Palladium-imidazole derivatives as highly active catalysts for Heck reactions

Article abstract of DOI:10.1016/j.tetlet.2004.11.124

N-Substituted 2-(2-bromophenyl)benzimidazole derivatives have been synthesized and used in palladium catalyzed Heck reactions to give coupled products in good yields.

Full text of DOI:10.1016/j.tetlet.2004.11.124

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 661–663
Palladium–imidazole derivatives as highly active
catalysts for Heck reactions
K. Rajender Reddy* and G. Gopi Krishna
Inorganic Chemicals Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
Received 26 September 2004; revised 16 November 2004; accepted 25 November 2004
Available online 10 December 2004
Abstract—N-Substituted 2-(2-bromophenyl)benzimidazole derivatives have been synthesized and used in palladium catalyzed Heck
reactions to give coupled products in good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
The imidazole ring system is a key structural fragment
found in many natural products.1 It also serves as a
good ligand for various metal ions.2 Metal binding
properties of imidazole-based ligands have been
explored in detail due to their presence at the active site
of metallo-proteins or enzymes involved in several
important metabolic processes.3 Numerous synthetic
approaches have been described for imidazole deriva-
tives because of their medicinal applications.4
R
N
R
N
Br
N
Pd
N
N
Br
N
Br
1. R=n-butyl
2. R=benzyl
3. R=benzoyl
4. R=tosyl
R
More recently such ligands have attracted attention
from a catalytic point of view because of the tunable
R= n-butyl
[M+-Br]=685 (100%)
basicities associated with the ligating nitrogen.5,6
A
fig(a)
fig(b)
change in ligand basicity has a marked effect on
metal–ligand bond strengths, which in turn effect the
catalytic properties. Recently Busacca et al., have shown
the influence of N-substitution versus catalytic activities
with phosphinoimidazolines in palladium catalyzed
asymmetric Heck reactions.7 To our knowledge no such
studies have been reported with imidazoles. We here
report different N-substituted ortho-brominated benzimid-
azoles and their activity in palladium catalyzed Heck
reactions.
To examine the catalytic activity of ligands 1–4 in palla-
dium catalyzed Heck reactions, we tested the reaction
between iodobenzene and methyl acrylate (MA), which
resulted in a quantitative yield of product with Pd(dba)2
as pre-catalyst (Table 1, entry 1).11 The reactivity was
maintained even at low temperature and no difference
in reactivity was observed on changing the ligands
(entries 2–5). In order to probe the influence of the
ligand on the reactivity, reactions with bromobenzene
were attempted. No reaction was observed during the
blank (entry 6). However under similar conditions
ꢀ9% of product formation was observed in the presence
of ligand 2 (entry 7), which clearly indicated association
of the ligand with the pre-catalyst. Furthermore, the
complex from the pre-catalyst and ligand 1 was isolated
and characterized by mass spectral studies, which clearly
indicated the formation of a palladacycle, Figure (b).
Formation of such palladacycles is well known in the lit-
erature and they are known to be highly active catalysts
Ligands 1–4, Figure (a) were readily synthesized by sim-
ple Phillips condensation of 2-bromobenzoic acid with
1,2-phenylenediamine8 and N-alkylation following the
general procedure reported for N-substituted imidazole
derivatives.9,10
Keywords: Heck reactions; Imidazole; Palladacycle.
*
Corresponding author. Tel.: +91 40 271 93510; fax: +91 40 271
60921; e-mail: rajender@iict.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.124

662
K. R. Reddy, G. G. Krishna / Tetrahedron Letters 46 (2005) 661–663
Table 1. Heck reactions between alkenes and aryl halides catalyzed by Pd-benzimidazole derived ligands 1–4a
R'
Pd(dba)2/Ligand
+
R'
X
R
R
NMP, Et3N
Entry
Ligand (mol %)
R0–X
Time (h)
Temp (°C)
100
84
Isolated yield (%)
R
1
2 (0.2)
2 (0.2)
2 (0.2)
1 (0.2)
4 (0.2)
—
Ph–I
Ph–I
MA16
MA20
BAb
116
50
2
3
Ph–I
Ph–I
20
50
89
4
MA20
MA20
MA23
MA23
MA21
MA21
MA21
MA21
MA
50
50
86
81
5
Ph–I
6
Ph–Br
Ph–Br
Ph–Br
Ph–Br
Ph–Br
Ph–Br
PBAP
100
100
116
116
116
116
—
7
2 (1.0)
2 (1.0)
1 (1.0)
3 (1.0)
4 (1.0)
1 (0.5)
1 (0.5)
9
41
45
14
23
8
9
10
11
12
13
21
116
88
PBAMA 21
116
12
a Reaction conditions: ligand and Pd(dba)2 in a 3:1 ratio (1 mol %), aryl halide (1 mmol), alkene (1.5 mmol), Et3N (2 mmol), NMP (3 mL).
b BA: n-butyl acrylate.
for various coupling reactions.12 Increasing the temper-
ature from 100 to 116 °C improved the conversion
(entries 7 and 8), however, a further increase to 140 °C
resulted in inconsistent results, possibly due to slow
decomposition of the metal complexes. Recently Alper
has reported thermal instabilities associated with bis-
imidazole–Pd(II) complexes during recycling studies on
Heck reactions in ionic liquids.13 Optimization studies
with different solvents and bases proved the N-methyl-
2-pyrrolidone (NMP) and triethylamine (NEt3) combi-
nation as the best. Further investigations were carried
out using this combination.
catalyzed Heck reactions to give the coupled products
in good yields. It is clear that the catalytic activities
are associated with the N-substitution on the imidazole
ligands. Further investigations on the improvement of
these imidazole ligands as well as the use of chiral ana-
logues are in progress.
Acknowledgements
We wish to thank the CSIR for financial support under
the Task Force Project COR-0003.
Ligands 1 and 2 having electron-donating groups on the
imidazole nitrogen showed higher activities (entries 8
and 9) compared to those possessing electron-accepting
groups 3 and 4 (entries 10 and 11). One possible expla-
nation for the higher activity associated with the elec-
tron donating groups could be the higher basicity of
the coordinating nitrogen. X-ray structural analysis of
Pd(II) complexes containing the pyridine–imidazoline
ligand showed that the Pd–N bond is much stronger
when the imidazoline nitrogen is substituted with an
electron donating benzyl group compared with the elec-
tron withdrawing triflate group.14
References and notes
1. (a) Grimmet, M. R. In Comprehensive Heterocyclic
Chemistry; Potts, K. T., Ed.; Pergamon: Oxford, 1984;
Vol. 4, pp 345–498; (b) Grimmet, M. R. In Comprehensive
Heterocyclic Chemistry II; Shinkai, I., Ed.; Pergamon:
Oxford, 1996; Vol. 3, pp 77–220.
2. Navarro, J. A. R.; Lippert, B. Coord. Chem. Rev. 2001,
222, 219–250.
3. Fausto da Silva, J. J. R.; Williams, R. J. P. The Biological
Chemistry of the Elements: The Inorganic Chemistry of
Life; Clarendon Press: Oxford, 1991.
4. (a) Zhong, Y. L.; Lee, J.; Reamer, R. A.; Askin, D. Org.
Lett. 2004, 6, 929–931; (b) Bleicher, K. H.; Gerber, F.;
Wuthrich, Y.; Alanine, A.; Capretta, A. Tetrahedron Lett.
2002, 43, 7687–7690; (c) Brain, C. T.; Brunton, S. A.
Tetrahedron Lett. 2002, 43, 1893–1895; (d) Claiborne, C.
F.; Liverton, N. J.; Nguyen, K. T. Tetrahedron Lett. 1998,
39, 8939–8942.
5. Jalil, M. A.; Fujinami, S.; Nishikawa, H. J. Chem. Soc.,
Dalton Trans. 2001, 1091–1098.
6. Ozdemir, I.; Centinkaya, B.; Demir, S. J. Mol. Catal. A
2004, 208, 109–114.
7. Busacca, C. A.; Grossbach, D.; So, R. C.; OÕBrien, E. M.;
Spinelli, E. M. Org. Lett. 2003, 5, 595–598.
8. Phillips, M. A. J. Chem. Soc. 1928, 172.
9. Crane, J. D.; Sinn, E.; Tann, B. Polyhedron 1999, 18,
1527–1532.
As is observed in Heck reactions, activated aryl bro-
mides, such as 4-bromoacetophenone (PBAP) resulted
in higher conversions (entry 12) in comparison to those
possessing deactivating groups, for example, 4-bromo-
anisole (PBA) (entry 13). These conversions were higher
than with the recently reported thiourea derived Pd-cata-
lysts.15 Such an observation implicates the higher stabil-
ity of the preformed palladacycle complexes as well as
the electronic influences associated with the metal com-
plexes upon N-substitution.
In conclusion, we have synthesized N-substituted 2-(2-
bromophenyl)-benzimidazole derivatives. The newly
synthesized ligands were successfully used in palladium

K. R. Reddy, G. G. Krishna / Tetrahedron Letters 46 (2005) 661–663
663
10. Typical procedure for ligand synthesis: (i) Preparation of
benzimidazoles: 2-bromobenzoic acid (40 mmol) and 1,2-
phenylenediamine (40 mmol) were taken in polyphos-
phoric acid (56 g) and heated to 150 °C for 6 h. The
reaction mixture was poured over crushed ice and kept in
a refrigerator overnight. The resulting violet solid precipi-
tate was filtered and added to 0.5 M Na2CO3 solution
(500 mL), stirred for 30 min and filtered. The precipitate
was dissolved in methanol (300 mL), carbon black was
added and the suspension stirred for 1 h. The methanol
solution was heated on a water bath for 5 min and filtered
through celite whilst hot to give a white solid (6.5 g, 60%).
(ii) N-Alkylation of benzimidazoles: To the benzimidazole
(3.66 mmol) in acetone (20 mL), KOH (7.32 mmol) was
added and the solution stirred at rt for 30 min. To this was
added RX (R = butyl, benzyl, benzoyl, p-toluenesulfonyl;
X = Br for 1 and 2, Cl for 3 and 4) and the mixture
refluxed for 2 h. The reaction mixture was diluted with
ethyl acetate and washed with water. The organic layer
was dried over Na2SO4 and subjected to column chroma-
tography on silica gel. Spectroscopic data: 1: 1H NMR
(200 MHz, CDCl3): d 0.80 (3H, t, J 7.5 Hz), 1.10–1.30
(2H, m), 1.60–1.75 (2H, m), 4.05 (2H, t, J 7.5 Hz), 7.20–
7.30 (2H, m), 7.35–7.55 (4H, m), 7.70 (1H, m), 7.80 (1H,
m). MS(EI) m/z 329 (M++2, 79.4%). Compound 2: 1H
NMR (200 MHz, CDCl3): d 5.25 (2H, s), 7.00–7.15 (2H,
m), 7.24–7.40 (9H, m), 7.75 (1H, m), 7.85 (1H, m).
1
MS(EI): m/z 363 (M++2, 13%). Compound 3: H NMR
(200 MHz, CDCl3): d 7.00–8.00 (11H, m), 7.75 (1H, m),
7.86 (1H, m). MS(FAB): m/z 379 (M++2, 44 %).
1
Compound 4: H NMR (200 MHz, CDCl3): d 2.40 (3H,
s), 7.10–7.20 (2H, m), 7.35–7.60 (7H, m), 7.61–7.88
(2H, m), 8.10–8.20 (1H, m). MS(FAB): m/z 429 (M++2,
12%).
11. Typical procedure for the Heck reaction: The ligand and
Pd(dba)2 (3:1) were taken in NMP and stirred at room
temperature for 1 h. To this reaction mixture methyl
acrylate, NEt3 and aryl halide were added sequentially and
heated at 116 °C for the specified time (see Table 1) under
an argon atmosphere. After completion, the reaction
mixture was diluted with chloroform and washed twice
with 5 N HCl and the organic layer was concentrated and
the residue was purified by silica gel column
chromatography.
12. Bedford, R. B. Chem. Commun. 2003, 1787–1796.
13. Park, S. B.; Alper, H. Org. Lett. 2003, 5, 3205–3212.
14. Bastero, A.; Ruiz, A.; Claver, C.; Milani, B.; Zangrando,
E. Organometallics 2002, 21, 5820–5829.
15. Yang, D.; Chen, Y. C.; Zhu, N. Y. Org. Lett. 2004, 6,
1577–1580.