Cross-coupling reactions with boronic acids in water catalysed by oxime-derived palladacycles

Article abstract of DOI:10.1016/S0022-328X(02)01727-8

Palladacycles derived from phenone-oximes 1 are efficient precatalysts for the Suzuki-Miyaura coupling of arylboronic acids with aromatic and heteroaromatic bromides and chlorides under water reflux under aerobic conditions. Alternatively, the coupling can also be carried out at room temperature in methanol-water. Aryl bromides gave biaryls with TON up to 10⁵ and TOF up to 7 × 10⁴ h^-1. Activated and deactivated aryl chlorides need the presence of TBAB for the couplings, showing slightly lower efficiency (TON up to 9000 and TOF up to 3850 h^-1). C(sp²)-C(sp³) bonds can also be formed by cross-coupling reactions of trimethylboroxine and butylboronic acid with aromatic bromides and chlorides under water reflux and of benzylic and allylic chlorides or acetates with arylboronic acids in acetone-water at room temperature.

Full text of DOI:10.1016/S0022-328X(02)01727-8

Journal of Organometallic Chemistry 663 (2002) 46ꢁ57
/
www.elsevier.com/locate/jorganchem
Cross-coupling reactions with boronic acids in water catalysed by
oxime-derived palladacycles
Luis Botella, Carmen Na´jera ꢀ
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Alicante, Apartado 99, E-03080 Alicante, Spain
´
´
Received 22 April 2002; accepted 18 July 2002
This paper is dedicated to Professor Pascual Royo on occasion of his 65th birthday
Abstract
Palladacycles derived from phenone-oximes 1 are efficient precatalysts for the Suzukiꢁ
with aromatic and heteroaromatic bromides and chlorides under water reflux under aerobic conditions. Alternatively, the coupling
can also be carried out at room temperature in methanolꢁ
water. Aryl bromides gave biaryls with TON up to 105 and TOF up to
7ꢂ
104 hꢃ1. Activated and deactivated aryl chlorides need the presence of TBAB for the couplings, showing slightly lower efficiency
(TON up to 9000 and TOF up to 3850 hꢃ1). C(sp2)ÃC(sp3) bonds can also be formed by cross-coupling reactions of
trimethylboroxine and butylboronic acid with aromatic bromides and chlorides under water reflux and of benzylic and allylic
chlorides or acetates with arylboronic acids in acetoneꢁwater at room temperature.
# 2002 Elsevier Science B.V. All rights reserved.
/
Miyaura coupling of arylboronic acids
/
/
/
/
Keywords: Oxime derived palladacycles; Cross-coupling reactions; Boronic acids
1. Introduction
chlorides, but mainly based on the use of toxic
phosphanes as co-catalysts or N-heterocyclic carbene
(NHC) complexes in organic solvents under inert atmo-
sphere [7]. On the other hand, this type of cross-coupling
processes can be also applied with organoboranes or ate
Organometallic catalysis in air and in water has
become an important goal in green chemistry specially
for the development of industrial processes under
simple, economical, safe and environmentally favour-
complexes to create C(sp2)Ã
/
C(sp3) [8ꢁ
/
16] and C(sp3)Ã
/
C(sp3) [17,18] bonds. Alkylboronic acids have been used
very recently for cross-coupling of sp2-hybridized ha-
lides and triflates, but in the presence of a high excess of
Ag(I) salts [19,20].
Concerning the use of organoaqueous media, aryl-
boronic acids and sodium tetraphenylborate are appro-
priate reagents for cross-coupling reactions under inert
atmosphere. A well-established strategy for the coupling
of arylboronic acids with aryl bromides is the use of
water soluble phosphanes such as sodium triphenylpho-
sphino-3-trisulfonate (TPPTS) in combination with
able conditions [1]. Palladium mediated carbonÃ
bond forming reactions are specially powerful and
versatile methodologies in synthesis [2ꢁ4]. Cross-cou-
pling reactions of aryl halides with organoboron com-
pounds, the well-known SuzukiꢁMiyaura reaction [5],
/carbon
/
/
has become a very potent and popular method for the
synthesis of biaryls, important building blocks and
pharmacophores [6]. This coupling is specially useful
because of the broad tolerance to different functional
groups, the ability to couple sterically demanding
substrates, mild reaction conditions, non-toxic and
easy to handle reagents. Recent progress in this field is
focused to the use of the inexpensive and accessible aryl
Pd(OAc)2 in acetonitrileꢁwater (3/1) at 80 8C. Under
/
these conditions, deactivated aryl bromides afforded
turnover numbers (TON) up to 6400 and turnover
frequencies (TOF) up to 300 hꢃ1 [21]. Higher activity
was found with sterically demanding water-soluble
alkylphosphanes even working at room temperature in
ꢀ Corresponding author. Tel.:
903549; www.ua.es/dept.quimorg
ꢄ
/
34-965-903728; fax:
ꢄ/34-965-
E-mail address: cnajera@ua.es (C. Na´jera).
0022-328X/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 3 2 8 X ( 0 2 ) 0 1 7 2 7 - 8

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47
acetonitrileꢁ
TOF 183 500 hꢃ1 [22]. Triarylphosphaneꢁ
complexes bound to a poly(ethyleneglycol)ꢁpolystyrene
graft copolymer (PEGꢁPS resin), were efficient catalyst
/
water (1/1) with TON up to 734 000 and
/
palladium
/
Scheme 1. Cross-coupling studies of p-bromoacetophenone and
/
phenylboronic acid.
in neat water for the coupling of arylboronic acids with
aryl bromides and allylic acetates at room temperature
in the presence of 2 mol% of Pd [23]. Phosphane-free
couplings were carried out with 0.2 mol% of Pd(AcO)2
in the presence of tetrabutylammonium bromide
(TBAB) with aryl bromides at 70 8C [24]. Sodium
tetraphenylborate and aryl chlorides derived from
phenols and benzoic acids were coupled in water as
water with K2CO3 as base (method A) in the presence of
complexes 1 with 10ꢃ2 mol% of Pd during 15 min, the
process took place with ca. 104 TON and 4ꢂ104 hꢃ1
/
TOF (Table 1, entries 1ꢁ3). Slightly lower yields were
/
obtained when Pd(OAc)2 or Li2PdCl4 were used as
catalysts. Decreasing the loading of 1b to 10ꢃ3 mol% of
Pd gave 92% conversion in 100 min (Table 1, entry 6).
well using 1ꢁ/3 mol% of PdCl2 or Pd(OAc)2 as catalysts
For room temperature couplings, a mixture of MeOHꢁ
/
[25].
H2O 3/1 and KOH as base gave the highest conversions
with complexes derived from p-hydroxyacetophenone
and benzophenone 1b and 1c in 5 h with 104 TON.
Acetophenone derivative 1a needed 4 days to afford
We have recently described that oxime-derived palla-
dacycles 1 (Fig. 1) are robust and versatile precatalysts
for a wide range of cross-coupling processes in organic
solvents such as Heck, Suzuki, Stille, Sonogashira and
Ullmann reactions under aerobic conditions [26,27].
These type of palladacycles were also active catalysts
precursors for the Suzuki coupling of arylboronic acids
and aryl chlorides in water [28]. In this account we
report the scope of these compounds as catalysts for the
similar TON (Table 1, entries 7ꢁ9). Pd salts such as
/
Pd(OAc)2 or Li2PdCl4 were not so efficient catalysts
under these reaction conditions and the reaction stopped
after 23 and 8 h with ca. 50% conversion (Table 1,
entries 10 and 11). When the reaction in MeOHÃ
/H2O
formation of C(sp2)Ã
/
C(sp2) and C(sp2)Ã
/
C(sp3) bonds in
and complex 1b was carried out at 60 8C (method C) a
higher efficiency was achieved after 2 h with 105 TON
(Table 1, entry 12). Catalyst 1b showed high stability in
five subsequent 2 h catalytic cycles with 10ꢃ3 mol% of
Pd under method C conditions (Table 1, entry 12) giving
in all cases more than 95% isolated yield of p-phenyla-
cetophenone.
neat water or in aqueous solvents, through the coupling
of aryl and alkylboronic acids with different organic
bromides and chlorides.
2. Results and discussion
The scope of the Suzuki reaction with different
aromatic and heteroaromatic bromides was studied
with complex 1b and using methods A and B (Scheme
2 and Table 2). In general both methods afforded similar
TONs (ca. 104) with activated and deactivated aryl
bromides. However, reaction times were shorter when
using method A. In some cases, method C was used
instead of method B in order to decrease reaction times
(Table 2, entries 8, 10 and 13). This methodology was
applied to the synthesis of the anti-inflammatory 4-
biphenylacetic acid (felbinac) and the analgesic 4-
phenylmandelic acid employing method A but at room
temperature with 0.05 mol% of complex 1b (Table 2,
entries 16 and 17). p-Bromophenylacetic acid was
coupled in only 2 h to give biphenylacetic acid in 79%
isolated yield. This result is very interesting as this
coupling has been previously reported under very harsh
reaction conditions, longer reaction times and higher
2.1. Cross-coupling of aromatic and heteroaromatic
bromides with arylboronic acids
New phenone oxime-derived palladacycles 1b and 1c
with hydroxy groups at the aromatic ring were prepared
by reaction of the corresponding oximes with Li2PdCl4
and NaOAc in methanol [26ꢁ29]. Its reduction with
/
sodium cyanoborohydride led to the expected deuter-
ated oximes 2b and 2c in 79 and 78% yield, respectively
(Fig. 1). The evaluation in the Suzuki reaction of
palladacycles 1 (Fig. 1) and other palladium salts was
carried out by using phenylboronic acid and p-bromoa-
cetophenone (Scheme 1 and Table 1). After several
studies about aqueous solvents, temperature, bases and
catalyst loading, the best conditions are summarized in
Table 1. When the reaction was carried out in refluxing
catalyst loadings (refluxing isopropanolꢁ/water during 4
h in the presence of 5 mol% of PdꢁC) [30]. In the case of
/
p-bromomandelic acid, full conversion was also
achieved in 2 h. Previously reported conditions for this
substrate involved the use of higher catalyst loadings
(Pdꢁ
/
C 2 mol%) and 62 8C affording the product in a
75% yield [31].
Fig. 1. Oxime-derived palladacycles and deuterated oximes.

´
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L. Botella, C. Najera / Journal of Organometallic Chemistry 663 (2002) 46ꢁ57
/
Table 1
Reaction conditions and catalyst studies on the Suzuki coupling of p-bromoacetophenone and phenylboronic acid
a
b
Entry
Catalyst (mol% Pd)
Method
Time
Yield (%)
TON
TOF (hꢃ1
)
1
2
1a (10ꢃ2
1b (10ꢃ2
)
)
A
A
A
A
A
A
B
B
B
B
B
C
15 min
15 min
15 min
15 min
15 min
100 min
4 days
5 h
93
88
73
86
57
92
100
9300
8800
3 7200
35 200
32 444
31 272
22 800
52 600
104
3
1c (9ꢂ10ꢃ3
)
8111
7818
4
Pd(OAc)2 (1.1ꢂ10ꢃ2
)
5
Li2PdCl4 (10ꢃ2
)
5700
6
1b (10ꢃ3
1a (10ꢃ2
1b (10ꢃ2
)
)
)
92 000
10 000
10 000
9400
7
c
8
100 (98)
2000
1880
9
1c (10ꢃ2
Pd(OAc)2 (10ꢃ2
Li2PdCl4 (10ꢃ2
1b (10ꢃ3
)
5 h
23 h
94
50
48
10
11
12
)
5000
4800
217
600
)
8 h
2 h
c
)
100 (98)
100 000
50 000
a
Method A: p-bromoacetophenone (2 mmol), PhB(OH)2 (3 mmol), K2CO3 (4 mmol), H2O (7 ml), reflux. Method B: p-bromoacetophenone (2
mmol), PhB(OH)2 (3 mmol), KOH (4 mmol), MeOHꢁ
/H2O: 3/1 (8 ml), r.t. Method C: method B but at 60 8C (bath temperature).
b
c
GC yield.
Isolated yield.
was also coupled with p-(trifluoromethyl)phenylboronic
acid under water reflux (Table 4, entry 5) to give in 76%
yield 4?-(trifluoromethyl)-2-biphenylcarbaldehyde a pre-
Scheme 2. Cross-coupling of aromatic bromides and phenylboronic
acid.
cursor of the xenalipin acid, a compound which reduces
cholesterol and trigliceride levels in plasma [21]. This
product was prepared in a 73% yield by Geneˆt et al. by
using 5 mol% of Pd(OAc)2 in the presence of TPPTS but
starting from o-bromobenzaldehyde [21]. This metho-
dology has been also applied to the synthesis of 4?-
methylbiphenyl-2-carbonitrile, an intermediate in the
preparation of modern angiotensin II receptor antago-
nists such as the antihypertensive drugs, losartan,
valsartan, irbesartan, and tasosartan [32]. This com-
pound was obtained in a 70% yield after coupling o-
chlorobenzonitrile with p-methylphenylboronic acid
either with 0.05 and 0.5 mol% of complex 1b in 2 days
and 2 h, respectively (Table 4, entries 6 and 7). Less
reactive chlorides such as p-chloroanisol and p-chlor-
ophenol were coupled in moderate yields (Table 4,
entries 9 and 10). Moreover, p-chloroaniline suffered
efficient coupling in 6 h with 0.5 mol% of palladacycle
1b (Table 4, entry 11). As in the case of the correspond-
ing bromides, biarylacetic acid and p-phenylmandelic
acid were prepared from the corresponding chlorides in
moderate yields after 2.5 h with 0.5 mol% of complex 1b
(Table 4, entries 12 and 13). Different chloro-substituted
pyridines and 1-chloroisoquinoline were coupled with
phenylboronic acid in good yields in short times ranging
2.2. Cross-coupling of aromatic and heteroaromatic
chlorides with arylboronic acids
Preliminary studies about the appropriate reaction
conditions for the Suzuki coupling of p-chloroaceto-
phenone with phenylboronic acid using the previously
mentioned methods A and B, showed that the presence
of TBAB was crucial to obtain good conversions
(Scheme 3 and Table 3), presumably due to the rapid
formation of Bu4Nꢄ PhB(OH)ꢃ3 [24]. Under water
reflux conditions (method A), 0.5 equivalent of TBAB
gave good conversions after 2 h with 5ꢂ
10ꢃ3 mol% of
/
complexes 1 (Table 3, entries 2 and 3). For room
temperature conditions (method B), higher catalyst
loadings (0.5 mol% of 1) and one equivalent of TBAB
had to be used when reagents were allowed to react for
18 h. As expected being the coupling more sluggish than
in the case of aryl bromides. Palladium(II) salts were
ineffective under both reaction conditions. The thermal
stability of these palladacycles was also studied follow-
ing method A conditions with 0.05 mol% of compound
1b in 1 h intervals. After the first and second cycle 99%
conversion was obtained. The conversion decrease in the
third and fourth cycle to 75 and 46%, respectively.
The reactivity of different aromatic and heteroaro-
matic chlorides with different arylboronic acids was
studied using precatalyst 1b under method A conditions
(Scheme 4 and Table 4). The amounts of complex 1b and
TBAB were optimized in each example. In the case of o-
chlorobenzaldehyde, a better result was obtained when
using method B (Table 4, entries 3 and 4). This aldehyde
from 3 to 4 h (Table 4, entries 14ꢁ18). In the case of
/
2,4,6-trichloropyrimidine, an excess of phenylboronic
acid was used affording after 2.5 h and in the presence of
0.35 mol% of complex 1b the corresponding triphenyl
substituted pyrimidine (Table 4, entry 19). This 2,4,6-
triphenylpyrimidine has been recently prepared in under
glyme reflux conditions during 24 h and using Pd(OAc)2
(2.5 mol%) and PPh3 (5 mol%) in 93% yield [33]. Finally,

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L. Botella, C. Najera / Journal of Organometallic Chemistry 663 (2002) 46ꢁ
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49
Table 2
Suzuki coupling of aryl bromides and phenylboronic acida
a
See footnote a in Table 1.
b
GC yield.
c
Isolated yield after recrystallization.
Isolated yield after column chromatography.
d
e
The reaction was performed at r.t.
HPLC yield.
f
of precatalyst 1b. Previously described synthesis was
carried out under nitrogen atmosphere with 3 mol% of
Pd(PPh3)4 in refluxing toluene [34].
Scheme 3. Cross-coupling studies of p-chloroacetophenone and phe-
nylboronic acid.
2.3. Cross-coupling of aromatic and heteroaromatic
bromides and chlorides with alkylboronic acids
this methodology was applied to the synthesis of 4,5-
diarylpyrazinones, a family of compounds, which pre-
sent important agrochemical and pharmaceutical activ-
ities [34]. Thus, diarylation of the 4,5-dichloro-2-methyl-
3(2H)pyridazinone took place after 4 h with 0.05 mol%
The formation of C(sp2)Ã
/
C(sp3) bonds was studied
with aromatic and heteroaromatic bromides and chlor-
ides employing trimethylboroxine (TMB) and butyl-

´
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L. Botella, C. Najera / Journal of Organometallic Chemistry 663 (2002) 46ꢁ57
/
Table 3
Reaction conditions and catalyst studies on the Suzuki coupling of p-chloroacetophenone and phenylboronic acid
a
b
Entry
Catalyst (mol% Pd)
Method
Time (h)
Yield (%)
TON
TOF (hꢃ1
)
1
2
1a (10ꢃ2
1b (10ꢃ2
1b (10ꢃ2
)
)
)
A
A
2
2
69
77
10
69
5
6900
7700
1000
6900
500
3450
3850
250
c
3
A
4
4
1c (10ꢃ2
)
A
A
A
B
B
B
B
2
3450
250
5
Pd(OAc)2 (10ꢃ2
)
2
6
Li2PdCl4 (10ꢃ2
1a (1)
)
2
ꢁ/
ꢁ/
ꢁ/
7
18
18
18
18
43
50
42
1.5
43
50
42
1.5
2.4
2.8
2.3
8
1b (1)
1c (1)
9
10
Pd(OAc)2 (1)
ꢁ/
a
Method A: p-chloroacetophenone (2 mmol), PhB(OH)2 (3 mmol), K2CO3 (4 mmol), TBAB (1 mmol), H2O (7 ml), reflux. Method B: p-
chloroacetophenone (2 mmol), PhB(OH)2 (3 mmol), KOH (4 mmol), TBAB (2 mmol), MeOHꢁ
/H2O 3/1 (8 ml), r.t.
b
c
GC yield.
0.4 mmol of TBAB were used.
boronic acid. The methylation of aryl bromides and
activated aryl chlorides has been recently performed
with TMB in the presence 10 mol% of Pd(PPh3)4 in
refluxing aqueous dioxane for 1 day under nitrogen [10].
We have found that the methylation of p-bromo and p-
chloroacetophenone can be carried out under water
reflux in the presence of K2CO3 as base (method A) with
5 mol% of palladacycle 1b giving p-methylacetophenone
in high yields after 80 min and 4 h, respectively (Scheme
5 and Table 5). All essayed aryl chlorides were
methylated in the presence of TBAB. In the case of
4,5-dichloro-2-methyl-3(2H)pyridazinone mono and di-
conditions. The reaction of benzylic chlorides with
arylboronic acids was performed at room temperature
with 0.05 mol% of complex 1b in acetoneꢁwater (3/2),
/
KOH as base and TBAB as additive (similar to method
B) to afford in good yields the corresponding bis(ar-
yl)methanes (Scheme 6 and Table 6). The presence of
TBAB decreased the reaction time (Table 6, compare
entries 1 and 2). These reaction conditions are more
convenient than the previoulsy described for the cou-
pling of benzyl bromides with 3 mol% of Pd(PPh3)4 as
catalyst, which should to be heated at reflux of
dimethoxyethane for 18 h under argon [8]. When the
reaction was carried out in refluxing water and K2CO3
as base (method A) the corresponding benzylic alcohols
were mainly formed and the use of aqueous MeOH
(method B) gave considerable amounts of benzylic
methyl ethers.
1
methylation was observed in ca. 1/1 ratio by H-NMR
(Table 5, entry 4). Both products were easily separated
by flash chromatography yielding 2,4,5-trimethyl-
3(2H)pyridazinone and 4-chloro-2,5-dimethyl-3(2H)-
pyridazinone in 20 and 35% yields, respectively.
The alkylation with n-butylboronic acid was also
carried out under method A (water reflux) adding one
equivalent of TBAB in the case of aryl chlorides (Table
For the cross-coupling of allylic chlorides or less
costly acetates with arylboronic acids we used the same
reaction conditions as for benzylic chlorides (acetoneꢁ
/
5, entries 5ꢁ10). For this cross-coupling reaction only 1
/
water at room temperature) (Scheme 7 and Table 7). In
the presence of 0.5 equivalent of TBAB the loading of
the catalyst and the reaction time could be decreased to
give full conversion to the corresponding products in
less than 7 h at room temperature (TON up to 104)
mol% of Pd was used and the presence of Ag(I) salts
[19,20] was not necessary. In all the cases symmetrical
biaryls were obtained in variable amounts as by-
products due to the Ullmann-type coupling processes
of the aryl halides.
(Table 7, entries 1ꢁ
and acetate 3,3-diaryl-1-propenes were obtained as the
minor regioisomers in 3ꢁ24% (Table 7, entries 1ꢁ4 and
7).
/
3). In the case of cinnamyl chloride
2.4. Cross-coupling of benzylic and allylic chlorides or
acetates with arylboronic acids
/
/
The extension of the Suzuki reaction to the coupling
of benzylic bromides and iodides [8], allylic bromides
[35] and allylic acetates [23] with arylboronic acids, has
increased considerably the scope of this methodology.
We have found that oxime-derived palladacycles cata-
lyse the cross-coupling of benzylic and allylic chlorides
as well as allylic acetates under very smooth reactions
Scheme 4. Cross-coupling of aromatic chlorides and arylboronic
acids.

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L. Botella, C. Najera / Journal of Organometallic Chemistry 663 (2002) 46ꢁ
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51
Table 4
Suzuki coupling of aryl chlorides and arylboronic acids
a
a
Method A was used (see footnote a in Table 3).
GC yield.
b
c
In parenthesis isolated yield.
Method B was used (see footnote a in Table 3).
Determined by 1H-NMR.
d
e

´
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L. Botella, C. Najera / Journal of Organometallic Chemistry 663 (2002) 46ꢁ57
/
Scheme 6. Cross-coupling of benzylic chlorides and arylboronic acids.
Scheme 5. Cross-coupling of aromatic bromides and chlorides with
alkylboronic acids.
bromides and chlorides in refluxing water, or in aqueous
methanol at room temperature under aerobic condi-
tions. Aliphatic boronic acids can also be coupled
efficiently in refluxing water with aromatic bromides
and chlorides, whereas benzylic and allylic chlorides can
be coupled with aromatic boronic acids in aqueous
acetone at room temperature.
3. Conclusions
We can conclude that oxime-derived palladacycles are
very versatile precatalysts for the cross-coupling under
very simple and environmentally friendly conditions, of
arylboronic acids with aromatic and heteroaromatic
Table 5
Alkylation of aromatic bromides and chlorides with boronic acids
a
a
Method A: aryl bromide (0.5 mmol), TMB (0.5 mmol) or n-BuB(OH)2 (1.5 mmol), K2CO3 (1.5 mmol), H2O (4 ml), reflux.
In parenthesis isolated yield.
GC yield.
b
c
d
e
f
TBAB (one equivalent) was also added.
A 52% of 4-chloro-2,5-dimethyl-3(2H)pyridazinone was also obtained.
4,4?-Bis(acetyl)biphenyl (20%) was also isolated.
4,4?-Bis(trifluoromethyl)biphenyl (14%) was also obtained.
4,4?-Bis(methoxy)biphenyl (12%) was also obtained.
4,4?-Bis(acetyl)biphenyl (13%) was also obtained.
4,4?-Bis(trifluoromethyl)biphenyl (55%) was also obtained.
4,4?-Bis(methoxy)biphenyl (11%) was also obtained.
g
h
i
j
k

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L. Botella, C. Najera / Journal of Organometallic Chemistry 663 (2002) 46ꢁ
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53
Table 6
Arylation of benzylic chlorides with arylboronic acids
a
a
Method B: benzylic chloride (2 mmol), ArB(OH)2 (3 mmol), 1b (0.05 mol%), TBAB (1 mmol), KOH (4 mmol), acetoneꢁwater 3/2 (8 ml), r.t.
/
b
c
GC yield.
In parenthesis isolated yield.
Without TBAB.
d
4. Experimental
4.2. Synthesis of palladacycles
To a solution of Li2PdCl4 (2.62 g, 10 mmol) in MeOH
(20 ml), a methanolic solution (10 ml) of the corre-
sponding oxime (10 mmol) and AcONa (0.82 g, 10
4.1. General
mmol) was added. Then, the solution was stirred for 2ꢁ3
/
Gas chromatographic analyses were performed on a
HP-5890 instrument equipped with a WCOT HP-1
fused silica capillary column. M.p.s were determined
with a Reichert Thermovar hot plate apparatus. IR were
recorded on a Nicolet 400D FT. NMR spectra were
performed on a Bruker AC-300 using CDCl3 as solvent
and Me4Si as internal standard unless otherwise stated.
Low-resolution electron impact (EI) mass spectra were
obtained at 70 eV on a Shimadzu QP-5000. High
resolution mass spectra (EI) were recorded with a
Finnigan MAT 95S. Microanalyses were performed by
the Microanalysis Service of the University of Alicante.
Analytical TLC was performed on Schleicher and
Schuell F1400/LS silica gel plates and the spots visua-
lized with UV light at 254 nm. For flash chromatogra-
days at room temperature (r.t.). After adding water (10
ml), the corresponding cyclopalladated complexes pre-
cipitated and were filtered off. The different catalysts 1
were obtained with yields between 75 and 92%.
4.2.1. Complex 1b
Yield: 92%; m.p. ꢀ
1622 (CÄ
N) cmꢃ1; dH (300 MHz, DMF-d7) 9.96 (2H,
brs, 2ꢂOH), 9.71 (2H, brs, 2ꢂOH), 7.20 (2H, brs,
ArH), 7.07 (2H, d, Jꢅ8.5 Hz, ArH), 6.50 (2H, dd, Jꢅ
7.9 and 2.4 Hz, ArH), 2.24 (6H, s, 2ꢂCH3); dC (75
/
250 8C; nmax (KBr) 3425 (OH),
/
/
/
/
/
/
MHz, DMF-d7) 167.3, 157.4, 152.7, 134.2, 127.2, 123.4,
111.3, 11,1; Anal. Found: C, 31.82; H, 2.94; N, 4.79.
Calc. for C16H16Cl2N2O4Pd2: C, 32.90; H, 2.76; N,
4.80%.
phy Merck silica gel 60 (0.040ꢁ0.063 mm) was
/
employed. All reagents and solvents were obtained
from commercial sources and generally used without
further purification.
4.2.2. Complex 1c
Yield: 75%; m.p. ꢀ
/
250 8C; nmax (KBr) 3405 (OH),
1612 (CÄ
/
N) cmꢃ1; dH (300 MHz, DMF-d7) 10.50ꢁ
/9.40

´
54
L. Botella, C. Najera / Journal of Organometallic Chemistry 663 (2002) 46ꢁ57
/
evaporated (15 mmHg) and the product was purified by
flash chromatography on silica gel.
Scheme 7. Cross-coupling of allylic chlorides and acetates with
arylboronic acids.
4.3.1. Deuterated oxime 2b
Yield: 79%; m.p. 141 8C; Rf (C6H14ꢁ
0.44; nmax (KBr) 3330 (OH), 1642 (CÄ
N) cmꢃ1; dH (300
MHz, Me2SO-d6) 10.85 (1H, s, OH), 9.63 (1H, s, OH),
7.46 (1H, d, Jꢅ8.5 Hz, ArH), 6.76ꢁ6.74 (2H, m, ArH),
/
EtOAc, 1/1)
(6H, brs, 6ꢂ
(2H, brs, ArH), 7.02 (4H, d, Jꢅ
d, Jꢅ8.5 Hz, ArH), 6.48 (2H, dd, Jꢅ
ArH); dC (75 MHz, DMF-d7) 167.8, 160.0, 157.5, 152.9,
134.3, 131.5, 129.4, 123.7, 121.0, 115.8, 111.5; Anal.
Found: C, 41.62; H, 2.71; N, 3.69. Calc. for
C26H20Cl2N2O6Pd2: C, 42.19; H, 2.72; N, 3.78%.
/
OH), 7.41 (4H, d, Jꢅ
8.5 Hz, ArH), 6.69 (2H,
7.9 and 2.7 Hz,
/
8.5 Hz, ArH), 7.26
/
/
/
/
/
/
2.08 (3H, s, CH3); dC (75 MHz, Me2SO-d6) 158.0, 152.6,
127.9, 126.9, 115.12, 115.07, 115.0, 11.5; m/z (EI) 152
(100, [Mꢄ]), 151 (83, [Mꢄꢃ
1]), 136 (40), 135 (62), 134
(32), 121 (73), 120 (88), 119 (34), 95 (47), 94 (70), 93 (32),
92 (16), 91 (15), 67 (16), 66 (55), 65 (58), 64 (23), 63 (21).
/
4.3. Reduction of palladacycles with sodium
cyanoborodeuteride
4.3.2. Deuterated oxime 2c
Yield: 78%; m.p. 264 8C; Rf (C6H14ꢁ
0.30; nmax (KBr) 3347 (OH), 1603 (CÄ
N) cmꢃ1; dH (300
MHz, Me2SO-d6) 10.82 (1H, s, OH), 9.66 (2H, s, 2ꢂ
OH), 7.19 (1H, d, Jꢅ9.7 Hz, ArH), 7.11 (2H, d, Jꢅ8.5
Hz, ArH), 6.79 (2H, d, Jꢅ8.5 Hz, ArH), 6.73-6.71 (2H,
m, ArH); dC (75 MHz, Me2SO-d6) 158.1, 157.4, 154.9,
130.7, 128.8, 128.4, 128.3, 124.2, 115.0, 114.9, 114.7; m/z
(EI) 230 (19, [Mꢄ]), 122 (61), 121 (100), 110 (39), 109
(65), 93 (20), 65 (21).
/
EtOAc, 1/1)
To a mixture of the complex to be reduced (0.125
mmol) in THF (2.5 ml) and MeOH (1.25 ml), sodium
cyanoborodeuteride (0.25 mmol, 17 mg) was added
portion wise at 0 8C and the mixture was stirred for 1
h allowing to warm to r.t. The black precipitate was
filtered off, the solvents were evaporated (15 mmHg)
and the residue hydrolysed with water and extracted
with AcOEt. The organic layer was dried (MgSO4) and
/
/
/
/
/
Table 7
Arylation of allylic chlorides and acetates with arylboronic acids
a
a
Method B: allylic chloride or acetate (2 mmol), ArB(OH)2 (3 mmol), 1b, TBAB (1 mmol), KOH (4 mmol), acetoneꢁwater 3/2 (8 ml), r.t.
/
b
c
d
e
f
GC yield using decane as internal standard.
In parenthesis isolated yield of the major regioisomer.
Without TBAB.
4% of the other regioisomer.
6% of the other regioisomer.
g
h
i
10% of the other regioisomer.
24% of the other regioisomer.
3% of the other regioisomer.

´
L. Botella, C. Najera / Journal of Organometallic Chemistry 663 (2002) 46ꢁ
/57
55
4.4. Typical experimental procedure for Suzuki coupling
of aromatic and heteroaromatic bromides and chlorides
with arylboronic acids
128.9, 127.5, 126.7, 122.6, 120.7, 116.9, 56.4; m/z (EI)
228 (100, [Mꢄ]), 182 (15), 129 (27), 128 (28); HRMS
(EI) [Mꢄ], Found: 228.0756. C14H12O3 requires
228.0786.
4.4.1. Method A
A 25 ml round bottom flask was charged with aryl
halide (2 mmol), arylboronic acid (3 mmol), K2CO3 (4
4.5. Typical experimental procedure for Suzuki coupling
of aromatic and heteroaromatic bromides and chlorides
with TMB
mmol, 553 mg), TBAB (1ꢁ
/
2 mmol, only with aryl
4) and water (7
chlorides) palladacycle 1b (see Tables 1ꢁ
/
ml). The mixture was stirred under reflux in air and the
reaction progress was analysed by GC. After the
reaction was completed or stopped, the reaction mixture
A 10 ml round bottom flask was charged with aryl
halide (0.5 mmol), TMB (0.5 mmol, 70 ml), K2CO3 (1.5
mmol, 207 mg), TBAB (0.5 mmol, 161 mg, only with
aryl chlorides), palladacycle 1b (0.025 mmol, 14.6 mg, 10
mol% Pd) and water (4 ml). The mixture was stirred
under reflux in air and the reaction progress was
analysed by GC. After the reaction was completed or
stopped, the reaction mixture was extracted with EtOAc
was extracted with EtOAc (3ꢂ15 ml). The organic
/
phases were dried and evaporated (15 mmHg). The
subsequent residue was purified by recrystallization or
by flash chromatography on silica gel.
4.4.2. Method B
A 25 ml round bottom flask was charged with aryl
halide (2 mmol), arylboronic acid (3 mmol), KOH (4
(3ꢂ10 ml). The organic phases were dried and evapo-
rated (15 mmHg). The subsequent residue was purified
by flash chromatography on silica gel.
The compounds 4-methylacetophenone and 4-methyl-
benzophenone are commercially available. Physical,
analytical and spectroscopic data of the other synthe-
sized compounds follow.
/
mmol, 224 mg), TBAB (1ꢁ
chlorides), palladacycle 1b (see Tables 1ꢁ
MeOHꢁwater 3/1 (8 ml). The mixture was stirred at
/2 mmol, only with aryl
/
4) and
/
r.t. and the reaction progress was analysed by GC.
Normally, the product was not soluble in the solvent
mixture. In those cases, when the reaction was com-
pleted or stopped, the mixture was filtered and the solid
4.5.1. 2,4,5-Trimethyl-3(2H)-pyridazinone
Rf (C6H14ꢁ
/
EtOAc, 1/1) 0.41; nmax (liquid film) 1641
O), 1596 (ArC) cmꢃ1; dH (300 MHz, CDCl3) 7.50
obtained was washed with MeOHꢁwater 3/1 and
/
(CÄ
/
purified by recrystallization. When both aryl halide
and biaryl were soluble, the reaction mixture was poured
(s, 1H, ArH), 3.73 (s, 3H, CH3N), 2.13 (s, 3H, CH3C),
2.12 (s, 3H, CH3C); dC (75 MHz, CDCl3) 161.4, 138.6,
137.8, 136.1, 40.2, 16.3, 12.3; m/z (EI) 138 (52, [Mꢄ]),
109 (16), 67 (34); HRMS (EI) [Mꢄ], Found: 138.0813.
C7H10N2O requires 138.0793.
into excess of water and extracted with EtOAc (3ꢂ15
/
ml). The organic phases were dried, evaporated (15
mmHg) and the crude product purified by recrystalliza-
tion or flash chromatography on silica gel.
The compounds 4-phenylacetophenone, 4-phenylani-
sole, 4-phenylphenol, 2-phenylbenzonitrile, 5-phenylpyr-
imidine, 5-phenyl-2-thiophenecarbaldehyde, biphenyl-
acetic acid, 2-phenylbenzaldehyde, 4?-metilbiphenyl-2-
carbonitrile, 4-phenylbenzamide, 4?-fluoro-4-hydroxybi-
phenyl, 4-phenylaniline, 2-phenylpyridine, 3-phenylpyri-
dine, 4-phenylpyridine and 1-phenylisoquinoline are
commercially available. The compounds 5-phenyl-2-
hydroxyacetophenone [36], 4-phenylmandelic acid [31],
4?-trifluoromethylbiphenyl-2-carbaldehyde [37], 5-phen-
yl-3-methoxy-2-nitropyridine [38], 2,4,6-triphenylpyrimi-
dine [33] and 4,5-diphenyl-2-methyl-3(2H)-pyridazinone
[34] have been previously reported. Physical, analytical
and spectroscopic data of the other synthesized com-
pounds follow.
4.5.2. 4-Chloro-2-5-dimethyl-3(2H)-pyridazinone
M.p. 128 8C; Rf (C6H14ꢁ
/
EtOAc, 1/1) 0.22; nmax
O) 1600 (ArC) cmꢃ1; dH (300 MHz,
CDCl3) 7.59 (1H, s, ArH), 3.79 (3H, s, CH3N), 2.28 (3H,
(KBr) 1645 (CÄ
/
s, CH3C); dC (75 MHz, CDCl3) 157.5, 139.2, 137.4,
134.4, 40.9, 17.0; m/z (EI) 160 (10, [Mꢄꢄ
2]), 158 (34,
/
[Mꢄ]), 142 (19), 130 (22), 87 (33); HRMS (EI) [Mꢄ],
Found: 158.0227. C6H7ClN2O requires 158.0247.
4.6. Typical experimental procedure for Suzuki coupling
of aromatic bromides and chlorides with butylboronic acid
A 25 ml round bottom flask was charged with aryl
halide (2 mmol), butylboronic acid (6 mmol, 611 mg),
K2CO3 (6 mmol, 829 mg), TBAB (2 mmol, 644 mg, only
with aryl chlorides), palladacycle 1b (0.01 mmol, 5.84
mg, 1 mol% Pd) and water (7 ml). The mixture was
stirred under reflux in air and the reaction progress was
analysed by GC. After the reaction was completed or
stopped, the reaction mixture was extracted with EtOAc
4.4.3. 5-Phenyl-2-hydroxy-3-methoxybenzaldehyde
M.p. 82 8C; Rf (C6H14ꢁ
3168 (OH), 1666 (CHO), 1268, 1076 (CÃ
(300 MHz, CDCl3) 11.09 (1H, s, OH), 9.97 (1H, s,
CHO), 7.57ꢁ7.32 (7H, m, ArH), 3.98 (3H, s, CH3); dC
(75 MHz, CDCl3) 196.7, 151.0, 148.5, 139.7, 133.2,
/
EtOAc, 7/1) 0.22; nmax (KBr)
/
O) cmꢃ1; dH
/
(3ꢂ15 ml). The organic phases were dried and evapo-
/

´
56
L. Botella, C. Najera / Journal of Organometallic Chemistry 663 (2002) 46ꢁ57
/
(b) A. Zapf, A. Ehrentraut, M. Beller, Angew. Chem. Int. Ed. 39
(2000) 4153;
rated (15 mmHg). The subsequent residue was purified
by flash chromatography on silica gel.
The compound 4-butylacetophenone is commercially
available and the compounds 1-butyl-4-trifluoromethyl-
benzene [39] and 4-butylanisole [40] have been previously
reported.
(c) A.F. Littke, C. Dai, G.C. Fu, J. Am. Chem. Soc. 122 (2000)
4020;
(d) K. Inada, N. Miyaura, Tetrahedron 56 (2000) 8661;
(e) J.P. Wolfe, R.A. Singer, B.H. Yang, S.L. Buchwald, J. Am.
Chem. Soc. 121 (1999) 9550;
(f) X. Bei, T. Crevier, A.S. Guram, B. Jandeleit, T.S. Powers,
H.W. Turner, T. Uno, W.H. Weinberg, Tetrahedron Lett. 40
(1999) 3855;
4.7. Typical experimental procedure for Suzuki coupling
of benzylic and allylic chlorides or acetates with
arylboronic acids
(g) X. Bei, H.W. Turner, W.H. Weinberg, A.S. Guram, J.L.
Petersen, J. Org. Chem. 64 (1999) 6797;
(h) F. Firooznia, C. Gude, K. Chan, Y. Satoh, Tetrahedron Lett.
39 (1998) 3985;
A 25 ml round bottom flask was charged with
benzylic or allylic chloride or acetate (2 mmol), aryl
boronic acid (3 mmol), KOH (4 mmol, 224 mg), TBAB
(1 mmol, 322mg), decane (2 mmol, 389 ml), palladacycle
(i) A.F. Littke, G.C. Fu, Angew. Chem. Int. Ed. 37 (1998) 3387;
(j) A. Zapf, M. Beller, Chem. Eur. J. 6 (2000) 1830;
(k) G.Y. Li, Angew. Chem. Int. Ed. 40 (2001) 1513;
(l) C. Zhang, M.L. Trudell, Tetrahedron Lett. 41 (2000) 595;
1b (see Tables 6 and 7) and C3H6Oꢁwater 3/2 (8 ml).
/
(m) V.P.W. Bohm, C.W.K. Gstottmayr, T. Weskamp, W.A.
¨ ¨
Herrmann, J. Organomet. Chem. 595 (2000) 186;
(n) C. Zhang, J. Huang, M.L. Trudell, S.P. Nolan, J. Org. Chem.
64 (1999) 3804;
The mixture was stirred at r.t. in air and the reaction
progress was analysed by GC. After the reaction was
completed or stopped, the reaction mixture was ex-
(o) T. Weskamp, V.P.W. Bohm, W.A. Herrmann, J. Organomet.
Chem. 585 (1999) 348;
tracted with EtOAc (3ꢂ15 ml). The organic phases
/
were dried and evaporated (15 mmHg). The subsequent
residue was purified by distillation or by column
chromatography on silica gel.
(p) W.A. Herrmann, C.-P. Reisinger, M.J. Spiegler, J. Organo-
met. Chem. 557 (1998) 93;
(q) C.R. LeBlond, A.T. Andrews, Y. Sun, J.R. Sowa, Jr., Org.
Lett. 3 (2001) 1555;
The compounds diphenylmethane, 9-benzylanthra-
cene, 1-benzyl-4-chlorobenzene, 2-methyl-3-phenypro-
pene and 3-phenylpropene are commercially available
and the compounds [3-benzylanisole] [41], 4-chlorophe-
nyl(4-fluorophenyl)methane [42], 5-benzyl-2-chloropyri-
dine [43], (E)-1,3-diphenylpropene [44] and (E)-3-(4-
fluorophenyl)-1-phenylpropene [45] have been previously
reported.
(r) R.B. Bedford, C.S. Cazin, Chem. Commun. (2001) 1540.
[8] S. Chowdhury, P.E. Georghiou, Tetrahedron Lett. 40 (1999)
7599.
[9] M.-L. Yao, M.-Z. Deng, Synthesis (2000) 1095.
[10] M. Gray, I.P. Andrews, D.F. Hook, J. Kitteringham, M. Voyle,
Tetrahedron Lett. 41 (2000) 6237.
[11] A. Furstner, A. Leitner, Synlett (2001) 290.
¨
[12] G. Zou, J.R. Falck, Tetrahedron Lett. 42 (2001) 5817.
[13] P.N. Collier, I. Patel, R.J.K. Taylor, Tetrahedron Lett. 42 (2001)
5953.
[14] B. Iglesias, R. Alvarez, A.R. De Lera, Tetrahedron 57 (2001)
3125.
Acknowledgements
[15] D.J. Lapinsky, S.C. Bergmeier, Tetrahedron Lett. 42 (2001) 8583.
[16] S.R. Chemler, D. Trauner, S.J. Danishefsky, Angew. Chem. Int.
Ed. 40 (2001) 4544.
This work was financially supported by the DGICYT
(project PB97-0123) from the Spanish Ministerio de
Educacio´n y Cultura. L.B. thanks the Generalitat
Valenciana for a predoctoral grant.
[17] M.R. Netherton, C. Dai, K. Neuschutz, G.C. Fu, J. Am. Chem.
¨
Soc. 123 (2001) 10099.
[18] D.J. Ca´rdenas, Angew. Chem. Int. Ed. 38 (1999) 3018.
[19] J.R. Falck, P.S. Kumar, Y.K. Reddy, G. Zou, J.H. Capdevila,
Tetrahedron Lett. 42 (2001) 7211.
[20] G. Zou, Y.K. Reddy, J.R. Falck, Tetrahedron Lett. 42 (2001)
7213.
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