Palladium(0) nanoparticles-catalyzed ligand-free direct arylation of benzothiazole via C-H bond functionalization

Article abstract of DOI:10.1016/j.tetlet.2010.08.063

Palladium nanoparticles, generated in situ efficiently catalyzes direct 2-C-H arylation of benzothiazole without requirement of any ligand. A wide range of substituted aryl and heteroaryl iodides participate in this reaction producing a series of 2-aryl/heteroaryl-benzothiazoles in high yields.

Full text of DOI:10.1016/j.tetlet.2010.08.063

Tetrahedron Letters 51 (2010) 5624–5627
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Tetrahedron Letters
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Palladium(0) nanoparticles-catalyzed ligand-free direct arylation
of benzothiazole via C–H bond functionalization
⇑
Debasree Saha, Laksmikanta Adak, Brindaban C. Ranu
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium nanoparticles, generated in situ efficiently catalyzes direct 2-C–H arylation of benzothiazole
without requirement of any ligand. A wide range of substituted aryl and heteroaryl iodides participate
in this reaction producing a series of 2-aryl/heteroaryl-benzothiazoles in high yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 30 July 2010
Revised 18 August 2010
Accepted 19 August 2010
Available online 24 August 2010
Keywords:
Palladium nanoparticles
C–H activation
Benzothiazole
Catalysis
Ligand-free
The heteroaromatics are of much importance in organic synthe-
sis as they constitute the core unit of many natural bioactive prod-
ucts1 and are extensively utilized in pharmaceutical and material
industries.2 A typical approach to connect one heteroarene and
arene nuclei via cross-coupling reaction of metalated arene/hetero-
arene and halogenated heteroarene/arene is widely utilized.3
However, the direct arylation of heteroarenes by catalytic C–H acti-
vation is a more convenient process and has received considerable
attention in recent times as an effective means for the synthesis of
functionalized heteroarenes.4 Several procedures using a variety
of catalysts such as Ni(OAc)2/bipy,4a [RhCl(coe)2]/phosphepine
ligand,4b Pd(TMHD)2,4c Pd(OAc)2/1-(benzhydryl)-3-(alkyl)benzima-
dazolium salts,4d [Pd(dppf)Cl2]ꢀCH2Cl2/PPh3,4e Pd(OAc)2/P(biphe-
nyl-2-yl)(t-Bu)2,4f PdCl2(PPh3)2/CuCl/polymethylhydrosiloxane,4g
Pd(OAc)2/PPh3,4h CuI/PPh3,4i and CuI/LiOtBu4j have been developed.
All these procedures except one4j use a metal salt and a ligand for
an effective reaction and most of these ligands are expensive, air
sensitive and toxic and their preparation also involved tedious
processes.
to explore the novel applications of metal nanoparticles7 we report
herein C–H functionalization of benzothiazole by aryl iodides cat-
alyzed by in situ generated palladium nanoparticles without the
use of any ligand (Scheme 1).
To standardize the reaction conditions, a series of experiments
were carried out using different solvents and varied reaction
parameters for a representative reaction of 4-iodoanisole and ben-
zothiazole. The uses of base and additive have much effect on this
reaction. After trying combinations of several bases, solvents and
additives,0 it was found that assembly of K2CO3/AgOAc/molecular
sieves (4 ÅA) in DMF (18 h) produced the best results (Table 1, entry
9). In the absence of molecular sieves, the yield of product is
reduced substantially (Table 1, entry 10). The use of Ag2CO3 in
place of K2CO3 and AgOAc also reduced the yield of product
appreciably (Table 1, entry 12). The absence of TBAB (tetrabutyl-
ammonium bromide) has a profound effect on this reaction
(Table 1, entry 14). It is believed that TBAB acts as a stabilizer for
Pd nanoparticles formed in situ, preventing them from fast agglo-
merization and thus helps in the progress of the reaction.5d The
preformed Pd nanoparticles are not equally active in this reaction
(Table 1, entry 16) possibly due to their inherent tendency for
agglomerization. The amount of Pd(OAc)2 generating Pd nanoparti-
cles7g,8 was optimized to 6.6 mol % for an effective reaction. Very
The use of metal nanoparticles as catalysts in organic reactions
has attracted considerable attention in recent times in the context
of green chemistry because of their benign character and ease of
preparation.5 Moreover, they show enhanced catalytic efficiency
because of their better ability to transfer electrons and large sur-
face area to volume ratio.6 As a part of our continuing program
Pd(OAc)2, TBAB
K2CO3, AgOAc
N
S
N
S
I
Ar
Ar
+
MS (4 Å), DMF
120 oC, 18 h
⇑
Corresponding author. Tel.: +91 3324734971; fax: +91 24732805.
E-mail address: ocbcr@iacs.res.in (B.C. Ranu).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.063

D. Saha et al. / Tetrahedron Letters 51 (2010) 5624–5627
5625
Table 1
Standardization of reaction conditions
Pd catalyst
Base, Additive
N
S
N
S
+ I
OMe
OMe
MS (4 Å)
Solvent
Pd catalyst
Base
Additive
Solvent
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2, TBAB
Pd(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KOtBu
K3PO4
K2CO3
K2CO3
K2CO3
Ag2CO3
AgOAc
K2CO3
K2CO3
K2CO3
—
—
—
—
—
—
—
—
AgOAc
AgOAc
AgOAc
—
THF
THF
75
75
9
18
18
9
0
10
0
20
30
0
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
DMF
DMF
DMF
DMF
DMF
120
120
120
120
120
120
120
120
75
120
120
120
120
120
18
18
18
18
18
18
18
18
18
18
18
18
10
0
78
50
35
45
40
45
15
35
10a
11
12
13
14
15
16
—
AgOAc
AgOAc
AgOAc
Pd(PPh3)4
Preformed Pd nps
The bold signifies that the entry 9 provides the best result.
a
The reaction was carried out in the absence of 4 Å molecular sieves.
interestingly, Pd(0) [Pd(PPh3)4] under identical reaction conditions
virtually failed to catalyze the reaction (Table 1, entry 15).
Thus, in a typical experimental procedure a mixture of iodoa-
rene, benzothiazole, Pd(OAc)2, tetrabutylammonium bromide
0
(TBAB), potassium carbonate, silver acetate, 4 ÅA molecular sieves
in DMF was heated with stirring at 125 °C under argon for 18 h
(TLC). The standard work-up and purification by column chroma-
tography provided the pure product.
To determine the active catalytic species in this reaction, an ex-
tract from the reaction mixture of iodoarene and benzothiazole
after 4 h from the start of the reaction was found to indicate the
formation of nanoparticles of 2–3 nm size by TEM (Transmission
Electron Microscope) image (Fig. 1). The identity of these particles
as Pd was confirmed by the selected area electron diffraction
(SAED) pattern (Fig. 2) which exhibited four diffused rings due to
(1, 1, 1), (2, 0, 0), (2, 2, 0), and (3, 1, 1) reflections of fcc Pd and indi-
cated the crystalline nature of nanoparticles.
Figure 2. SAED pattern of Pd nps.
A wide range of diversely substituted aryl iodides underwent
reactions with benzothiazole by this procedure9 to produce the
corresponding 2-substituted benzothiazoles. The results are sum-
marized in Table 2. The electron-donating as well as electron-with-
drawing substituents on the aryl iodides are uniformly compatible
in this reaction. The F, Cl, Br groups remained inactive in the reac-
tion with benzothiazole (Table 2, entries 2, 3, 8, and 9). The phar-
maceutically important trifluoromethyl and trifluoromethoxy
moieties-substituted aryl iodides participated in this reaction
without any difficulty. The pyridyl iodides (Table 2, entries 18
and 19) also underwent reactions with benzothiazole to provide
bis-heteroaryl systems which are also of much potential in phar-
maceutical industries.
In general, the reactions are clean and high yielding. Several sen-
sitive functionalities such as F, Cl, Br, OMe, OCF3, CF3, CN, NO2, COMe,
CO2Et, and heterocyclic system, pyridinyl unit are compatible in this
reaction. Very significantly, as mentioned earlier, when this reaction
was performed under identical conditions in the presence of tetra-
kis(triphenylphosphine)palladium, no appreciable reaction was ob-
served (Table 1, entry 15). This demonstrates the importance of
Pd(0) nanoparticles for this C–H functionalization.
It is suggested that Pd(0) nanoparticles generated in situ undergo
oxidative addition with the aryl iodide in the usual way to provide an
intermediate Ar–Pd–I which on reaction with benzothiazole in pres-
ence of K2CO3 and AgOAc leads to
r-adduct of arylpalladium(II)
(A)4h,10 with insertion of Ar moiety. This complex A via deprotona-
tion produces an intermediate B which on reductive elimination
provides the product regenerating Pd(0) (Fig. 3).
Figure 1. TEM image of Pd nps.

5626
D. Saha et al. / Tetrahedron Letters 51 (2010) 5624–5627
Table 2
Arylation of benzothiazole
2008). D.S. and L.A. are also thankful to CSIR, New Delhi for their
fellowships.
Pd(OAc)2, TBAB
K2CO3, AgOAc
N
S
N
References and notes
Ar
I
Ar
+
MS (4 Å), DMF
120 oC, 18 h
S
1. Jin, Z. Nat. Prod. Rep. 2005, 22, 196–229. and references cited therein.
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1598–1600; (j) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404–
12405.
Entry
Ar
C6H5
3-Cl–C6H4
4-Cl–C6H4
3-Me–C6H4
4-Me–C6H4
3-MeO–C6H4
4-MeO–C6H4
3-F–C6H4
Yielda (%)
Ref.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
81
72
83
80
85
75
78
81
70
84
82
72
79
73
70
84
81
75
78
4a
11
4a
4a
4a
12
4a
13
14
4a
—
4-Br–C6H4
3-F3C–C6H4
4-F3CO–C6H4
3,5-Me2–C6H3
4-NC–C6H4
4-O2N–C6H4
4-MeOC–C6H4
4-EtO2C–C6H4
1-Naphthyl
2-Pyridyl
—
4a
14
4d
—
4a
14
4a
5. (a) Astruc, D. Inorg. Chem. 2007, 46, 1884–1894; (b) Astruc, D.; Lu, F.; Aranzaes,
J. R. Angew. Chem., Int. Ed. 2005, 44, 7852–7872; (c) Polshettiwar, V.; Baruwati,
B.; Varma, R. S. Green Chem. 2009, 11, 127–131; (d) Reetz, M. T.; Westermann,
E. Angew. Chem., Int. Ed. 2000, 39, 165–168; (e) Durand, J.; Teuma, E.; Gomez, M.
Eur. J. Inorg. Chem. 2008, 3577–3586.
3-Pyridyl
a
Yields refer to those of purified isolated products charac-
terized by spectroscopic data (IR, 1H NMR and 13C NMR).
6. Roucoux, A.; Schulz, J.; Patin, H. Chem. Rev. 2002, 102, 3757–3778.
7. (a) Ranu, B. C.; Chattopadhyay, K. Org. Lett. 2007, 9, 2409–2412; (b) Ranu, B.
C.; Chattopadhyay, K.; Adak, L. Org. Lett. 2007, 9, 4595–4598; (c) Ranu, B. C.;
Dey, R.; Chattopadhyay, K. Tetrahedron Lett. 2008, 49, 3430–3432; (d) Dey,
R.; Chattopadhyay, K.; Ranu, B. C. J. Org. Chem. 2008, 73, 9461–9464; (e)
Saha, D.; Chattopadhyay, K.; Ranu, B. C. Tetrahedron Lett. 2009, 50, 1003–
1006; (f) Adak, L.; Chattopadhyay, K.; Ranu, B. C. J. Org. Chem. 2009, 74,
3982–3985; (g) Adak, L.; Bhadra, S.; Ranu, B. C. Tetrahedron Lett. 2010, 51,
3811–3814.
N
Ar
S
Ar-X
Pd(0)
8. Tong, X.; Zhao, Y.; Huang, T.; Liu, H.; Liew, K. Y. Appl. Surf. Sci. 2009, 255, 9463–
9468.
9. Representative procedure for the reaction of benzothiazole and iodobenzene (Table
N
S
PdAr
2, entry 1):
a mixture of iodobenzene (245 mg, 1.2 mmol), benzothiazole
ArPdX
(135 mg, 1 mmol), Pd(OAc)2 (15 mg, 6.6 mol %), tetrabutylammonium bromide
(350 mg, 1.08 mmol), potassium carbonate (300 mg, 2.17 mmol), silver acetate
N
S
B
KHCO3
(332 mg, 2 mmol), activated (preheated for 5 min in domestic microwave
+
AgOAc
+
0
oven) 4 ÅA MS (0.75 g) in DMF (4 mL) was heated with stirring at 125 °C under
argon for 18 h (TLC). The reaction mixture was extracted with Et2O (4 ꢂ 15 mL).
The extract was washed with water, brine and then dried (Na2SO4).
Evaporation of solvent left the crude product, which was purified by column
chromatography over silica gel (60–120 mesh) (hexane/ether 98:8) to provide
AcOK
N
PdAr
K2CO3
AgX
H
S
_
A
OAc
2-phenylbenzothiazole (171 mg, 81%) as a white solid. The mp and
spectroscopic data (IR, 1H NMR and 13C NMR) of this compound are in good
agreement with those reported earlier.4a
Figure 3. Plausible mechanism.
This procedure was followed for the synthesis of all the products listed in Table
2. Many of these products are known compounds and were identified by
comparison of their spectra with those reported earlier (see references in Table
2). The new compounds were characterized by their IR, 1H NMR and 13C NMR
and HRMS spectroscopic data which are provided below in order of their
entries in Table 2.
The role of AgOAc in this reaction is also very significant. Possibly,
Ag(I) abstracts the Iꢁ from the Pd(II) complex thereby generating an
electrophilic-cationic-Pd intermediate15 and thus accelerates the
reaction. Moreover, Iꢁ might have an inhibitory effect and Ag+ min-
imizes this effect by removing Iꢁ from the system.4e
In conclusion, we have developed a simple and efficient palla-
dium(0) nanoparticles-catalyzed direct arylation and heteroaryla-
tion of benzothiazole based on C–H activation under ligand-free
condition. This protocol provides an easy access to a wide range
of 2-substituted benzothiazoles.
2-(4-(Trifluoromethoxy)phenyl)benzo[d]thiazole (Table 2, entry 11): white solid;
mp 97 °C; IR (KBr) 3059, 2993, 1913, 1607, 1593, 1556, 1516, 1483, 1437, 1410,
1273, 1257, 1224, 1203, 1157 cmꢁ1 1H NMR (300 MHz, CDCl3) d 7.30–7.41(m,
;
3H), 7.46–7.49 (m, 1H), 7.89 (d, J = 7.95 Hz, 1H), 8.05–8.12 (m, 3H); 13C NMR
(75 MHz, CDCl3) d 121.3, 121.8, 122.2, 123.5, 125.6 (2C), 126.6, 129.2 (2C),
132.3, 135.3, 151.1, 154.2, 166.3; HRMS Calcd for
296.0357; Found 296.0351.
C
14H8F3NOS (M+H)+
2-(3,5-Dimethylphenyl)benzo[d]thiazole (Table 2, entry 12): yellow liquid; IR
(neat) 3059, 3030, 3009, 2957, 2918, 2862, 2733, 1716, 1684, 1601, 1558, 1506,
1456, 1435 cmꢁ1 1H NMR (500 MHz, CDCl3) d 2.39 (s, 6H), 7.13 (1H, s), 7.38 (t,
;
J = 8 Hz, 1H), 7.49 (t, J = 8.5 Hz), 7.73 (s, 2H), 7.90 (d, J = 8 Hz, 1H), 8.09 (d,
J = 8 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 21.3 (2C), 121.7, 123.2, 125.2, 125.5
(2C), 126.4, 132.9, 133.5, 135.1, 138.9 (2C), 154.1, 168.7; HRMS Calcd for
To the best of our knowledge, this is the first report of benzothi-
azole arylation using palladium(0) nanoparticles. Significantly,
Pd(0) is not effective for this reaction and this demonstrates the
potential and distinction of Pd(0) nanoparticles over Pd(0).
C
15H13NS (M+H)+ 240.0847; Found 240.0843.
Ethyl-4-(benzo[d]thiazole-2-yl)benzoate (Table 2, entry 16): white solid; mp
118 °C; IR (KBr) 3057, 3022, 2960, 2926, 2903, 2872, 2854, 1709, 1666, 1607,
1479, 1452, 1435, 1406 cmꢁ1 1H NMR (500 MHz, CDCl3) d 1.42 (t, J = 6.75 Hz,
;
3H), 4.40 (t, J = 6.75 Hz, 2H), 7.39 (t, J = 7 Hz, 1H), 7.50 t, J = 7.5 Hz, 1H), 7.66 (d,
J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 1H), 8.08–8.13 (m, 3H); 13C NMR (125 MHz,
CDCl3) d 14.4, 61.3, 121.8, 123.7, 125.8, 126.7, 127.4 (2C), 130.3 (2C), 135.4,
137.4, 144.4, 154.2, 166.4, 166.7; HRMS Calcd for
284.0745; Found 284.0741.
Acknowledgments
C
16H13NO2S (M+H)+
We are pleased to acknowledge the financial support from DST,
Govt. of India under J. C. Bose fellowship to B.C.R. (SR/S2/JCB-11/

D. Saha et al. / Tetrahedron Letters 51 (2010) 5624–5627
5627
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