Highly effective activation of aryl chlorides for Suzuki coupling in aqueous media using a ferrocene-based Pd(II)-diimine catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.02.102

The Suzuki coupling of aryl chlorides with boronic acids using a ferrocene-containing Pd(II)-diimine complex as catalyst, in aqueous media, under microwave heating is reported. A small amount of the catalyst (0.1%) was found to be highly effective for coupling unactivated aryl chlorides with boronic acids to form sterically hindered ortho-substituted biaryls. The same catalyst also enabled the coupling of aryl bromides and iodides with various boronic acids in very high yields. The catalyst is air stable and the catalytic reaction can be completed in 15 min.

Full text of DOI:10.1016/j.tetlet.2012.02.102

Tetrahedron Letters 53 (2012) 2388–2391
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly effective activation of aryl chlorides for Suzuki coupling in aqueous
media using a ferrocene-based Pd(II)–diimine catalyst
Murat Emre Hanhan a, , Ramon Martínez-Máñez b,c, Jose Vicente Ros-Lis b
⇑
a Zonguldak Karaelmas University, Science and Letters Faculty, Chemistry Department, 67100 Zonguldak, Turkey
b Departamento de Quimica, Universidad Politécnica de Valencia, Camino de Vera s/n, 46022 Valencia, Spain
c CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The Suzuki coupling of aryl chlorides with boronic acids using a ferrocene-containing Pd(II)–diimine
complex as catalyst, in aqueous media, under microwave heating is reported. A small amount of the cat-
alyst (0.1%) was found to be highly effective for coupling unactivated aryl chlorides with boronic acids to
form sterically hindered ortho-substituted biaryls. The same catalyst also enabled the coupling of aryl
bromides and iodides with various boronic acids in very high yields. The catalyst is air stable and the cat-
alytic reaction can be completed in 15 min.
Received 1 December 2011
Revised 13 February 2012
Accepted 23 February 2012
Available online 3 March 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Suzuki coupling
Green chemistry
Pd(II) complexes
Microwave irradiation
Aryl chlorides
Among palladium-catalyzed cross-coupling processes, the
Suzuki reaction of aryl and vinyl halides/triflates with boronic
acids has gained significant attention and is a very powerful meth-
od for the formation of biaryls.1,2 This popularity of the Suzuki
reaction is attributable to a variety of factors including the large
number of boronic acid derivatives that are commercially avail-
able, their good stability and nontoxic nature and tolerance to a
large number of functional groups. However, Suzuki coupling reac-
tions still show some limitations, especially in relation to the use of
certain reagents. In particular, for many years, a major restriction
of palladium-catalyzed coupling processes has been the poor reac-
tivity of aryl chlorides. Moreover, in many cases, the use of aryl
chlorides is more desirable when compared with the correspond-
ing bromides, iodides, and triflates, mainly due to their low cost
and ready availability.3 Until 1998, there were no examples of
effective palladium-catalyzed Suzuki reactions using electron-neu-
tral or electron-rich aryl chlorides.
In attempts to utilize aryl chlorides as substrates in Suzuki cou-
pling reactions several catalysts have been developed. For example,
Fu and Buchwald independently discovered that certain phosphine-
based catalysts were very effective for the coupling of aryl chlorides
with various aryl boronic acids. The key property of their catalysts
was to have ligands that were both electron-rich and sterically
bulky. By using these catalysts the authors were able to activate
both electron-rich and electron-poor aryl chlorides for Suzuki cou-
pling reactions at room temperature.4,5 Since these seminal works,
some additional studies have been reported. Najera and co-workers
prepared oxime-derived palladacycles for the Suzuki coupling of
aryl chlorides in aqueous media which were not very effective for
the coupling of unactivated aryl chlorides.6 Buchwald and co-work-
ers reported that the use of water soluble sulfonated salts in Suzuki
coupling reactions of aryl chlorides, gave excellent yields of prod-
ucts. This procedure however, required high temperatures, long
reaction times, and high catalyst loadings.7 Hanhan and Zhou inde-
pendently studied sulfonated Pd-diimine catalysts for the coupling
of several aryl halides with aryl boronic acids showing negligible
activity for the coupling of aryl chlorides.8,9 Ferrocene derivatives
have attracted significant attention as ligands because of their large
size and electron-rich nature. In fact, several examples using ferro-
cene-like derivatives have been described as very effective in acti-
vating aryl chlorides.10–15 In these examples, ferrocene-containing
phosphine ligands were used, however the use of other ligands such
as diimines has received limited study.16,17 The use of diimine or
pyridylimine ligands instead of phosphine ligands has major advan-
tages such as easy synthetic procedures, simple handling, and easy
tuning of the steric and electronic properties of the final catalysts.
We report herein
a new ferrocene-containing Pd(II)–diimine
complex catalyst as a highly effective system for the Suzuki cross-
coupling of aryl chlorides (including unactivated and sterically hin-
dered substrates) in aqueous media under microwave irradiation.
The ferrocene based diimine ligand (L) was synthesized via a
simple condensation procedure involving the reaction of
⇑
Corresponding author. Tel.: +90 372 257 4010; fax: +90 372 257 4181.
E-mail addresses: emrehanhan@karaelmas.edu.tr (M.E. Hanhan), rmaez@
qim.upv.es (R. Martínez-Máñez).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.102

M. E. Hanhan et al. / Tetrahedron Letters 53 (2012) 2388–2391
2389
Table 1
ferrocenecarboxaldehyde with the sodium salt of 5,6-diamino-1-
Effect of conventional heating versus microwave irradiationa
naphthalenesulfonic acid in toluene under reflux. The precipitated
derivative was then dissolved in iso-propanol in the presence of ex-
cess tetrabutylammonium chloride to give the ammonium salt L.
Complex 1 was obtained via reaction of the ferrocene-containing
diimine ligand L and PdCl2(CH3CN)2 in acetonitrile under reflux
(Scheme 1).18
As has been reported previously, one disadvantage of the use of
ionic diimine ligands is their potential hydrolysis in water even
when they are forming complexes with metal cations.19,20 There-
fore, prior to the testing of 1 as a catalyst, studies of the stability
of 1 in water were carried out using 1H NMR spectroscopy. The ex-
tent of hydrolysis of ligand was followed by the signal due to the
aldehyde proton. These studies demonstrated that the catalyst
was fairly stable in water and only after a period of 4 h was evi-
dence of decomposition observed. Nevertheless catalyst 1 was
found to be stable within the range of time of the tested Suzuki
coupling reactions which typically required periods of 15 min (vide
infra).
Entry
Heating typeb
Temperature (°C)
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
C.H.
C.H.
C.H.
C.H.
rt
300
300
300
360
20
N/A
N/A
89
92
N/A
54
50
100
100
—
—
—
M.W.d
M.W.e
M.W.f
20
20
99
a
Conditions: p-chloroacetophenone (1.0 equiv), phenyl boronic acid (1.0 equiv),
K2CO3 (1.5 equiv), 1 (0.1 mol%), H2O (5 mL).
b
C.H. = conventional heating, M.W. = microwave irradiation (Industrial Bosch-
Mars Microwave System with reflux glassware).
c
Yields estimated by GC.
180 W M.W. irradiation.
360 W M.W. irradiation.
800 W M.W. irradiation.
d
e
f
Next, simple preliminary tests demonstrated that the ferro-
cene–diimine Pd(II) complex was active in catalyzing Suzuki cou-
pling reactions between aryl chlorides and boronic acids. In order
to select the best reaction conditions, different heating regimes
were studied in water using the coupling of p-chloroacetophenone
and phenylboronic acid in the presence of K2CO3 as a model sys-
tem. The Suzuki coupling reaction did not proceed at room temper-
ature or at 50 °C when using catalyst 1 (Table 1, entries 1 and 2).
When the temperature was increased to 100 °C, yields >89% were
obtained (Table 1, entries 3 and 4). When 800 W microwave irradi-
ation was used instead of conventional heating, the yield increased
to 99% in 20 min without any appreciable decomposition of the
catalyst (Table 1, entry 7). To assess the effect of M.W. irradiation,
lower power output irradiation (180 and 360 W) was studied. The
yields did not pass 54% yield (Table 1, entries 5 and 6).
reached after 15 min when using K2CO3 or Cs2CO3. Despite the fact
that slightly better yields were obtained when using Cs2CO3, fur-
ther studies were carried out with K2CO3 due to its ready availabil-
ity and low cost. In addition a reaction time of 15 min was selected.
After the reaction conditions had been optimized, the effect of
the amount of catalyst was examined. A 0.1% catalyst loading
was found to be very effective for coupling unactivated aryl chlo-
rides. On the other hand, amounts as low as 0.0001% of the catalyst
was sufficient to couple aryl bromides and iodides with boronic
acids in yields that ranged from 97% to 99% (Table 3, entries 13
and 14).
Finally, the effect of the catalyst on the Suzuki reaction using
various aryl chlorides and boronic acid substrates was studied. Ta-
ble 3 summarizes the results. Significantly catalyst 1 was able to
couple unactivated electron-rich aryl chlorides with various boro-
nic acids in yields >91% (Table 3, entries 3–5). The Suzuki reaction
using catalyst 1 was also tested using sterically hindered sub-
strates. It is well-known that Suzuki coupling reactions using ste-
rically demanding substrates are difficult and generally occur
Additional studies were carried out in order to test the effect of
different bases. K2CO3, Na2CO3, Cs2CO3, K3PO4, and NaOMe were
investigated as bases for the coupling of p-chloroacetophenone
and phenylboronic acid in the presence of catalyst 1 in water using
800 W microwave irradiation for 5, 10 and 15 min (Table 2, entries
1–9). In general it was found that yields of almost 99% were
NaO3S
NaO3S
activated Al2O3
24h, N2, toluene, reflux
N
N
O
2
Fe
+
Dean-Stark
Fe
Fe
H2N
NH2
Bu4NO3S
Bu4NO3S
Tetrabutylammoniumchloride
(TBAC)
PdCl2(CH3CN)2
24h, N2, CH3CN, r.t.
iso-propanol, 60°, 24h
N
N
N
N
Pd
Cl
Cl
Fe
Fe
Fe
Fe
1
L
Scheme 1. Synthetic route to catalyst 1.

2390
M. E. Hanhan et al. / Tetrahedron Letters 53 (2012) 2388–2391
Table 2
be obtained in remarkably high yields (>94%). Aryl chlorides with
different functional groups also underwent the coupling reaction
efficiently (Table 3, entries 9–12).
Base and time optimization resultsa
Entry
Base
Time (min)
Yieldb (%)
In summary, we have reported the Suzuki coupling of aryl chlo-
rides with boronic acids using a ferrocene-containing Pd(II)–dii-
mine complex as catalyst, in aqueous media, under microwave
heating. The use of the diimine ligand containing two ferrocene
units was found to be very effective for Suzuki coupling reactions
due to the sterically demanding nature of the ligand and the
electron-rich properties of the ferrocene moiety.21 These proper-
ties of the catalyst allow stabilization of the active Pd(0) species
in the catalytic cycle to sustain the reaction. A series of aryl boronic
acids and aryl halides were tested in the Suzuki coupling reaction
using 1 as the catalyst. Small amounts of 1 (0.1%) were found to be
very effective for the coupling of unactivated aryl chlorides with
boronic acids to form sterically hindered ortho-substituted biaryls
under aqueous conditions. On the other hand, the use of very low
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K3PO4
5
61
89
99
69
91
99
86
79
86
10
15
5
10
15
15
15
15
NaOMe
a
Conditions: p-chloroacetophenone (1.0 equiv), phenylboronic acid (1.0 equiv),
base (1.5 equiv), 1 (0.1%), 800 W M.W. irradiation, H2O (5 mL).
b
Yields estimated by GC.
with the formation of unwanted homocoupling products.4 As
shown in Table 3 (entries 6–8) sterically hindered biaryls could
Table 3
Suzuki cross-couplings between aryl halides and boronic acids using 1 as the catalysta
Entry
1
Aryl halide
Cl
Boronic acid
Product
Yieldd (%)
93
(HO)2B
2
3
H3CCO
MeO
Cl
97
91
B(OH)2
Me
(HO)2B
H3CCO
MeO
Cl
Cl
Me
4
5
(HO)2B
(HO)2B
90
93
H2N
Me
H N
2
Cl
Me
Me
Me
Me
6
7
97
94
Cl
(HO)2B
(HO)2B
Me
Me
Me
Cl
Me
Me
Me
Me Me
MeMe
Me
(HO)2B
Me
8
Cl
96
Me
Me
Me
NC
CN
(HO)2B
9
99
96
Cl
N
Cl
(HO)2B
(HO)2B
10
N
S
S
Cl
11
12
77
92
H2N
Cl
(HO)2B
(HO)2B
H2N
O
13
14
97b
Br
I
O
(HO)2B
99b,c
a
b
c
Conditions: aryl chloride (1.0 equiv), boronic acid (1.0 equiv), K2CO3 (1.5 equiv), 1 (0.1%), 800 W M.W. irradiation, 15 min, H2O (5 mL).
Compound 1 (0.0001%).
AgBF4 (1.1 equiv) was added.
Isolated yield after column chromatography.
d

M. E. Hanhan et al. / Tetrahedron Letters 53 (2012) 2388–2391
2391
12. Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67,
5553–5566.
amounts of catalyst (0.0001%) permitted the coupling of aryl bro-
mides and iodides with boronic acids in very high yields. When 1
was compared with other reported catalysts for Suzuki couplings,
catalyst 1 did not need any additional solvent other than H2O or
additives such as TBAB.22–25 Furthermore, 1 is air-stable and the
reactions were complete in 15 min. The effects of catalyst 1 on
other cross-coupling reactions are currently under investigation.
13. Hierso, J. C.; Fihri, A.; Amardeil, W.; Meunier, P.; Doucet, H.; Santelli, M.;
Donnadieu, B. Organometallics 2003, 22, 4490–4499.
14. Baillie, C.; Zhang, L. X.; Xiao, J. L. J. Org. Chem. 2004, 69, 7779–7782.
15. Thimmaiah, M.; Fang, S. Tetrahedron 2007, 63, 6879–6886.
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697–702.
17. Guo, X. M.; Zhou, J.; Li, X. Y.; Sun, H. J. J. Organomet. Chem. 2008, 693, 3692–
3696.
18. Characterization data for selected compounds; L: (ATR, m
, cmÀ1) 1632 (C@N),
Acknowledgments
1181 (S@O); 1H NMR (DMSO-d6, d, ppm) 8.21 (2H, s, CH@N), 7.54–7.43 (3H, m,
Ar-H), 7.03 (2H, Ar-H, m), 4.91 (4H, t, J 1.7 Hz, C5H4), 4.73 (4H, t, J 1.6 Hz, C5H4),
4.38 (10H, s, C5H5), 3.17 (8H, m, N(CH2–CH2–CH2–CH3)4), 1.72 (8H, m, N(CH2–
CH2–CH2–CH3)4), 1.29 (8H, m, N(CH2–CH2–CH2–CH3)4), 0.96 (12H, m, N(CH2–
CH2–CH2–CH3)4); 13C NMR (DMSO-d6, d, ppm) 159.3 (N@CH), 142.4 (Ar-C),
133.6 (Ar-C), 130.2 (Ar-C), 127.6 (Ar-C), 122.1 (Ar-C), 121.9 (Ar-C), 121.6 (Ar-C),
121.1 (Ar-C), 119.6 (Ar-C), 117.3 (Ar-C), 80.9 (C5H5), 72.4 (C5H5), 71.3 (C5H5),
70.4 (C5H5), 61.3 (N(CH2–CH2–CH2–CH3)4), 30.7 (N(CH2–CH2–CH2–CH3)4), 18.2
The authors thank the Research Board of Zonguldak Karaelmas
University (BAP-2010-13-02-02, BAP-2011-10-03-11 and BAP-
2011-10-03-012), the Spanish Government (projects MAT2009-
14564-C01) and the Generalitat Valenciana (project PROMETEO/
2009/016) for support.
(N(CH2–CH2–CH2–CH3)4), 15.4 (N(CH2–CH2–CH2–CH3)4); LC–MS (API-ES) m/z
631 (M++1-NBu4, 14%), 630 (M+-NBu4, 36%), 415(28), 260 (100), 242 (NBu4
,
+
48%), 205(14). Anal. Calcd for C48H61Fe2N3O3S: C, 66.13; H, 7.05; N, 4.82.
Supplementary data
Found: C, 66.21; H, 6.97; N, 4.61. Compound 1: FT-IR (ATR,
m
, cm-1) 1562
(C@N), 1183 (S@O); 1H NMR (DMSO-d6, d, ppm) 9.04 (2H, s, CH@N), 7.61–7.58
(3H, m, Ar-H), 7.14 (2H, Ar-H, m), 4.96 (4H, t, J 1.9 Hz, C5H4), 4.77 (4H, t, J
2.0 Hz, C5H4), 4.46 (10H, s, C5H5), 3.36 (8H, m, N(CH2–CH2–CH2–CH3)4), 1.87
(8H, m, N(CH2–CH2–CH2–CH3)4), 1.41 (8H, m, N(CH2-CH2-CH2-CH3)4), 1.14
(12H, m, N(CH2–CH2–CH2–CH3)4); 13C NMR (DMSO-d6, d, ppm) 168.6 (N@CH),
145.7 (Ar-C), 134.1 (Ar-C), 133.7 (Ar-C), 131.6 (Ar-C), 126.3 (Ar-C), 125.3 (Ar-C),
125.1 (Ar-C), 124.9 (Ar-C), 123.1 (Ar-C), 121.7 (Ar-C), 84.1 (C5H5), 75.9 (C5H5),
75.1 (C5H5), 73.6 (C5H5), 66.9 (N(CH2–CH2–CH2–CH3)4), 37.2 (N(CH2–CH2–
CH2–CH3)4), 23.8 (N(CH2–CH2–CH2–CH3)4), 17.6 (N(CH2–CH2–CH2–CH3)4); LC-
MS (API-ES) m/z 807 (M++1-NBu4, 21%), 606 (M+-NBu4, 77%), 421(39), 272 (14),
242 (NBu4+, 21%), 106(100). Anal. Calcd for C48H61Cl2Fe2N3O3PdS; C, 54.95; H,
5.86; N, 4.01; Cl, 6.76. Found: C, 54.59; H, 6.07; N, 4.42; Cl, 7.11.
19. Buffin, B. P.; Fonger, E. B.; Kundu, A. Inorg. Chim. Acta 2003, 355, 340–346.
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.102. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
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