Ligand and base-free Heck reaction with heteroaryl halides

Article abstract of DOI:10.1016/j.tetlet.2011.06.081

Pd(CH₃CN)₂Cl₂-catalyzed Heck reaction of different heteroaryl halides with olefins is carried out in the absence of both the ligand and base to obtain the corresponding coupling products in good yields.

Full text of DOI:10.1016/j.tetlet.2011.06.081

Tetrahedron Letters 52 (2011) 4490–4493
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ligand and base-free Heck reaction with heteroaryl halides
M. Lakshmi Kantam a, , P. Vishnuvardhan Reddy a, P. Srinivas a,b, Suresh Bhargava b,c
⇑
a I & PC Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
b IICT-RMIT Research Centre, Indian Institute of Chemical Technology, Hyderabad 500607, India
c Advanced Materials & Industrial Chemistry Group, School of Applied Sciences, RMIT University, Melbourne, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Pd(CH3CN)2Cl2-catalyzed Heck reaction of different heteroaryl halides with olefins is carried out in the
absence of both the ligand and base to obtain the corresponding coupling products in good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 23 April 2011
Revised 15 June 2011
Accepted 19 June 2011
Available online 25 June 2011
Keywords:
Heck reaction
Palladium
Heteroaryl halides
Ligand and base-free
Homogeneous
Among the different Pd catalyzed C–C bond forming reactions,
the Heck reaction is important in palladium catalysis.1 Since its
discovery in the early 1970’s, it has been used in the synthesis of
natural products, pharmaceuticals, and materials.2 Its broad func-
tional group tolerance, mild reaction conditions, and performance
with a variety of aryl halides and olefins make the Heck reaction
very attractive in the field of synthetic organic chemistry. Signifi-
cant advances have been made in the past two decades on the Heck
reaction using different phosphine ligands3, palladacylces4, and
non-phosphine Pd-catalysts, such as N-heterocyclic5, carbocyclic
carbenes6, and N, O, S- donor7 atoms containing Pd-catalysts. How-
ever, the industrial application of this reaction is limited owing to
the high cost of the ligands and catalysts.8
work on ligand-free Heck reactions with aryl halides,10 we hypoth-
esized that it was possible to accomplish the Heck reaction with
different heteroaryl halides under ligand-free conditions. There
are early indications that, the base-free Heck type reactions are
possible with inorganic Pd(II) salts. For example, coupling of aryl
diazonium salts with olefins can be catalyzed by Pd salts under
Table 1
Optimization of Pd(CH3CN)2Cl2-catalyzed Heck reactiona
Catalyst
+
Solvent, 140 oC
N
N
Br
20 h
Although the first protocol of the Heck reaction of aryl iodides
under ligand-free conditions has been known for years9, Pd(OAc)2
in combination with a suitable base has been traditionally used as
an effective catalyst for the coupling of aryl bromides with termi-
nal olefins.10 It has been shown that the palladium catalyst, irre-
spective of the nature of its precursor, is rapidly reduced to Pd(0)
at high temperature, which has a strong tendency to form col-
loids,11 and the palladium nanoparticles that are present in these
colloids catalyze the Heck reaction. However, the ligand-free ap-
proaches are usually limited to aryl iodides and aryl bromides.
It is well known that the synthesis of substituted heteroaryl
derivatives is of great importance because they are present in a
variety of biologically active compounds.12 Prompted by the recent
Entrya
Catalyst
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
10
Pd(OAc)2
Pd(OAc)2
Pd(CH3CN)2Cl2
PdCl2
DMA
DMA
DMA
DMA
DMA
Toluene
DMSO
DMF
57c
30
40
25
10
0
<5
55
20d
25e
Pd2(dba)3
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
DMF
DMF
a
The reactions were carried out with 2-bromopyridine (1 mmol), styrene
(2 mmol), catalyst (4 mol %) in 2.5 mL solvent at 140 °C for 20 h.
b
Isolated yields.
In the presence of LiOH (2 mmol).
Reaction at 120 °C.
Reaction with 2 mol % catalyst.
c
d
⇑
Corresponding author. Fax: +91 40 27193510.
E-mail address: mlakshmi@iict.res.in (M. Lakshmi Kantam).
e
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.081

M. Lakshmi Kantam et al. / Tetrahedron Letters 52 (2011) 4490–4493
4491
base-free conditions.13 Likewise, it is expected that the Pd salts cat-
alyze the Heck reaction of heteroaryl halides with styrene under
base-free conditions. Herein, we report the Pd(CH3CN)2Cl2 cata-
lyzed Heck reaction of heteroaryl bromides under both ligand
and base-free conditions. This novel method is economically
attractive since, in contrast to the traditional Pd-catalyzed Heck
reactions,3,4a,14 it does not use any ligand and base.
Table 2
Heck reaction of various heteroaryl bromides with styrene catalyzed by
Pd(CH3CN)2Cl2
a
Pd(CH3CN)2Cl2(4 mol%)
+
Het-ArBr
DMF, 140 oC
Ar-Het
Entry
HE-ArBr
Product
Yeildb (%)
Initially, the Heck reaction between the 2-bromopyridine and
styrene was carried out using Pd(OAc)2 as a catalyst and LiOH as
a base in N,N-dimethylacetamide (DMA) without using any phos-
phine or non-phosphine ligands and the reaction gave the corre-
sponding product 2-styryl-pyridine in 57% yield (Table 1, entry
1). Later, we examined the same reaction in the absence of both
the ligand and the base to make the protocol more attractive to
the industry. Surprisingly, the reaction even in the absence of base
afforded the product in 30% yield (entry 2). Further, the reaction
was optimized with different palladium salts and solvents to in-
crease the efficiency of this reaction; results are summarized in
Table 1. As shown in Table 1, different palladium salts, such as
Pd(OAc)2, PdCl2, Pd2(dba)3, and Pd(CH3CN)2Cl2 were screened for
this reaction in the absence of both the ligand and the base by
using DMA as solvent at 140 °C (Table 1, entries 2–5). The choice
of palladium precursor has a profound effect on the reaction in
terms of the yield of the Heck product. The maximum yield was
obtained when Pd(CH3CN)2Cl2 was used as a catalyst (entry 3).
Further, we have screened different solvents and N,N-dimethyl-
formamide (DMF) proved to be the best solvent and the product
was formed in good yield (entry 8). When the reaction was carried
out at 120 °C, the reaction provided only 20% yield, which shows
that temperature 140 °C is mandatory to obtain the maximum
yield of the product (entry 9). Next, the reaction was carried out
with 2 mol % of Pd(CH3CN)2Cl2 (entry 10) and it was found that
4 mol % of Pd(CH3CN)2Cl2 was the most effective catalytic loading.
Using the above mentioned optimized reaction conditions,16 we
further extended the scope of reaction with a variety of heteroaryl
halides, using 4 mol % of Pd(CH3CN)2Cl2 catalyst, and the results
are presented in Table 2. The Heck reaction of 3-bromopyridine
with styrene has given high yield of the product when compared
to 2-bromopyridine under the optimized conditions (entries 1 vs
2). Thus the position of the bromo substituent on pyridines influ-
ences the yield of the products.15 Similar tendency was not found
1
2
55
80
N
N
Br
Br
N
N
Br
3
4
84
82
S
S
S
Br
S
Br
5
6
7
80
82
76
N
N
Br
O
O
Br
OMe
OMe
N
N
N
N
Br
Br
8
9
86
5
NO2
CH3
NO2
CH3
N
N
a
in the case of
p-electron excessive heteroaryl halides such as 2-
Reactions and conditions: heteroaryl halide (1 mmol), styrene (2 mmol),
and 3-bromothiophenes and the yield of the products in both the
cases under the same reaction conditions was nearly the same (en-
tries 3 vs 4). With these interesting results, we further examined
4 mol % Pd(CH3CN)2Cl2 and 2.5 mL DMF at 140 °C for 20 h.
b
Isolated yield.
Table 3
a
Heck reaction of various heteroaryl bromides with olefins catalyzed by Pd(CH3CN)2Cl2
Het-Ar
Pd(CH3CN)2Cl2(4 mlo%)
DMF, 140 oC
Het-ArBr
+
R
R
Entry
1
Het-Br
R
Product
Yeild (%)b
Br
Br
H3C
4-Me-C6H4
4-Cl-C6H4
82
N
N
Cl
2
80
N
N
(continued on next page)

4492
M. Lakshmi Kantam et al. / Tetrahedron Letters 52 (2011) 4490–4493
Table 3 (continued)
Entry
Het-Br
R
Product
Yeild (%)b
Br
Br
3
4
5
C10H7
84
N
N
O
nBu-CO2
60
73
O
N
N
Br
H3C
4-Me-C6H4
S
S
S
Br
Cl
6
4-Cl-C6H4
72
85
S
Br
7
C10H7
N
N
a
Reactions and conditions: heteroaryl halide (1 mmol), olefin (2 mmol), Pd(CH3CN)2Cl2 (4 mol %) and 2.5 mL DMF at 140 °C for 20 h.
Isolated yield.
b
the reaction of 3-bromoquinoline and 3-bromofuran with styrene,
where the products were formed in essentially good yields (entries
5 and 6). Furthermore, it was found that the reaction also pro-
ceeded nicely with the electron-rich and electro-deficient 3-
bromohetero arenes, such as 5-methoxy-3-bromopyridine and 2-
nitro-5-bromopyridine with styrene in 76% and 86% yield, respec-
tively (entries 7 and 8), whereas the reaction with electron-rich 5-
methyl-2-bromopyridine gave the product in only 5% yield under
the same reaction conditions (entry 9). No product was formed
when 2- or 3-chlorohetero arenes were used under the above opti-
mized conditions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.081.
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16. General procedure: The reaction vessel was charged with aryl halide (1 mmol),
alkene (2 mmol), and the catalyst Pd(CH3CN)2Cl2 (4 mol %) in N,N-
dimethylformamide (2.5 mL). The reaction mixture was heated at 140 °C for
the desired time 20 h and the progress of reaction was monitored by TLC. At
the end of the reaction, the reaction mixture was cooled to room temperature
and was diluted with EtOAc (20 mL), and, washed with water. The combined
organic phase was dried over anhydrous Na2SO4. After removal of the solvent,
the residue was subjected to column chromatography on silica gel using ethyl
acetate and hexane (1:9) to afford the desired product in high purity.