Investigation of Pd-PEPPSI catalysts and coupling partners towards direct C2-arylation/heteroarylation of benzoxazole

Article abstract of DOI:10.1002/aoc.6296

2-Aryl/heteroaryl-substituted benzoxazoles are important heterocyclic motifs extensively found in several bioactive molecules, pharmaceuticals and natural products. In view of the importance of these compounds, there is need to develop easiest and simplest synthetic routes. The motive of this current work is to conduct the direct C2-arylation reaction on benzoxazole with various cross-coupling partners like aryl/heteroaryl halide/carboxylic acid/diazonium tetrafluoroborate/sulfonyl chloride/boronic acids in the presence of different symmetrical and unsymmetrical Pd-PEPPSI (pyridine-enhanced pre-catalyst preparation by stabilization initiation) catalysts via C (sp²)–C (sp²) bond formation. Compared with other coupling partners, boronic acids coupled with benzoxazole very efficiently in the presence of sterically and electronically tunable bulky1,3-bis(N,N′-2,4,6-triisopropylbenzyl)benzimidazolium-Pd-PEPPSI complex in open air to offer the corresponding C2-aryl/heteroaryl benzoxazole compounds. Further, it is worthy to mention that there is no need of any external oxidant/ligand/additive for the complete conversion of starting molecules to products. The reactions progressed successfully with a wide range of substrate scope and attained the products in good to excellent yields in a short reaction time in ethanol/water (1:1) medium. Greatly, catalysts can be recovered and reused for few cycles with significant reactivity.

Full text of DOI:10.1002/aoc.6296

Received: 17 March 2021
DOI: 10.1002/aoc.6296
Revised: 19 April 2021
Accepted: 30 April 2021
F U L L P A P E R
Investigation of Pd-PEPPSI catalysts and coupling partners
towards direct C2-arylation/heteroarylation of benzoxazole
Anusha Gokanapalli
| Venkata Krishna Reddy Motakatla
|
Vasu Govardhana Reddy Peddiahgari
Department of Chemistry, Yogi Vemana
2-Aryl/heteroaryl-substituted benzoxazoles are important heterocyclic motifs
extensively found in several bioactive molecules, pharmaceuticals and natu-
ral products. In view of the importance of these compounds, there is need
to develop easiest and simplest synthetic routes. The motive of this current
work is to conduct the direct C2-arylation reaction on benzoxazole with
various cross-coupling partners like aryl/heteroaryl halide/carboxylic acid/
diazonium tetrafluoroborate/sulfonyl chloride/boronic acids in the presence
of different symmetrical and unsymmetrical Pd-PEPPSI (pyridine-enhanced
pre-catalyst preparation by stabilization initiation) catalysts via C (sp2)–C
(sp2) bond formation. Compared with other coupling partners, boronic
acids coupled with benzoxazole very efficiently in the presence of sterically
University, Kadapa, India
Correspondence
Vasu Govardhana Reddy Peddiahgari,
Department of Chemistry, Yogi Vemana
University, Kadapa 516005, India.
Email: pvgr@yogivemanauniversity.ac.in
Funding information
Department of Science and Technology,
New Delhi, India, Grant/Award Number:
DST/INSPIRE Fellowship/[IF160138];
Council of Scientific and Industrial
Research (CSIR), Pusa, New Delhi,
India, Grant/Award Number: 02
(0248)/15/EMR-II
and
electronically
tunable
bulky1,3-bis(N,N0-2,4,6-triisopropylbenzyl)
benzimidazolium-Pd-PEPPSI complex in open air to offer the corresponding
C2-aryl/heteroaryl benzoxazole compounds. Further, it is worthy to
mention that there is no need of any external oxidant/ligand/additive for
the complete conversion of starting molecules to products. The reactions
progressed successfully with a wide range of substrate scope and attained
the products in good to excellent yields in a short reaction time in ethanol/
water (1:1) medium. Greatly, catalysts can be recovered and reused for few
cycles with significant reactivity.
K E Y W O R D S
benzoxazole, C (sp2)-C (sp2) bond formation, direct C2-arylation, Pd-PEPPSI catalysts,
recoverability studies
1 | INTRODUCTION
direct arylations towards the synthesis of an assortment
of arylated heterocycles.[3] Triflates[4a] or aryl diazonium
Since two decades, much attention has been paid on the
development of novel methods for C2-arylation reaction
via cross-coupling or oxidative homo-coupling reactions
on various heterocycles.[1] For the first time in 1990, Ohta
et al.[2] reported palladium-catalysed direct arylation on
furan with bromobenzene, however with only 23% yield.
Since then, many literature reports have been arriving on
salts[4b] were utilized as alternative coupling partners to
aryl halides for the direct arylation of heterocycles in the
presence of conventional palladium catalysts. Recently,
other coupling reagents like arylboronic acids[4c] and
benzoic acids[4d] were also employed to achieve the
respective aryl-substituted benzofused heterocycles under
oxidative conditions. Several researchers exploited
Appl Organomet Chem. 2021;e6296.
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© 2021 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.6296

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GOKANAPALLI ET AL.
transition-metal-catalysed C–X/C–H cross-couplings
between benzo[b]fused heterocycles and different
counter partners that offered valuable strategies for the
assembly of diverse C2-aryl/heteroaryl heterocycles
(Scheme 1a).[5] Although most of the protocols explored
with conventional copper/nickel/palladium catalysts,
there exist few limitations like tedious synthetic steps,
requirement of high catalyst load, use of external ligands
and additives, high temperature and long reaction time.
These methodologies are thus increasing the expense of
the reaction. Further, some of the metal complexes are
less tolerant to air, and to protect the M(0) species, they
are typically run under an inert atmosphere. Ligands play
a key role in the stability and reactivity of metal com-
plexes[6]; hence, the finest way for developing efficient
and robust catalysts towards challenging transformations
is via constructing innovative ligand systems, judging the
electron density around metal atoms through σ-donor or
π-acceptor properties. Of the various available ligands,
N-heterocyclic carbenes (NHCs) are the good candidates.
They form the metal–ligand σ-bonds by donating lone
pair of electrons to the d-orbital of metal centres and
thereby increase the electron density on the metal atom.
Apart from that, these can also act as π-acceptor ligands,
because they decrease the electron density on metal
atoms by delocalizing the electrons present on them.
Compared with phosphine and other ligands or catalysts,
NHCs are more nucleophilic and form stable complexes
with metals. They display good tunability through the
electronic and steric properties by substituents and are
likely been used to progress the cross-coupling reactions
more efficiently. For illustration, Pd-NHC-catalysed
direct C–H bond activation for arylation could offer green
and sustainable methodologies. In spite of the interesting
properties, Nolan, Herrmann, Glorius and other
researchers have been putting their maximum efforts in
identifying the role of different metal-NHC complexes
towards cross-coupling reactions.[7] Although several
research groups have been continuously focusing on the
synthesis of Pd-NHC complexes, they are however found
to prepare under careful and anhydrous reaction condi-
tions. Hence, the development of flexible protocols has
become essential for the preparation of stable, moisture-
resistant and easy-to-handle Pd-NHC pre-catalysts. In
SCHEME 1 (a) Previous literature reports
on C2-aryl/heteroaryl benzo[b]fused
heterocycles. (b) Benzimidazole bearing Pd-
PEPPSI complexes catalysed C2-arylation/
heteroarylation on benzoxazole with various
coupling partners

GOKANAPALLI ET AL.
3 of 11
this view point, Michael G. Organ in 2006 has introduced
a new class of pyridine-enhanced pre-catalyst preparation
by stabilization initiation (PEPPSI)-type catalysts bearing
one NHC ligand, two anionic ligands (e.g. Cl, Br and
OAc) and a fourth, ‘throwaway’ ligand ‘pyridine’ from
the readily available starting materials under a mild
reaction condition. Moreover, the method of preparation
of these complexes is a substantial improvement over
previously reported Pd-NHC complexes. From the early
discovery of the Pd-NHC-Py skeleton complexes, an array
of Pd-PEPPSI complexes of exciting catalytic activity have
come into existence with several organic conversions.[8]
In 2019, Lee et al.[9] prepared a series of imidazopyridine-
based Pd-PEPPSI catalysts and studied their ability
to catalyse the direct C–H arylation between
1,2-dimethylimidazole and aryl halides. Recently, Yang
and his group synthesized a variety of this kind of com-
plexes for direct C2-arylation reaction on free NH indoles
with aryl sulfonyl hydrazides.[10] Here, trifluoromethyl
sulfonic acid was also used as an additive to get good
yields of products. Few more literature reports of
C2-arylation on various substrates is displayed below in
Scheme 1a, which represent most of the reactions to
take place in the presence of supplementary reagents
and/or ligands in long reaction time and at high
temperature conditions. Hence, we set our goal to find
out new alternative catalysts that could effectively run
the C2-arylations and herein reported coupling of
benzoxazole with various partners like aryl/heteroaryl
chloride/carboxylic acid/diazonium tetrafluoroborate/
sulfonyl chloride and boronic acids by using Pd-PEPPSI
catalysts with high catalytic activity under mild reaction
conditions (Scheme 1b).
for C–C and C–N bond formation reactions, we
attempted similar reaction by employing 1-n-butyl-
3-methylimidazolium tetrafluoroborate (NHC) as ligand,
but did not observe better variation in yield (Table 1, Entry
2). In the next trial, reaction was repeated with Cu-NHC
complex (chloro[1,3-bis(2,6-diisoporopylphenyl)imidazol-
2-ylidene]copper(I)). In this case too, we did not notice
much change in yield even after the end point of reaction
(Table 1, Entry 3). Due to these poor results, we then
switched to palladium catalysts and performed reaction
with Pd(OAc)2 in presence of triphenylphosphine (PPh3),
1,2-bis(diphenylphosphino)ethane (dppe) and 2-dicy
clohexyl-phosphino-20,40,60-triisopropylbiphenyl (XPhos)
ligands in toluene at 110ꢀC for 24 h and identified small
improvement in yields compared with the earlier (Table 1,
Entries 4–6). Keeping this in mind, investigations were
continued with Pd-PEPPSI catalysts (1–9) that were
synthesized before or freshly in our laboratory. At first,
C2-arylation was carried out with Pd-PEPPSI-1 in toluene
without using any ligand in open air and gained an
enhancement in yield (Table 1, Entry 7). This turned our
attention to carefully scrutinize the ability of a series of
Pd-PEPPSI complexes 2–9 for the effective catalysis
towards the formation of corresponding C2-arylated
benzoxazole adduct. Among the library of catalysts tested,
Pd-PEPPSI-9 with bulky N,N0-2,4,6-triisopropylphenyl
groups revealed excellent catalytic activity, whereas
Pd-PEPPSI-2 and Pd-PEPPSI-5 containing ꢁNO2 group
furnished lower yields due to steric and electronic
properties (Table 1, Entries 8–15). Originally, the above
reactions were conducted in toluene solvent at 110ꢀC and
received the product up to 71% yield (Table 1, Entry 15).
To make the condition more practical, template reaction
was performed in other solvents such as tetrahydrofuran,
1,4-dioxane and ethanol/water (1:1) at 80ꢀC and obtained
the best product yield in later case (Table 1, Entries
16–18). Subsequently, to find the effective temperature
condition, reaction was repeated at 25ꢀC until 24 h but
regrettably did not observe the desire product formation
(Table 1, Entry 19). Therefore, it was affirmed that 80ꢀC
temperature was required to convert benzoxazole into
C2-substituted compound, indicating temperature has a
distinguishable effect on this reaction. In a further accom-
plishment, the role of bases like K2CO3, Cs2CO3, NEt3 and
pyridine was also supervised and noticed superior result
with NaOtBu only (Table 1, Entries 20–23).
2 | RESULTS AND DISCUSSION
Because there is a growing demand on the synthesis of
new viable palladium catalysts for different organic
transformations, we recently have developed an improved
protocol for the preparation of a series of different sym-
metrical and unsymmetrical Pd-PEPPSI complexes 1–9[11]
for C2-arylation on N-substituted benzimidazolium
derivatives.[11b] In continuation of our efforts towards
extending the scope of these catalysts for the other
precursor molecules, we herein demonstrated their utility
for C–H activation on benzoxazole nucleus. For optimizing
the reaction condition, we have chosen benzoxazole and
chlorobenzene as coupling partners and initiated an
experiment in the presence of Cu(OAc)2 and PPh3 in
toluene solvent at 110ꢀC for 24 h in open air, but unfortu-
nately obtained a very low product yield (Table 1, Entry 1).
Later, from the investigations on catalytic activity of NHCs
From the above studies, it was analysed that NaOtBu
and Pd-PEPPSI-9 were the more favourable reagents to
couple benzoxazole and chlorobenzene in ethanol/water
(1:1) solvent system at 80ꢀC.
Although several teams put forth C2-arylation on
benzoxazoles with aryl halides, these were however
reported to progress with less yields. For illustration,

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GOKANAPALLI ET AL.
TABLE 1 Optimization of reaction conditions and reagents for C2-arylation on benzoxazole with chlorobenzene
Entry
1
Catalyst
Ligand
PPh3
Base
Solvent
Temp (ꢀC)
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
80
Time (h)
Yield[a] (%)
Cu(OAc)2
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
K2CO3
Toluene
24
24
24
24
24
24
8
<5
15
19
22
25
30
51
42
45
48
43
47
54
59
71
65
62
84
N.P.
72
78
61
58
2
Cu(OAc)2
NHC
None
PPh3
Toluene
3
Cu-NHC
Toluene
4
Pd(OAc)2
Toluene
5
Pd(OAc)2
Dppe
XPhos
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
None
Toluene
6
Pd(OAc)2
Toluene
7
Pd-PEPPSI-1
Pd-PEPPSI-2
Pd-PEPPSI-3
Pd-PEPPSI-4
Pd-PEPPSI-5
Pd-PEPPSI-6
Pd-PEPPSI-7
Pd-PEPPSI-8
Pd-PEPPSI-9
Pd-PEPPSI-9
Pd-PEPPSI-9
Pd-PEPPSI-9
Pd-PEPPSI-9
Pd-PEPPSI-9
Pd-PEPPSI-9
Pd-PEPPSI-9
Pd-PEPPSI-9
Toluene
8
Toluene
8
9
Toluene
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Toluene
8
Toluene
8
Toluene
8
Toluene
8
Toluene
8
Toluene
8
THF
8
1,4-Dioxane
Ethanol/water (1:1)
Ethanol/water (1:1)
Ethanol/water (1:1)
Ethanol/water (1:1)
Ethanol/water (1:1)
Ethanol/water (1:1)
80
8
80
8
25
24
8
80
Cs2CO3
NEt3
80
8
80
8
Pyridine
80
8
Note: Reaction conditions: benzoxazole (1.0 mmol), chlorobenzene (1.0 mmol), base (3.0 mmol), solvent (3 mL), catalyst (0.5 mol%), ligand (0.5 mol%), open air.
Abbreviations: Cu-NHC, chloro[1,3-bis(2,6-diisoporopylphenyl)imidazol-2-ylidene]copper(I); NHC, 1-n-butyl-3-methylimidazolium tetrafluoroborate; N.P., no
product.
aIsolated yield.

GOKANAPALLI ET AL.
5 of 11
Itami and his team conducted nickel-catalysed direct
arylation of benzoxazole with aryl halides and triflates
and obtained the corresponding product in a lower
yield.[12] Also, these aryl halides are hazardous in nature
involving tedious work-up procedure with the formation
of by-products/impurities.[13b] Therefore, considering the
environmental impact through minimizing the complex
precipitate formation and to increase yield percentage,
optimization reactions were conducted with other cou-
pling partners. In this objective, a reaction was performed
between benzoxazole and benzoic acid in the presence of
Pd-PEPPSI-9 and NaOtBu in toluene at 80ꢀC in open air
for 24 h but obtained less product yield (Table 2, Entry
1). Literature reports too emphasized that the reaction
between these two partners requires additives and takes
place at high temperature with limited use to two
substituted derivatives.[14] Hence, in a next trial, benzene
diazonium tetrafluoroborate was selected as a coupling
partner and performed the reaction under similar condi-
tion, whereby it achieved 85% of yield (Table 2, Entry 2).
Although a comparatively better product yield was
obtained, this kind of coupling partners is relatively
expensive with limited substrate scope and hence not
economical for such use. It is for this reason that two
more individual reactions were performed by employing
benzenesulfonyl chloride or phenylboronic acid in the
same method and gained an outstanding yield with the
latter case in a small reaction time (Table 2, Entries 3 and
4). Also, boronic acids are known to exhibit desirable
characteristics that are advantageous when compared
with other organometallic and organometalloid reagents.
Worthily, a variety of air- and moisture-stable boronic
acids can be synthesized from the valuable precursors
and can be stored easily. Further, aryl/heteroarylboronic
acids with a variety of functional groups, ring sizes and
conjugated systems are commercially available. In
TABLE 2 Identification of suitable
reaction partner for C2-arylation on
benzoxazole
Entry
Coupling partner
Time (h)
Temperature (ꢀC)
Yield[a] (%)
1
24
80
48
2
3
4
6
80
80
80
85
59
95
24
4
Note: Reaction conditions: benzoxazole (1.0 mmol), coupling partner (1.5 mmol), Pd-PEPPSI-9 (0.5 mol%),
NaOtBu (3.0 mmol), ethanol/water (1:1, 3 mL), open air.
aIsolated yield.

6 of 11
GOKANAPALLI ET AL.
addition, the diversity in boronic acid substrates could
facilitate the mechanistic insights into reactivities with
different substrates. More precisely, boronic acids and
boron-containing by-products are non-toxic and can be
removed easily from the reaction mixtures even on a
large scale. The availability of large number of
arylboronic acids makes the palladium-catalysed reac-
tions highly attractive in throughput medicinal chemistry
for the generation of ‘privileged scaffolds’. Thus, the
diversity among the readily accessible arylboronic acids is
larger than among the corresponding aryl halides or
other partners. Together, the widespread availability and
unique reactivity properties of boronic acids are advanta-
geous to explore the C2-arylation of benzoxazole with
boronic acids under different catalytic conditions for the
synthesis of 2-aryl benzoxazoles.[13]
FIGURE 1 Reactivity profiles of benzoxazole with
phenylboronic acid using Pd-PEPPSI complexes 1–9
2.1 | Rate of reaction of C2-arylation of
benzoxazole with phenylboronic acid in
presence of Pd-PEPPSI complexes 1–9
4-chlorophenylboronic acid also underwent competent
reactivity and released the desired chloro-substituted
benzoxazole (3h) in 84% yield. This functional-group tol-
erance could allow further derivatization of compound
3h via cross-coupling reactions like Suzuki–Miyaura,
Sonogashira, Buchwald or other similar reactions. Even
the sterically crowded 2,4,6-trimethylbenzene boronic
acid offered good yield (Table 3; 3d), and thus, the
C2-arylation on benzoxazoles is quite insensitive to steric
effects with these catalysts. Furthermore, the catalysts
also coupled heterocyclic boronic acids such as
3-thiopheneboronic acid, 3-quinolineboronic acid and
5-isoquinolineboronic acids at a better rate, giving the
corresponding products in attractive yields (Table 3,
3k–3m). Thus, Pd-PEPPSI catalysts triggered the boronic
acids to couple with benzoxazole, yielding cross-coupling
products more efficiently, while leaving only traces of
homo-coupled products.
In our next attempt to screen the rate of reaction, we con-
ducted
a
sequence of C2-arylation reactions of
benzoxazole with phenylboronic acid in the presence of -
Pd-PEPPSI complexes 1–9 (0.5 mol% loading) and
NaOtBu in ethanol/water (1:1) medium at 80ꢀC. In all
the cases, reaction started slowly in 30 min and produced
maximum yields within 4 h of time. After that, no further
progression in yield was noticed. From Figure 1, a high
yield (95%) of product would be observed with
Pd-PEPPSI-9 and low yield with Pd-PEPPSI-2, and this
has driven the exact idea of carrying out C2-arylation
reactions on benzoxazole with highly active Pd-PEPPSI-9.
Benzoxazole finds differential reactivity with various
coupling partners depending on the nature of substitu-
ents/functional groups present on them. Hence, we
aimed at the identification of tolerance of various boronic
acids for this reaction. With the optimized reaction
conditions in hand, we proceeded to investigate the
C2-arylation of benzoxazole with various activated/
deactivated arylboronic acids (2a-m) in open atmospheric
condition, and the results were shown in Table 3.
Catalyst was very effective for the reaction of benzoxazole
with arylboronic acids bearing electron-donating groups
like ꢁCH3, ꢁOCH3 than those with electron-
withdrawing groups like ꢁCF3 and ꢁNO2 to produce
corresponding products in comparatively better yields
(Table 3; 3b, 3c, 3e, 3f, 3g). More specifically,
p-tolylboronic acid coupled very smoothly with the best
product yield of 98% (Table 3; 3b), whereas the
p-nitrobenzeneboronic acid coupled less efficiently
2.2 | Recoverability of catalyst
Reusability of the catalyst is becoming a green chemistry
and economical concern in nowadays. Hence, to know
the ability of Pd-PEPPSI complexes to recover and reuse
for successive cycles, we conducted an experiment
between benzoxazole 1 and benzeneboronic acid 2a,
making use of Pd-PEPPSI-9 in homogeneous condition
under the optimized reaction condition. After the
complete conversion of starting material into product
(monitored through thin-layer chromatography [TLC]),
the reaction mixture was cooled to 25ꢀC, distilled off the
with
82%
yield
(Table
3;
3g).
Enticingly,

GOKANAPALLI ET AL.
7 of 11
TABLE 3 Substrate scope of
catalyst for C2-arylation on benzoxazole
with boronic acids
Note: Reaction conditions: benzoxazole 1 (1.0 mmol), aryl/heteroarylboronic acids 2a-m (1.5 mmol),
Pd-PEPPSI-9 (0.5 mol%), NaOtBu (3.0 mmol), ethanol/water (1:1, 3 mL), open air.
solvent by using rotary evaporator, extracted with water
and ethyl acetate and purified through column chroma-
tography to obtain the product and the catalyst. The
recovered catalyst was utilized for the next cycle follow-
ing the same reaction condition, and the procedure was
repeated for six consecutive cycles to afford the product
in 95%, 95%, 89%, 77%, 61%, and 43% yields, respectively.
In every cycle, we identified a little amount of catalyst
leaching. However, a considerable drop in the product
yield was noticed only after the third cycle. This indicates
that there is no significant loss of catalytic activity until
three cycles after which a gradual decrease in yield can
be noticed (Figure 2). The isolated catalyst after sixth
cycle was characterized by scanning electron microscopy
with energy-dispersive x-ray analysis (SEM-EDX) and
x-ray photoelectron spectroscopy (XPS) experiments and
compared with freshly prepared complex (SEM and XPS
details of fresh Pd-PEPPSI-9 were discussed in detail

8 of 11
GOKANAPALLI ET AL.
in our previous work and recovered here for com-
parison[11b]). The SEM-EDX spectroscopy experiment
was performed to assess the change in palladium content
in recovered Pd-PEPPSI-9 complex and observed decrease
in palladium content from 9.27 (fresh complex) to 0.49 wt
% (recovered complex) (Figure 3). Next, the elemental
scan was also conducted by XPS analysis, which showed
the presence of palladium, chlorine, nitrogen and carbon
atoms in recovered Pd-PEPPSI-9 complex. This was
compared with the freshly prepared complex (Figure 4).
In the XPS survey spectrum report of recovered
catalyst, we detected the lowering of peak intensity of
palladium and chloride (majorly). Thus, the SEM and
XPS analysis revealed that the complex underwent slow
degeneration of complex to Pd(0) and other species after
few cycles.
3 | CONCLUSION
In summary, we have established Pd-PEPPSI-catalysed
direct C2-arylation of benzoxazoles with wide variety of
coupling partners such as aryl chloride/carboxylic acid/
diazonium tetrafluoroborate/sulfonyl chloride/boronic
acid in ethanol/water system. Catalytic findings disclosed
FIGURE 2 Recyclability of the catalyst
FIGURE 3 SEM-EDX interpretation. (a) SEM image. (b) EDX smart quant analysis. (c) EDS plots of (a) freshly prepared Pd-PEPPSI-9
complex and (b) recovered Pd-PEPPSI-9 complex after sixth cycle
FIGURE 4 XPS. Survey spectrum
of (a) freshly prepared Pd-PEPPSI-9
complex and (b) recovered Pd-PEPPSI-9
complex after sixth cycle

GOKANAPALLI ET AL.
9 of 11
that 0.5 mol% of 1,3-bis(N,N0-2,4,6-triisopropylphenyl)
benzimidazolium-NHC bearing Pd-PEPPSI-9 complex
was very efficient and have shown a substantial catalytic
performance due to its bulky nature. Further, the catalyst
described herein extends a green protocol for the direct
C2-arylation of benzoxazole with the following merits:
Boronic acids are attractive coupling partners in terms of
cost and availability, a simple purification, controlled
temperature, outstanding stability and resistance to
leaching into the solution. Hence, we reported the
synthesis of a series of 2-aryl/heteroaryl benzoxazoles
with benzoxazole and aryl/heteroarylboronic acids in
the presence of 1,3-bis(N,N0-2,4,6-triisopropylphenyl)
benzimidazolium bearing Pd-PEPPSI complex. Worthily,
catalyst can be recycled and reused for few cycles without
considerable decrease in performance.
4.2 | General procedure for the synthesis
of Pd-PEPPSI complexes 1–9
Pd-PEPPSI complexes 1–9 were prepared according to
our previous reports.[11]
4.3 | General procedure for the
preparation of C2-aryl/heteroaryl
benzoxazoles (3a–3m)
A freshly dried 25-mL round-bottom flask was charged
with benzoxazole 1 (1.0 mmol), arylboronic acids
(1.5 mmol), Pd-PEPPSI complexes (0.5 mol%) and
sodium tert-butoxide (3.0 mmol) in ethanol/water (1:1,
3 mL) and allowed to stir at 80ꢀC in open air for
3–4 h. After the completion of reaction (observed over
TLC), the reaction mixture was brought to 25ꢀC, added
a small quantity of water and extracted with ethyl ace-
tate twice (2 ꢃ 5 mL). The combined organics was
dried over anhydrous sodium sulfate and distilled
under reduced vacuum by rotary evaporator, and the
obtained crude mass was purified through column
chromatography using 100–200 silica mesh with ethyl
acetate in petroleum ether (1:9) as eluent to obtain the
products as solids (3a–3m).
4 | EXPERIMENTAL SECTION
4.1 | General experimental section
Reactions were carried out in an open atmosphere in
tetrahydrofuran, toluene, 1,4-dioxane and ethanol/water.
Progress of reactions was monitored through TLC analy-
sis using Merck silica gel F254 plates by visualizing under
ultraviolet (UV) lamp. Benzoxazole, chlorobenzene,
benzoic acid, benzenediazonium tetrafluoroborate,
benzenesulfonyl chloride, aryl/heteroarylboronic acids,
bases, palladium and copper reagents, ligands, solvents,
etc., were procured from Aldrich, Alfa, Acros Organics,
TCI, Merck Scientific and Avra Synthesis and used as
received without further purification. Melting points of
the synthesized compounds were uncorrected. Infrared
spectra of final compounds were obtained using Bruker
Alpha-Eco ATR-FTIR (attenuated total reflection-Fourier
transform infrared) interferometer with single-reflection
4.4 | Gram-scale synthesis of
2-phenylbenzo[d]oxazole
After the important advances having been made on
the development of Pd-PEPPSI complexes for the prep-
aration of different C2-aryl/heteroaryl benzoxazoles, we
decided to identify the applicability of this method for
the gram-scale synthesis. Hence, we performed a reac-
tion between benzoxazole (0.70 g, 5.88 mmol) and phe-
nylboronic acid (1.07 g, 8.82 mmol) in the presence of
Pd-PEPPSI-9 under the optimized reaction conditions
(Table 3, scheme) and isolated the desired product
(1.10 g, 96%). This proved that the methodology is
more convenient even for the bulk-scale preparation of
compounds.
1
sampling module equipped with KBr crystal. H and 13C
NMR were recorded with Bruker Topspin 400- and
100-MHz spectrometers using tetramethylsilane (TMS) as
an internal standard. Chemical shifts (δ) were reported
in ppm. Multiplicities in the 1H NMR spectra were
described as s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet; coupling constants were
reported in Hz. SEM-EDX was recorded using JEOL
SEM-EDS instrument to characterize the elemental com-
position of the fresh and recovered Pd-PEPPSI-9 complex.
XPS system (Omicron ESCA+, Oxford Instruments,
Germany) operated with an Argus analyser (mean radius
of 124 mm) was used to identify the elements present in
recovered Pd-PEPPSI-9 for comparison with fresh com-
plex. Resolution was confirmed using a full width at half
maximum (FWHM) of ꢂ0.60 eV.
4.5 | General procedure for recycling of
the catalyst
The optimized reaction condition for C2-arylation of
benzoxazole with phenylboronic acid was the same for
the recyclability experiment. After the reaction, solvent
was distilled off under reduced pressure by using rotary
evaporator. To that was added a little amount of water

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ACKNOWLEDGMENTS
The authors are grateful to Council of Scientific and
Industrial Research (CSIR), Pusa, New Delhi, India,
for the financial support to this project (Project
File No. 02(0248)/15/EMR-II). The research fellow
G. Anusha acknowledges the Department of Science and
Technology, New Delhi, India, for encouraging with
DST-INSPIRE-JRF fellowship (No. DST/INSPIRE Fellow-
ship/[IF160138]).
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AUTHOR CONTRIBUTIONS
Anusha Gokanapalli: Methodology. Venkata Krishna
Reddy Motakatla: Methodology. Vasu Govardhana
Reddy Peddiahgari: Methodology.
CONFLICT OF INTEREST
All the authors declare no conflicts of interest.
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DATA AVAILABILITY STATEMENT
The analytical data and copies of 1H and 13C NMR
spectra for C2-aryl benzoxazoles supporting the findings
of this study are available in Data S1.
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ORCID
Anusha Gokanapalli https://orcid.org/0000-0001-8449-
6936
Venkata Krishna Reddy Motakatla https://orcid.org/
0000-0002-4364-7790
Vasu Govardhana Reddy Peddiahgari https://orcid.org/
0000-0001-8837-0847
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How to cite this article: A. Gokanapalli, V. K.
R. Motakatla, V. G. R. Peddiahgari, Appl
Organomet Chem 2021, e6296. https://doi.org/10.
1002/aoc.6296