Palladium bis(2,2,6,6-tetramethyl-3,5-heptanedionate): an efficient catalyst for regioselective C-2 arylation of heterocycles

Article abstract of DOI:10.1016/j.tetlet.2007.11.209

Palladium bis(2,2,6,6-tetramethyl-3,5-heptanedionate), a structurally well defined O-containing transition metal complex is reported as an efficient catalyst for regioselective direct C-2 arylation of heterocycles with aryl halides. The present protocol is applicable to a wide variety of heterocycles providing good to excellent yields of products.

Full text of DOI:10.1016/j.tetlet.2007.11.209

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1045–1048
Palladium bis(2,2,6,6-tetramethyl-3,5-heptanedionate):
an efficient catalyst for regioselective C-2 arylation of heterocycles
Nitin S. Nandurkar, Mayur J. Bhanushali, Malhari D. Bhor, Bhalchandra M. Bhanage *
Department of Chemistry, Institute of Chemical Technology (Autonomous), University of Mumbai, N. Parekh Marg, Matunga, Mumbai 400 019, India
Received 29 October 2007; revised 17 November 2007; accepted 30 November 2007
Available online 5 December 2007
Abstract
Palladium bis(2,2,6,6-tetramethyl-3,5-heptanedionate), a structurally well defined O-containing transition metal complex is reported
as an efficient catalyst for regioselective direct C-2 arylation of heterocycles with aryl halides. The present protocol is applicable to a wide
variety of heterocycles providing good to excellent yields of products.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: C-Arylation; Heterocycles; Aryl halides; Palladium complex; Regioselectivity
Heteroaromatics are important structural units frequ-
ently found in natural products,1 pharmaceutically
active substances,2 agrochemicals,3 compounds used to
treat endoparasitic diseases of domestic animals4 and
organic functional materials such as liquid crystals and
fluorescent dyes.5 The direct arylation of heterocycles has
received considerable interest among synthetic chemists
as it would eliminate the need for establishing a reactive
functionality (halogenation or stoichiometric metalation)
prior to C–C coupling, enabling direct elaboration and
expansion of the core motif. The pioneering work in this
field was performed by Ohta and co-workers.6 Subse-
quently, other groups extended this methodology to aryl-
ation of a number of heterocycles with aryl halides
employing catalysts such as [RhCl(coe)2]2/PR3,7
employ a structurally well defined and stable Pd-complex
as catalyst.13 Thus, there is a need to develop an efficient
protocol, which could catalyze directly the arylation of a
wide range of heterocycles employing a single-component
Pd-complex as catalyst.
Previously, we reported N-arylation of aliphatic, aro-
matic and heteroaromatic amines with aryl halides using
preformed copper bis(2,2,6,6-tetramethyl-3,5-heptane dio-
nate) as the catalyst.14 The use of 2,2,6,6-tetramethyl-3,5-
heptanedione (TMHD) as a ligand resulted in excellent
yields of products and such reactivity could be attributed
to the fact that a good balance exists between the steric
and electronic properties of the complex. Herein, we report
a facile C-2 arylation of heterocycles with aryl halides
catalyzed by a well defined and stable O-containing
transition metal complex, viz Pd bis(2,2,6,6-tetramethyl-3,
[RuCl2(p-cymene)]2/(1-Ad)2PHO,8
Pd(OAc)2/BuAd2P,9
PdCl2/PCy3,10 Pd(OAc)2/CuI,
PdCl2(PPh3)/CuI12 and
11
Pd(I2)PPh3–NHC.13 In spite of their utility, the use of
expensive, air sensitive and toxic phosphine ligands, the
addition of stoichiometric amounts of copper salt addi-
tives, use of sealed reaction vessels and substrate incompat-
ibility limit their applications. Moreover, very few methods
Y
Z
Y
Z
Pd(TMHD)
2
+
X
K PO , NMP
3
4
R
R
(Y = CH, Z = NMe, O, S) (Y = N, Z = O, S)
(X = I, Br) (R = Me, OMe, NO )
2
*
Corresponding author. Tel.: +91 2224145616; fax: +91 2224145614.
Scheme 1. C-Arylation of heterocycles with aryl halides.
E-mail address: bhalchandra_bhanage@yahoo.com (B.M. Bhanage).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.209

1046
N. S. Nandurkar et al. / Tetrahedron Letters 49 (2008) 1045–1048
in organic solvents, indefinite shelf life, stability towards air
and compatibility with a wide variety of heterocycles
makes it an ideal complex for direct C-2 arylation of het-
erocycles (Scheme 1).
Table 1
Effect of catalyst, base and solvent on the arylation of benzothiazole with
iodobenzenea
Entry
Catalyst
Base
Solvent
Yield (%)
Initially, the direct arylation of benzothiazole with iodo-
benzene was chosen as a model reaction and the roles of
various metal–TMHD complexes, bases and solvents were
investigated (Table 1). Complexes of Ru and Co were found
to be completely ineffective using the present conditions,
whereas Cu(TMHD)2 was found to give only a 20% yield.
In comparison, Pd(TMHD)2 was found to be highly active
providing an excellent yield (86%) of the desired product.
The influence of various organic and inorganic bases
such as K3PO4, Cs2CO3, KOtBu, K2CO3 and KOH was
studied for the standard reaction (entries 1, 5–8). It was
observed that the bases K2CO3, Cs2CO3 and K3PO4 affor-
ded good yields of the desired product. However, due to
cost considerations K3PO4 was preferred over Cs2CO3.
The effect of various solvents on the reaction system was
1
2
3
4
5
6
7
8
9
10
11
12
a
Pd(TMHD)2
Cu(TMHD)2
Ru(TMHD)3
Co(TMHD)2
Pd(TMHD)2
Pd(TMHD)2
Pd(TMHD)2
Pd(TMHD)2
Pd(TMHD)2
Pd(TMHD)2
Pd(TMHD)2
Pd(TMHD)2
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
KOtBu
K2CO3
KOH
K3PO4
K3PO4
K3PO4
K3PO4
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Toluene
DMF
Dioxane
DMSO
86
20
—
—
80
10
76
17
22
28
11
83
Reaction conditions: benzothiazole (1 mmol), iodobenzene (1.5 mmol),
catalyst (10 mol %), base (2 mmol), solvent (5 mL), 36 h at 125 °C.
5-heptanedionate) [Pd(TMHD)2] in an efficient manner.
The ease of preparation of the complex,15 its high solubility
Table 2
Arylation of heterocycles with aryl halidesa
Entry
Heterocycle
Aryl halide
Product
Yield (%)
96
1
I
N
N
Me
Me
NO2
2
3
67
86
I
I
NO2
N
N
Me
Me
N
S
N
S
N
S
N
S
4b
60
45
Br
N
S
N
S
I
5
Me
Me
N
N
6
7
8
67
40
55
I
I
I
S
S
N
N
OMe
OMe
S
S
N
N
O
O
N
O
N
O
9
62
I

N. S. Nandurkar et al. / Tetrahedron Letters 49 (2008) 1045–1048
1047
Table 2 (continued)
Entry
Heterocycle
Aryl halide
Product
Yield (%)
63
N
N
10
11
I
OMe
OMe
O
O
N
N
N
N
76
I
N
N
Me
Me
12
13
14
35
30
83
I
I
I
S
S
S
Me
Me
S
O
O
15b
65
60
Br
I
O
O
Me
N
Me
O
N
O
N
N
N
16b
N
N
N
Me
Me
Me
Me
O
O
a
Reaction conditions: heterocycle (1 mmol), aryl halide (1.5 mmol), Pd (TMHD)2 (10 mol %), K3PO4 (2 mmol), NMP (5 mL), 36 h at 125 °C.
48 h at 140 °C.
b
also examined (entries 1, 9–12). It was observed that non-
groups such as methyl and methoxy at the ortho or para
positions of the iodoarene were viable partners under the
present conditions (entries 5, 7, and 10). 1-Methyltriazole
was found to be arylated selectively at the more active
C-5 position (entry 11). We also tested the applicability
of this method with other heteroarenes such as benzothio-
phene and benzofuran (entries 12–15). However, reaction
of benzothiophene was found to be sluggish using the pre-
sent catalytic system, while benzofuran was found to react
efficiently with both iodo and bromobenzene providing
good yields of the desired product. Encouraged with the
above results, the system was further extended to the
aryaltion of caffeine, as the products are of interest as
adenosine receptor antagonists.17 Caffeine was arylated
effectively under the present conditions providing an excel-
lent yield of 60% of product (entry 16). If C–H activation
methodology is not used, the synthetic sequence leading to
these compounds requires several steps instead of a single
step.17
polar solvents such as toluene gave a low yield of product
probably due to the poor solubility of reactant and catalyst
in the reaction medium. It was also observed that pro-
longed reaction of the catalyst in toluene led to decompo-
sition of the catalyst and precipitation of Pd metal. The
use of polar solvents such as NMP and DMSO led to an
increase in the yield without any catalyst deactivation.
However, N-methyl-2-pyrrolidine (NMP) was found to
give the best results and was used for further studies.
Thus, using Pd(TMHD)2 as catalyst, K3PO4 as base and
NMP as solvent, a wide variety of heterocycles possessing
different steric and electronic properties were coupled with
aryl iodides or bromobenzene under mild reaction condi-
tions (Table 2).16
N-Methylindole was found to react smoothly with iodo-
benzene providing an excellent yield (96%) of the C-2 ary-
lated product. The reaction also worked well with an
electron withdrawing substituent such as nitro on the aryl
iodide (entry 2). To check the generality of the procedure
the system was extended to various azoles including benzo-
thiazole, thiazole, benzoxazole, oxazole and triazole
(entries 3–11). Benzothiazole was found to react efficiently
with both iodo and the less reactive bromoarene providing
good yields of the desired product. Also, electron donating
In summary, the first example of the direct, regioselec-
tive C-2 arylation of heterocycles catalyzed by the cheap,
air stable and well defined Pd(TMHD)2 complex as a cata-
lyst is described. The system works equally well for a wide
variety of heterocycles and tolerates various functional
groups.

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N. S. Nandurkar et al. / Tetrahedron Letters 49 (2008) 1045–1048
8. Ackermann, L. Org. Lett. 2005, 7, 3123–3125.
Acknowledgement
9. Hendrich, A. C.; Daugulis, O. Org. Lett. 2007, 9, 1449–1451.
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2007, 63, 1970–1980; (b) Bellina, F.; Cauteruccio, S.; Mannina, L.;
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The financial assistance from the Department of Atomic
Energy/Board of Research in Nuclear Science (DAE/
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15. Typical procedure for the preparation of Pd(TMHD)2: Palladium
chloride (1.8 g, 10 mmol) and sodium chloride (0.59 g, 10 mmol) were
dissolved in methanol (50 mL) and stirred at room temperature
overnight. The solution was filtered into a 100 mL volumetric flask
and diluted with methanol to give a solution of 0.1 M palladium(II)
concentration. A mixture of this solution (100 mL), the ligand 2,2,6,6-
tetramethyl-3,5-heptanedione (4.6 g), and sodium carbonate (1.06 g,
10 mmol) was stirred overnight. The resulting yellow precipitate was
filtered and dried, mp 238–240 °C.
16. General procedure: Under a N2 atmosphere, heterocycle (1 mmol),
aryl halide (1.5 mmol), Pd(TMHD)2 (10 mol %) and K3PO4 (2 mmol)
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