crystallised in the monoclinic space group P21/c with four
molecules in the unit cell.29,30 Hydrogen bonding was not
observed despite the presence of an oxygen function (methoxy
substituent). The phenanthrene and phenyl aromatic systems
exhibit a torsion angle of 61.2° between them. All phenyl
rings are coplanar throughout the crystal lattice while the
phenanthrene planes are found in two orientations, with the C-
H functions of one orientation pointing towards the π-system
of the other and vice versa in nearly perpendicular
arrangements.
3h
3h crystallised in the monoclinic space group P21/n with four
molecules in the unit cell.31 Hydrogen bonding interactions
were observed between the two oxygen atoms of the nitro
group and C-H functions (O1…H12-C12, 2.698 Å; O2…H18-
C18, 2.637 Å). They are comparably weak, however, and the
packing in the crystal lattice appears to be dominated by the
arrangement of the aromatic ring systems with all anthracene
moieties of two adjacent rows viewed along being coplanar
and all phenyl rings of these rows being coplanar. The
distances between the respective planes are too long to
indicate actual π-π stacking, though. Phenyl ring and
anthracene moiety of a molecule are tilted against each other
with a torsion angle of 69.3° between them.
Figure 4: Single crystal structure for 2l, 3f and 3h.
Further exploration of the scope for the heterocoupling
reaction led to successfully employing heteroaryl boronic
acids such as 2-benzofuranyl, 2-furanyl, dibenzofuranyl as
well as 2-thiophenyl boronic acids as the electron-rich
coupling partners. The coupling reaction with an electron-
poor 3-nitrophenyl boronic acid resulted in good yields of the
cross-coupled products. Similar outcomes were observed
when utilizing 4-chlorophenyl boronic acid and 4-
methoxycarbonylphenyl boronic acid as the electron-poor
coupling partners. These results further demonstrate the high
and wide potential of the developed protocol.
6.
Tandem
One-Pot
Sequential
Oxidative
Heterocoupling/Suzuki-Miyaura coupling:
The success with the heterocouplings of different boronic
acids encouraged us to explore the possibility of developing a
unique protocol involving the tandem32 heterocoupling of two
different arylboronic acids followed by a Suzuki-Miyaura
coupling of the resultant chlorobiphenyl with a 3rd arylboronic
acid. Activation of the C–Cl bond in the second step was
performed by the addition of an electron-rich X-Phos ligand
system, which activated the palladium centre and facilitated
the subsequent coupling.
2l
Despite, the overall yield of the terphenyl system having been
low (mainly due to the competing by-products listed in the
scheme), the overall applicability of such a protocol renders it
a useful tool towards obtaining polyarenes in a selective
manner.
3f
Scheme 4: Heterocoupling of aryl/heteroaryl boronic acids.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
The initial arylboronic acid heterocoupling proceeded
smoothly to provide the desired products in competitive
unique sequential tandem protocol for the oxidative
heterocoupling/Suzuki-Miyaura coupling symbiosis. Although
yields. However, a slight excess of 4-chlorophenyl boronic only moderate to decent yields of the differently substituted
acid added in the first catalytic process needs to be considered
when carrying out the second one-pot sequential Suzuki-
Miyaura cross-coupling procedure as it can compete with the
oxidative cross-coupled product (although in relatively lower
amounts). Keeping this in mind, we performed the second
terphenyls (up to 55% by GCMS and 51% isolated) were
obtained as of yet, further development of this synthetic
strategy holds quite some promise as it provides an expedient
access to triaryl adducts. This may include inter alia working
without additional catalyst and exploiting the elimination of
activation of the C–Cl bond by employing an activated extra purification steps.
phosphine ligand (X-Phos) resulting in the development of a
Scheme 5: One-pot sequential boronic acid heterocoupling/Suzuki-Miyaura cross-coupling.
7. TEM studies of Pd colloids in catalytic solution post-
catalysis: To gain insight into the nature of the Pd colloids
after the catalytic oxidative heterocoupling, the catalytic
solution thus obtained was submitted to TEM studies (same
reaction depicted in Table 1 between 3-nitrophenyl boronic
acid and 4-methoxyphenyl boronic acid). Initially, Pd colloids
catalyst had earlier shown colloids of size ~2 nm (HRTEM
analysis reported in reference 20) when subjected to the
catalytic conditions could bring about variation in size or
morphology. To ascertain such a possibility the catalytic
solution was subjected to a detailed transmission electron
microscopic (TEM) study. It was observed that in the case of
the palladium colloids obtained after the reaction had
increased in size from ~2 nm to 4-7 nm (Figure 5). Although,
in spite of this slight increase in size of the colloidal particles
it was possible to perform simultaneous catalytic oxidative
heterocouplings (for the same substrates) using the same
catalytic solution by simple addition of a fresh batch of
(A)
(B)
1st Catalytic cycle yield
86
2nd Catalytic cycle yield
84
substrates after the first reaction was completed. It was
observed that the catalytic activity on re-using the colloidal
catalyst was retained providing further evidence about the
active nature of the synthesized colloids in the given oxidative
heterocoupling reactions.
Figure 5: (A) TEM analysis of catalytic solution for oxidative
heterocoupling post-catalysis. (
(GC yield).
B) Catalyst recycle studies
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
CCDC number
formula weight
crystal system
space group
a, Å
1588746
299.31
Monoclinic
P21/n
1588745
1588744
31.80
8. Conclusion
284.34
Monoclinic
P21/c
In conclusion, the unprecedented oxidative heterocoupling of
unsymmetrical arylboronic acids under aerobic conditions in
ACN:H2O (1:1) system, presented herein facilitates the access
to a large number of substituted biaryls. This was achieved by
the judicious choice of electronically distinct arylboronic
acids and the scope was found to embrace simple arylboronic
acids, bulky ones as well as heteroarylboronic acids which
were all efficiently coupled at the optimized conditions. The
colloidal catalyst exhibits a unique selectivity for the
heterocoupling over the homocoupling pathways, which was
further promoted with an optimum concentration of water
Orthorhombic
Pbca
12.996(3)
6.0624(12)
18.004(4)
90
13.261(3)
15.134(3)
7.5763(15)
90
9.4861(5)
9.7245(6)
36.986(2)
90
b, Å
c, Å
α, deg
β, deg
93.83(3)
90
100.66(3)
90
90
γ, deg
V, Å3
90
1415.4(5)
4
1494.3(5)
4
3411.9(3)
8
Z
T, K
μ,mm-1
Dcalcd,g/cm3
170
298
298
(50%).
heterocoupling/Suzuki-Miyaura
further yielded differently
A
tandem one-pot sequential boronic acid
0.091
0.076
0.230
cross-coupling
substituted
protocol
terphenyls,
1.405
1.264
1.237
F (000)
624
600
1344
demonstrating that the developed heterocoupling process has
significant potential for being part of synthetically relevant
applications.
unique reflections
collected reflections
Rint
GOF on F2
R1[I>2σ(I)][a]
Rw[I>2σ(I)][b]
Δρ max/min [e Å-3]
3902
3054
3380
15363
0.0923
0.875
12679
0.1424
0.836
14966
0.0418
1.014
9. Experimental Section
0.0459
0.0983
0.0492
0.1014
0.0506
0.1316
Synthetic procedures, catalytic process details and complete
1
characterization data including H and 13C NMR data have
0.285
0.236
/
-
0.120 / -0.163 0.134 / -0.286
been provided in the Supporting information.
X-ray structural analysis: Suitable single crystals of 2l, 3f and
3h were mounted on a thin glass fibre coated with paraffin oil.
X-ray single-crystal structural data were collected at low
temperature (170 k) in case of 3h and at r.t. in case of 3f and
2l (cooling system was dysfunctional at time of measurement)
using a STOE-IPDS 2T diffractometer equipped with a
normal-focus, 2.4 kW, sealed-tube X-ray source with
graphite-monochromated MoKα radiation (λ =0.71073 Å).
The program XArea was used for integration of diffraction
profiles; numerical absorption correction (3h and 2l) was
applied using the programs X-shape and X-red32; all from
STOE © 2010. The structures were solved by SHELXT-
201633 and refined by full-matrix least-squares methods using
SHELXL-201634. All non-hydrogen atoms were refined
anisotropically. Unless otherwise stated, the hydrogen atoms
were refined isotropically on calculated positions using a
riding model with their Uiso values constrained to 1.5 Ueq of
their pivot atoms for terminal sp3 carbon atoms and 1.2 times
for all other carbon atoms. The nitrogen bound hydrogen atom
of the carbamate moiety of 2l was found and refined freely
resulting in a relatively short N-H distance. All calculations
were carried out using SHELX-2016 and the WinGX GUI,
Ver2014.135. Selected crystallographic and refinement data
are summarized in table below.
General procedure for the synthesis of Pd colloids
In an oven dried schlenk tube, add palladacycle
.
1
(9.37 mg,
1.0 mmol, 1 mol%) under a continuous flow of nitrogen
followed by K2CO3 (276 mg, 2.0 mmol) and 4-
chlorobenzaldehyde (0.140 mg, 1.0 mmol) via syringe.
Chloroform (2.0 mL) was then added under nitrogen and the
reaction mass was stirred and refluxed in an oil bath at 80°C
for 24hrs. The reaction mass was then cooled and transferred
to a conical flask containing ethanol (4.0 mL) and stirred for
30 min at room temperature. The suspension thus obtained
was centrifuged at 10,000 RPM for 15 min. and the
supernatant was discarded, while the obtained precipitate was
washed with water (4.0 mL) and again centrifuged at 10000
RPM for 15 min. This procedure was repeated 3 times to get a
black residue, which was then vacuum dried for 1 hr and
subjected to all the characterization techniques.
10. Acknowledgements
The authors would like to thank Prof. Ian Fairlamb for fruitful
discussion about the work presented. ARK acknowledges
‘The Alexander von Humboldt Foundation’ for the equipment
grant and research cooperation linkage programme with CS.
ARK also likes to thank the University Grants Commission
India for the start-up grant and UGC-SAP fellowship for SB.
Crystallographic data were deposited with the Cambridge
Crystallographic Data Centre, CCDC, 12 Union Road,
Cambridge CB21EZ, UK. These data can be obtained free of
charge on quoting the depository numbers CCDC 1588744-
Keywords: Heterocoupling • Boronic Acids • Palladium Colloids
• Tandem • One-pot
1588746
by
FAX
(+44-1223-336-033),
email
(deposit@ccdc.cam.ac.uk) or their web interface (at
http://www.ccdc.cam.ac.uk).
11. References
1) a) P. E. Fanta, Chem. Rev. 1946, 38, 139. b) J. Wencel-
Delord, A. Panossian, F. R. Leroux, F. Colobert, Chem.
Parameters
3h
3f
2l
empirical formula
C20H13NO2
C21H16O
C18H20ClNO2
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
Soc. Rev. 2015, 44, 3418. c) J.-A. Garcia-Lopez, M. F.
17) H. Peng, Y. Xi, N. Ronaghi, B. Dong, N. G. Akhmedov,
X. Shi, J. Am. Chem. Soc. 2014, 136, 13174.
18) W. Yin, C. He, M. Chen, H. Zhang, A. Lei, Org. Lett.
2009, 11, 709.
19) L. Su, J. Dong, L. Liu, M. Sun, R. Qiu, Y. Zhou, S.-F.
Yin, J. Am. Chem. Soc. 2016, 138, 12348.
Greaney, Chem. Soc. Rev. 2016, 45, 6766.
2) a) R. Capdeville, E. Buchdunger, J. Zimmermann, A.
Matter, Nat. Rev. Drug Discovery 2002, 1, 493 – 502. b)
A. Markham, K. L. Goa, Drugs 1997, 54, 299 – 311. c)
K. F. Croom, G. M. Keating, Am. J. Cardiovasc. Drugs
2004, 4, 395. d) M. E. Matheron, M. Porchas, Plant Dis.
2004, 88, 665.
20) V. Sable, K. Maindan, A. R. Kapdi, P. S. Shejwalkar, K.
Hara, ACS Omega 2017, 2, 204.
3) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem.
Int. Ed. 2005, 44, 4442.
21) a) A. Molnar, Chem. Rev. 2011, 111, 2251. b) J. A.
Delgado, O. Benkirane, C. Claver, D. Curulla-Ferre, C.
Godard, Dalton Trans. 2017, 46, 12381.
22) a) S. Navalon, H. Garcia, Nanomaterials 2016, 6, 123. b)
Y. Xia, H. Yang, C. T. Campbell, Acc. Chem. Res. 2013,
46, 1671.
23) a) H. C. Hailes, Org. Process Res. Dev. 2007, 11, 114. b)
A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725.
24) I. Svensson, E. Wehtje, P. Adlercreutz, B. Mattiasson,
Biotech. Bioengg. 1994, 44, 549.
4) a) R. Martin, S. L. Buchwald, Acc. Chem. Res. 2008, 41,
1461. b) C. C. C. Johansson Seechurn, M. O. Kitching, T.
J. Colacot, V. Snieckus, Angew. Chem. Int. Ed. 2012, 51,
5062. c) F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270.
5) C. Cardovilla, C. Bartolome, J. M. Martinez-Ilarduya, P.
Espinet, ACS Catal. 2015, 5, 3040.
6) D. Haas, J. M. Hammann, R. Greiner, P. Knochel, ACS
Catal. 2016, 6, 1540.
7) a) ) K. Godula, D. Sames, Science 2006, 312, 67. b) L.
Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. Int.
Ed. 2009, 48, 9792. c) J. F. Hartwig, M. A. Larsen, ACS
Cent. Sci. 2016, 2, 281. d) Y. Wei, P. Hu, M. Zhang, W.
Su, Chem. Rev. 2017, 117, 8864. e) Z. Nairoukh, M.
Cormier, I. Marek, Nat. Rev. Chem. 2018,
doi:10.1038/s41570-017-0035.
8) G. Shulpin, Org. Biomol. Chem. 2010, 8, 4217.
9) a) L. Wang, W. Zhang, D. S. Su, X. Meng, F. S. Xiao,
Chem. Commun. 2012, 48, 5476. b) G. Cheng, M. Luo,
Eur. J. Org. Chem. 2011, 2519. c) B. Kaboudin, Y.
Abedi, T. Yokomatsu, Eur. J. Org. Chem. 2011, 6656. d)
Z. Xu, J. Mao, Y. Zhang, Catal. Commun. 2008, 9, 97. e)
J. P. Parrish, Y. C. Jung, R. J. Floyd, K. W. Jung,
Tetrahedron Lett. 2002, 43, 7899. f) A. Prastaro, P. Ceci,
E. Chiancone, A. Boffi, G. Fabrizi, S. Cacchi,
Tetrahedron Lett. 2010, 51, 2550. g) J.-S. Chen, K.
Krogh-Jespersen, J. G. Khinast, J. Mol. Catal. A: Chem.
2008, 285, 14−19.
10) a) S. Punna, D. D. Diaz, M. G. Finn, Synlett 2004, 2351.
b) Z. Jin, S. X. Guo, X. P. Gu, L. L. Qiu, H. B. Song, J.
X. Fang, Adv. Synth. Catal. 2009, 351, 1575. c) J. S.
Yadav, K. U. Gayathri, H. Ather, H. Rehman, A. R.
Prasad, J. Mol. Catal. A: Chem. 2007, 271, 25. d) M.
S.Wong, X. L. Zhang, Tetrahedron Lett. 2001, 42, 4087.
e) G. Cravotto, M. Beggiato, A. Penoni, G. Palmisano, S.
Tollari, J. M. Leveque, W. Bonrath, Tetrahedron Lett.
2005, 46, 2267. f) C. Amatore, C. Cammoun, A. Jutand,
Eur. J. Org. Chem. 2008, 4567. g) Y. Yamamoto, R.
Suzuki, K. Hattori, H. Nishiyama, Synlett 2006, 1027.
11) a) J. Zheng, S. Lin, X. Zhu, B. Jiang, Z. Yang, Z. Pan,
Chem. Commun. 2012, 48, 6235. b) B. Kaboudin, R.
Mostafalu, T. Yokomatsu, Green Chem. 2013, 15, 2266.
c) P. K. Raul, A. Mahanta, U. Bora, A. J. Thakur, V.
Veer, Tetrahedron Lett. 2015, 56, 7069.
25) a) C. Rohlich, A. S. Wirth, K. Kohler, Chem. Eur. J.
2012, 18, 15485. b) R. N. Butler, A. G. Coyne, Org.
Biomol. Chem. 2016, 14, 9945.
26) a) J. W. B. Fyfe, C. P. Seath, A. J. B. Watson, Angew.
Chem. Int. Ed. 2014, 53, 12077. b) J. W. B. Fyfe, E.
Valverde, C. P. Seath, A. R. Kennedy, J. A. Redmond, N.
A. Anderson, A. J. B. Watson, Chem. Eur. J. 2015, 21,
8951.
27) C.-R. Chang, Z.-Q. Huang, J. Li, WIREs Comput. Mol.
Sci. 2016, 6, 679.
28) CCDC number for 2l is 1588744
29) CCDC number for 3f is 1588745
30) R. Jin, Y. Chen, W. Liu, D. Xu, Y. Li, A. Ding, H. Guo,
Chem. Commun. 2016, 52, 9909.
31) CCDC number for 3h is 1588746
32) a) D. E. Fogg, E. N. dos Santos, Coord. Chem. Rev. 2004,
248, 2365. b) T. L. Lohr, T. J. Marks, Nat. Chem. 2015, 7,
477. c) M. M. Lorion, K. Maindan, A. R. Kapdi, L.
Ackermann, Chem. Soc. Rev. 2017, 46, 7399.
33) G. Sheldrick, Acta Cryst. A 2015, 71, 3.
34) G. Sheldrick, Acta Cryst. C 2015, 71, 3.
35) L. Farrugia, J. Appl. Crystallogr. 2012, 45, 849.
12) a) S. Carrettin, J. Guzman, A. Corma, Angew. Chem. Int.
Ed. 2005, 44, 2242. b) C. Gonzalez-Arellano, A. Corma,
M. Iglesias, F. Sanchez, Chem. Commun. 2005, 1990. c)
S. Carrettin, A. Corma, M. Iglesias, F. Sanchez, Appl.
Catal. A 2005, 291, 247. d) C. Gonzalez-Arellano, A.
Corma, M. Iglesias, F. Sanchez, J. Catal. 2006, 238, 497.
13) A. R. Kapdi, G. Dhangar, J. L. Serrano, J. A. De Haro, P.
Lozano, I. J. S. Fairlamb, RSC Adv. 2014, 4, 55305.
14) G. Cahiez, C. Duplais, J. Buendia, Angew Chem. Int. Ed.
2009, 48, 6731.
15) G. Cahiez, L. Foulgoc, A. Moyeux, Angew. Chem. Int.
Ed. 2009, 48, 2969.
16) H. G. Galeshahi, G. Antonacci, R. Madsen, Eur. J Org.
Chem. 2017, 1331.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800358
Chemistry - An Asian Journal
FULL PAPER
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.