Benzaldimines as ligands for palladium in Suzuki-Miyaura reactions

Article abstract of DOI:10.1016/j.tetlet.2008.08.056

Schiff bases derived from substituted benzaldehydes are effective ligands for palladium(0) in the Suzuki-Miyaura coupling of phenylboronic acid with aryl, benzyl and allyl bromides under mild conditions.

Full text of DOI:10.1016/j.tetlet.2008.08.056

Tetrahedron Letters 49 (2008) 6304–6307
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Benzaldimines as ligands for palladium in Suzuki–Miyaura reactions
*
Dipankar Srimani, Amitabha Sarkar
Department of Organic Chemistry, Indian Association for the Cultivation of Science, 2A & 2B, Raja S. C. Mullick Road, 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:
Schiff bases derived from substituted benzaldehydes are effective ligands for palladium(0) in the Suzuki–
Miyaura coupling of phenylboronic acid with aryl, benzyl and allyl bromides under mild conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 30 June 2008
Revised 11 August 2008
Accepted 15 August 2008
Available online 22 August 2008
The biaryl linkage is an important structural motif in several
natural products and bioactive compounds.1 It is also a critical
structural component of axially dissymmetric ligands that are used
extensively with various metals in homogeneous enantioselective
catalysis. The Suzuki–Miyaura coupling reaction is a powerful
and widely used method for the synthesis of biaryls.2 Allyl and
vinyl halides, similarly, can be coupled with boronic acids to afford
allyl- and vinylarenes, respectively. Such a reaction is usually cat-
alyzed by a palladium(0) complex featuring a suitable ligand that
controls the selectivity and efficiency. While phosphines are used
extensively as ligands,3 their sensitivity to air and moisture is
known to limit their stability and shelf-life. The search for effective
non-phosphine ligands has yielded viable alternatives such as N-
heterocyclic carbenes (NHC),4 imine,5 amine5 and oxime6 pallada-
cycles, diazabutadienes,7 oxazolines,8 amines9 and hydrazones10
for use in this reaction. Examples of Schiff base ligands, however,
remain scarce to date.11 We recently reported the use of pyr-
azole-tethered aryl phosphines and aryl Schiff bases as effective
ligands for palladium in Suzuki reactions.12 Simplifying the design
further, we now report that simple Schiff bases themselves serve as
extremely useful ligands in Suzuki coupling reactions.
bases used are displayed in Table 1 along with the yields of the
coupling products.
The molar ratio of metal:ligand was maintained at 1:2.5
throughout the present set of experiments since a lower propor-
tion of ligand decreased the yield. As seen from Table 1, the Schiff
base 1c derived from o-anisaldehyde and
a-methylbenzylamine
provided the highest yield of coupled product (92%, entry 3). The
absence of an o-OMe group (entry 1) or the presence of an o-OH
group (entry 2) led to a reduction in the yield. Increasing the steric
bulk using an o-OiPr group did not improve the yield. Yields were
low to moderate using Schiff bases derived from cyclohexylamine
or tert-butylamine (entries 6 and 7). The Schiff base derived from
2,6-diisopropylaniline (entry 8) afforded the coupling product in
a slightly higher yield. We observed that for an activated aryl bro-
mide, such as 4-bromoacetophenone, the ligands were of compara-
ble activity. For a deactivated aryl bromide, ligand 1c was more
active than ligand 1a or 1b. An investigation on the influence of
base indicated that KF was more effective than Na2CO3, K2CO3
t
and BuOK. Both THF and DMF gave comparable yields with KF
as base, but the yields were lower when toluene, benzene or aceto-
nitrile was used.
The Schiff base ligands 1a–h, prepared by standard procedures
from the corresponding aldehydes and amines, were screened for
the Suzuki–Miyaura coupling reaction of p-bromoanisole with
phenylboronic acid. Coupling reactions were examined using two
procedures that differed slightly in detail. According to the first
protocol, 1 mmol of substrate, 1.5 mmol of boronic acid and
3 mmol of KF were stirred with 2 mol % of Pd(OAc)2 and 5 mol %
of ligand in THF at 35 °C. In the second method, the reagents were
first stirred at 0 °C for 15 min and then the temperature was grad-
ually increased to 35 °C. The latter method afforded a better yield
of the coupling product and hence it was adopted for the examples
described below (Scheme of Table 1). The structures of the Schiff
While salen-type complexes with imine donors were investi-
gated earlier for developing catalysts immobilized on a solid sup-
port,11a other report on Schiff base ligands for palladium catalysis
describes imines derived from aromatic ketones11c or di-imines
affording a six-membered chelate.11d The ligands discussed in the
present Letter, on the other hand, are monodentate imines derived
from an aromatic aldehyde and an aliphatic or aromatic amine.
A significant advantage of using such ligands is that the reaction
can be performed at a much lower temperature and with a shorter
reaction time than required by other ligands without jeopardizing
the yield. That the coordination to palladium is primarily through
the imine nitrogen is borne out by the requirement of over two
equivalents of imine per equivalent of palladium during catalysis.
The usefulness of an o-OMe group on the aldehyde part suggests
a hemilabile participation of the methoxy group which adds to
the stability of the catalyst and its efficiency. The superior
* Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805.
E-mail address: ocas@iacs.res.in (A. Sarkar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.056

D. Srimani, A. Sarkar / Tetrahedron Letters 49 (2008) 6304–6307
6305
Table 1
Table 2
Schiff base ligands used and the yields of product from the coupling reactiona
Pd(OAc)2/ligand 1 catalyzed coupling of aryl halides with phenyl boronic acida
2 mol% Pd (OAc)2
5 mol% ligand
2 mol% Pd (OAc)2
5 mol% gand
li
MeO
Ar
+ (HO) B
(HO) B
MeO
Br
2a
Ar X
+
2
2
3 mmol KF, THF
0 ºC to 35 ºC, 6 h
2
3 mmol KF, THF
0 ºC to 35 ºC
3
3a
X=Br, Cl
Entry
1
Ligand
Ar
Product
Time (h) % Yield
Entry
Ligand
% Yield
55
H3COC
H3COC
3b
1a
3
98
1
2
N
Ph
CH3
2b
1a
OH
2
3
4
5
6
7
1b
1c
1d
1f
1g
1h
2b
2b
2b
2b
2b
2b
3b
3b
3b
3b
3
1.5
3
3
3
90
99
99
95
95
98
60
92
N
Ph
CH3
3b
1b
3
O2N
O2N
OMe
8
1c
2.5
99
3
4
N
Ph
CH3
2c
1c
3c
CH3
CH3
Ph
O2N
O2N
O
9
1c
1c
3.5
2.5
98
95
3d
80
2d
N
1d
CH3
NO2
NO2
10
MeO
OMe
3e
2e
5
6
90
70
N
Ph
CH3
1e
NC
NC
11
12
1c
1c
2.5
3
98
88
OMe
3f
2f
N
CHO
CHO
1f
OMe
N
H3C
3g
2g
7
8
72
80
CH3
CH3
1g
OHC
OHC
OHC
3h
OHC
13
14
1c
1c
2.5
2.5
95
96
2h
OMe
H3C CH3
N
1h
H3C
3i
3j
2i
CH3
15
16
1c
1a
3
4
95
75
a
Reaction conditions: aryl bromide (1 mmol), phenyl boronic acid (1.5 mmol),
2j
Pd(OAc)2: 2 mol %, ligand: 5 mol%, base: KF: 3 mmol, THF: 4 mL, temp: 0 °C for
15 min, then 35 °C. Yields are based on isolated pure product and reflect an average
of two runs.
H3C
H3C
3k
2k
17
18
19
20
21
1b
1c
1d
1e
1h
2k
2k
2k
2k
2k
3k
3k
3k
3k
3k
4
4
4
4
4
75
92
80
90
84
performance of the ligand 1c with respect to ligands 1a, 1b and 1d
perhaps reflects a better balance of steric bulk and donor ability.
These data do not indicate, whether a benzylic amine is necessary
for superior activity.
CH3
CH3
The reaction was extended to variously substituted aromatic
and heteroaromatic bromides and with different ligands on palla-
dium (Table 2). For aryl groups with electron-withdrawing groups,
the yields were excellent irrespective of the ligand selected. In gen-
eral, ligand 1c was found to be the most effective. High yields of
products prompted an examination of the influence of a low cata-
lyst loading on the coupling reaction. The quantity of the catalyst
was decreased to 0.002 mol %, giving the product in high yield
(90%) after 20 h stirring at 35 °C. This indicated that the catalyst
not only has high efficiency, but also has stability under the reac-
tion conditions. The results are summarized in Table 3.
22
1c
4.5
82
3l
2l
23
1c
2.5
95
2m
3m
24
25
1c
1c
5
5
98
90
MeO
MeO
2n
3n
Encouraged by these results, we proceeded to exploit this meth-
od to synthesize diarylmethanes via a similar Pd-catalyzed reac-
tion13 (Table 4). Diarylmethane derivatives are important
structural constituents of pharmacologically important com-
N
N
2o
3o
(continued on next page)

6306
D. Srimani, A. Sarkar / Tetrahedron Letters 49 (2008) 6304–6307
Table 2 (continued)
Table 4
Pd(OAc)2/ligand 1 catalyzed coupling of benzyl and allyl halides with phenylboronic
Entry
Ligand
Ar
Product
Time (h)
5
% Yield
88
acida
Entry
1
Substrate
Br
Product
Time (h)
2.5
% Yield
95
N
2p
26
1c
N
3p
5a
4a
MeO
27
28
1h
1c
2p
3p
5
7
82
MeO
Br
Br
2
3
4
2.5
2.5
2.5
98
96
98
O2N
O2N
82b
5b
5c
4b
4c
3d
3h
2d
2h
OHC
OHC
29
1c
7
40b
MeO
Me
MeO
Me
a
Reaction conditions: as described in Table 1.
For chloro substrate, 20 mol % TBAB (tetrabutylammonium bromide) was
Br
b
4d
Br
5d
added, reaction at 65 °C.
Table 3
Influence of low catalyst loading on the coupling reactiona
5
3.5
3.5
98
98
Substrate
Product
Pd (mol %)
Time (h)
% Yield
4e
5e
2.0
2.5
3
15
20
99
98
95
90
Br
0.20
0.02
0.002
Br
Reaction conditions: as described in Table 1.
6
O2N
O2N
4f
5f
a
a
Reaction conditions: as described in Table 1.
pounds14 as well as useful subunits of a wide range of macrocycles,
catenanes and rotaxanes.15
of the ligand to a solution of Pd(OAc)2 in THF was consistent with
Pd(II) gradually being transformed to Pd(0) nanoparticles (Fig. 1).
However, it is not possible to conclude solely on this basis
whether nanoclusters or palladium complexes are responsible for
the catalysis. Despite extensive and rigorous experiments to settle
the issue,18 it is still unclear in most instances whether the reaction
takes place on the surface of the solid Pd nanocluster or whether
the active catalyst is a solvated Pd molecule leached from the clus-
ter that simply acts as a Pd reservoir. There are recent reports that
suggest Suzuki–Miyaura couplings to be actually catalyzed by pal-
ladium nanoparticles produced by palladacycles originally added
to the reaction.19 Poisoning experiments are often used to distin-
guish between ‘homogeneous’ and ‘heterogeneous’ catalysis.18 Fol-
lowing the procedure developed by Widergren and Finke,18 we
observed that at least 0.8 equiv of CS2 was required to poison our
reaction effectively. This is substantially higher than the amount
that would have been required to poison active metals on the sur-
face of the nanocluster. Addition of even 300 M equiv of mercury
failed to contain the catalytic turnover indicating, once again, that
nanoparticles are perhaps not the catalytic agents in this reaction.
Coupling of electrophiles containing sp3C–X bonds with arylbo-
ronic acids utilizes benzyl bromide, chloride, carbonate or phos-
phate as the X-group.13,16 We applied the optimized reaction
conditions described above for the coupling reaction of different
benzyl and allyl bromides with phenylboronic acid. All the sub-
strates furnished the expected coupling products in high yield (Ta-
ble 4). The tolerance of functional groups is well known for such
coupling reactions.17 The reactivity of benzyl and allyl bromides
thus enhances the scope of this reaction significantly for complex
synthetic targets.
A change in colour of the solution from yellow to dark brown
during the Suzuki reaction indicated the possibility of nanoparticle
formation during the reaction. From the reaction between phenyl-
boronic acid and 4-bromoacetophenone in THF, an aliquot was
withdrawn and submitted to transmission electron microscopy
(TEM) which established that palladium nanoparticles with a
diameter of ꢀ6 nm were formed in the reaction mixture (Fig. 1).
The spectral change in the UV region during incremental addition
a
b
2
f
e
d
c
b
1
a
0
400
600
Wavelength/nm
Figure 1. (a) UV–vis spectral changes during the addition of ligand 1c in THF solution to Pd(OAc)2 in THF Pd: ligand 1c molar ratio (a) 1:0, (b) 1:0.5, (c) 1:1.0, (d) 1:1.5, (e) 1:2
and (f) 1:2.5, respectively. (b) TEM micrograph of palladium nanoparticles generated from the coupling reaction catalyzed by 1c.

D. Srimani, A. Sarkar / Tetrahedron Letters 49 (2008) 6304–6307
6307
In summary, an inexpensive and highly efficient method20 was
developed for the Suzuki–Miyaura coupling that can be performed
under phosphine free conditions and at near ambient temperature.
Various aryl bromides, benzyl bromides and heteroaryl bromides
were converted to the coupled products in excellent yields when
Pd(0) was used in combination with ligand 1c. The challenge of
chloride activation, however, still persists. Further studies on the
applicability of these ligands on other synthetic transformations
are currently under investigation in our laboratory.
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Acknowledgements
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We thank CSIR, India, and Syngene International, Bangalore,
India, for financial support. D.S is thankful to CSIR, India, for a
Research Fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.08.056.
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bottomed flask was cooled under argon and charged with aryl halide (1 mmol),
phenyl boronic acid (1.5 mmol), Pd(OAc)2 (2 mol %), ligand (5 mol %), and base
(3 mmol). The flask was evacuated and flushed with argon once again, and THF
(4 mL) was added to the reaction mixture by a syringe. The reaction mixture
was primarily stirred at 0 °C for 15 min and then stirring was continued at
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