Atom economic palladium catalyzed novel approach for arylation of benzothiazole and benzoxazole with triarylbismuth reagents via C[sbnd]H activation

Article abstract of DOI:10.1016/j.catcom.2016.10.005

We have developed a novel method for the direct C[sbnd]H functionalization of benzothiazole and benzoxazole using triarylbismuth reagents. The arylation proceeds using the homogeneous catalytic system PdCl₂, Cu(OAc)₂ and PPh₃ ligand. Triarylbismuthines, which act as threefold arylating reagents, have low toxicity, are green and ecofriendly. These methodologies are particularly useful to prepare arylated benzothiazoles and benzoxazoles.

Full text of DOI:10.1016/j.catcom.2016.10.005

Catalysis Communications 89 (2017) 29–33
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Catalysis Communications
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Short communication
Atom economic palladium catalyzed novel approach for arylation of
benzothiazole and benzoxazole with triarylbismuth reagents via
C\\H activation
⁎
Kishor Eknath Balsane, Sitaram Haribhau Gund, Jayashree Milind Nagarkar
Department of Chemistry, Institute of Chemical Technology (Deemed University), Nathalal Parekh Marg, Matunga (E), Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2016
Received in revised form 7 October 2016
Accepted 8 October 2016
Available online 11 October 2016
We have developed a novel method for the direct C\\H functionalization of benzothiazole and benzoxazole using
triarylbismuth reagents. The arylation proceeds using the homogeneous catalytic system PdCl2, Cu(OAc)2 and
PPh3 ligand. Triarylbismuthines, which act as threefold arylating reagents, have low toxicity, are green and
ecofriendly. These methodologies are particularly useful to prepare arylated benzothiazoles and benzoxazoles.
© 2016 Elsevier B.V. All rights reserved.
Keywords:
C\\H functionalization
Azoles
Triarylbismuth reagents
Palladium-copper catalysis
Triphenylphosphine
1. Introduction
salts [19,20]. The major advantage of triarylbismuth compounds is the
low Bi\\C dissociation energy [21]. They also offer threefold coupling
Transition-metal-catalyzed direct functionalization of C\\H bonds
represents a powerful approach for the development of more sustain-
able chemical processes [1]. Direct arylation of arenes is an attractive al-
ternative to traditional cross-coupling reactions [2]. These arylation
reactions of benzothiazoles and benzoxazoles achieve regioselectivity
using transition metal catalysts [3–6]. These moieties are part of com-
pounds having several biological properties such as antibacterial, anti-
tumor and anti-inflammatory [7–9]. The synthesis of such heterocycles
and their derivatives has been a topic of research as they have important
applications in a variety of fields. Transition metal catalyzed C\\H
functionalization reactions of arenes and hetero arenes have gained
more attention in the preparation of various organic and biologically im-
portant scaffolds [10]. A variety of aryl sources, such as aryl halides [11],
arylboronic acids [12], iodobenzenediacetate [13], arenediazonium salts
[14], aryl sulfamates [15], aryltrimethylammonium triflates [16], arene
benzenesulfonyl chlorides [17] and substituted benzoic acids [18] have
been used for the arylation of benzothiazoles and benzoxazoles. Some
examples are given in Fig. 1.
reactivity with other coupling partners under palladium catalyzed con-
ditions [22]. They show various applications in organic transformations,
either as reagents or catalysts [23].
Triarylbismuthines show various applications such as synthesis of
unsymmetrical diaryl selenides [24], various arylation reactions [25,
26], C\\P bond formation [27] and cross-coupling with bromopyridines
and bromoquinolines [28]. Organobismuth reagents are also used in S-
arylation of diaryldisulfides [29], N-arylation of amines [30], azoles
[31] and N-cyclopropylation of cyclic amides [32]. They also find impor-
tant applications in O-arylation of N-protected 1,2-aminoalcohols [33],
phenols [34], and in the synthesis of α-diimines from isocyanides [35].
To the best of our knowledge, this is the first report on the applica-
tion of triarylbismuth as the arylating agent for the synthesis of
benzothiazoles and benzoxazoles by C\\H activation. Here, we devel-
oped a PdCl2-Cu(OAc)2-PPh3 catalytic system for the arylation of
benzothiazole and benzoxazole using triarylbismuth as the arylating
agent.
We have used triarylbismuthines as the arylating agent for the direct
C\\H functionalization of benzothiazole and benzoxazole.
Triarylbismuth compounds are stable, have low toxicity and can be eas-
ily prepared from aryl Grignard or lithium reagents and BiX3 inorganic
2. Results and discussion
Initially, we have optimized various reaction parameters to develop
this protocol. PdCl2-Cu(OAc)2 acts as a catalytic system over the model
reaction of benzothiazole (1a) and only 0.33 equivalent of
triphenylbismuth (2a) to get the arylated product (3a). The experimen-
tal results are summarized in Table 1. We first carried out the reaction
⁎
Corresponding author.
E-mail address: jm.nagarkar@ictmumbai.edu.in (J.M. Nagarkar).
http://dx.doi.org/10.1016/j.catcom.2016.10.005
1566-7367/© 2016 Elsevier B.V. All rights reserved.

30
K.E. Balsane et al. / Catalysis Communications 89 (2017) 29–33
Fig. 1. Various methods for arylation of azoles via C\\H activation using different arylating agents.
Table 1
Optimization of reaction parameters for benzothiazole with triphenylbismuth reagent.a
Entry
Catalyst (mol%)
Ligand (mol%)
Cu(OAc)2 (mol%)
Base
Solvent
Temperature
Time
Yield 3a (%)b
1
2
3
4
5
6
7
8
PdCl2(5)
0
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
0
0
0
0
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
6
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
12
54
16
66
34
36
46
49
90 (87)
74
48
59
72
34
21
15
22
11
10
15
8
2,2′-Bipyridine (30)
1,10-Phenathroline (30)
TMEDA (30)
DPPB (05)
DPPP (05)
DPPF (05)
PPh3 (10)
0
9
PdCl2 (5)
PdCl2 (5)
10
11
12
13
14
15
16
17
18
19
20
21
22
Pd(PPh3)4 (5)
Pd(dba)2 (5)
Pd(dppf)Cl2 (5)
Pd(PPh3)2Cl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
0
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (20)
water
Dioxane
DMA
DMSO
DMSO
PdCl2 (5)
RuCl2(PPh3)3(5)
NiCl2 (5)
a
Reaction conditions: benzothiazole (0.5 mmol, 1 equivalent), triphenylbismuth (0.167 mmol, 0.33 equivalent), base (1.5 mmol), ligand (mol%), solvent (3 mL), 100 °C, 12 h.
GC yield based on 1a. The yield of isolated product is shown in parenthesis. PPh3- triphenylphosphine, TMEDA-tetramethylethylenediamine, DPPB-1,4-
b
bis(diphenylphosphino)butane, DPPP-1,3-bis(diphenylphosphino)propane, DPPf-1,1′-ferrocenediyl-bis(diphenylphosphine), Pd(dba)2-bis(dibenzylideneacetone)palladium(0),
Pd(dppf)Cl2–1,1′-bis(diphenylphosphino) ferrocenedichloropalladium(II).

K.E. Balsane et al. / Catalysis Communications 89 (2017) 29–33
31
with PdCl2 as a catalyst and obtained product 3a with 6% GC yield (entry
1, Table 1). We also used Cu(OAc)2 as a catalyst and obtained only 12%
GC yield of 3a (entry 2, Table 1). When we employed Pd/Cu (5:10 mol%)
catalytic system, it gave 54% yield of 3a (entry 3, Table 1). After getting
these encouraging results, we tried to get better product yield of 3a by
employing various ligands. We screened various nitrogen containing li-
gands such as 2,2′-bipyridine, 1,10-phenanthroline and TMEDA. They
showed 16%, 66% and 34% yield respectively (entries 4–6, Table 1).
Phosphorus containing ligands such as DPPB, DPPP, and DPPF provided
36%, 46% and 49% yields of 3a (entries 7–9, Table 1). We got very sur-
prising results when we used 10 mol% PPh3 as ligand. It offered 90%
GC yield and 87% isolated yield of 3a (entry 10, Table 1). We also tried
some palladium species such as Pd(PPh3)4, Pd(dba)2, Pd(dppf)Cl2,
Pd(PPh3)2Cl2 along with Cu(OAc)2 as a co-catalyst and PPh3 as a ligand
but obtained only 74%, 48%, 59% and 72% GC yield respectively (entries
11–14, Table 1). We also tried other bases such as Cs2CO3 and K2CO3 but
got only 34% and 21% yield of 3a (entries 15–16, Table 1). The model re-
action was carried out using various solvents such as DMF, water, diox-
ane and DMA. The obtained results revealed that DMSO is the best
solvent for this reaction (entries 17–20, Table 1). Reaction using
RuCl2(PPh3)3 and NiCl2 afforded only 15% and 8% GC yield respectively
(entries 21–22, Table 1). Optimized reaction parameters for the reaction
between benzothiazole (0.5 mmol) and triphenylbismuth
(0.167 mmol) include the catalytic system PdCl2 (5 mol%), Cu(OAc)2
(10 mol%), PPh3 (10 mol%), K3PO4 base (1.5 mmol), DMSO (3 mL) as a
solvent, at 100 °C for 12 h.
triarylbismuth out of which 4-chloro substituted bismuth gave higher
yield as compared to 4-fluoro (entries 4–5, Table 2). Sterically hindered
2-Me arylbismuth gave 62% yield (entry 6, Table 2), whereas 3-Me and
3-OMe arylbismuth afforded fairly good yields of desired products
(entry 7–8, Table 2). Also, 3,4-OMe arylbismuth gave 82% yield whereas
tris(2-napthyl)bismuth derivative provided 80% yield of the corre-
sponding product (entry 9–10, Table 2).
The same reaction conditions were employed for the arylation of
benzoxazole and the arylated products were obtained higher yields
compared to benzothiazole derivatives. Initially, triphenylbismuth was
used and offered 90% yield (entry 1, Table 3). Similarly, electron rich
arylbismuth 4-Me and 4-OMe gave 85% and 90% yields respectively (en-
tries 2–3, Table 3). Among the halo arylbismuth derivatives, arylation
using 4-chloro gave good yield of the desired product whereas 4-fluoro
afforded moderate yield with benzoxazole (entries 4–5, Table 3). Some
sterically hindered bismuth derivatives showed 70% yield (entry 6,
Table 3) whereas the 3-Me and 3-MeO afforded good yields (entries
7–8, Table 3). We also tried 3,4-MeO derivative and obtained the corre-
sponding benzoxazole in 86% yield (entry 9, Table 3). We carried out the
reaction using tris(2-napthyl)bismuth derivative which afforded good
yield of the corresponding product (entry 10, Table 3). We also carried
out the reaction with substituted benzoxazoles and obtained good
yields of the respective arylated products (entry 11–12, Table 3).
The plausible mechanistic pathway for C\\H functionalization reac-
tion of benzothiazole is illustrated in Fig. 2. Initially, reaction between
PdCl2 and phosphine ligand results in the formation of complex (A)
which subsequently reacts with BiAr3 to form complex (B) [35]. Depro-
tonation of benzothiazole by K3PO4 and reaction with copper acetate
then gives the corresponding heteroaryl copper intermediate (C) [10],
which on reaction with (B) forms intermediate (D). Reductive elimina-
tion from (D) furnishes the desired arylated product (E), thus complet-
ing the catalytic cycle by regenerating complex (A).
Under these optimized reaction conditions, a series of substituted
triarylbismuth compounds were applied for C\\H functionalization of
benzothiazole. Initially, triphenylbismuth gave 87% isolated yield
(entry 1, Table 2). When we used electron rich triarylbismuth deriva-
tives such as 4-Me and 4-OMe, 78% and 86% yields were obtained (en-
tries 2–3, Table 2). We also tested 4-chloro and 4-fluoro substituted
Table 2
Arylation of benzothiazole with triarylbismuth reagents.a
Entry
1
Benzothiazole
Triarylbismuth
Product
Yieldb (%)
87
2
3
4
5
6
78
86
84
40
62
7
8
75
78
9
82
80
10
a
Reaction conditions: benzothiazole (0.5 mmol), triarylbismuth (0.167 mmol), PdCl2 (5 mol%), Cu(OAc)2 (10 mol%), K3PO4 (1.5 mmol), PPh3 (10 mol%), DMSO (3 mL), 100 °C, 12 h;
Isolated product yield.
b

32
K.E. Balsane et al. / Catalysis Communications 89 (2017) 29–33
Table 3
Arylation of benzoxazole with triarylbismuth reagents.a
Entry
1
Benzoxazole
Triarylbismuth
Product
Yieldb (%)
90
2
3
4
5
85
90
87
57
6
70
82
84
86
83
7
8
9
10
11
12
79
81
a
Reaction conditions: benzoxazole (0.5 mmol), triarylbismuth (0.167 mmol), PdCl2 (5 mol%), Cu(OAc)2 (10 mol%), K3PO4 (1.5 mmol), PPh3 (10 mol%), DMSO (3 mL), 100 °C, 12 h.
Isolated product yield.
b
3. Conclusion
Acknowledgement
In conclusion, we have developed an effective and readily available
PdCl2-Cu(OAc)2-PPh3 catalytic system for the C\\H functionalization
of benzothiazoles and benzoxazoles with a variety of triarylbismuth
compounds. The triarylbismuth reagents are stable, green, low toxic,
eco-friendly and act as threefold arylating agents.
The authors are very thankful to the UGC-SAP, New Delhi, India for
awarding the research fellowship.
Note: All compounds are well known and confirmed by GC–MS
analysis. 1H and 13C spectra of the representative products are provided
in the Supporting information.
Fig. 2. Proposed mechanistic pathway for C\\H functionalization reaction of benzothiazole.

K.E. Balsane et al. / Catalysis Communications 89 (2017) 29–33
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