Palladium-catalyzed carbonylative coupling of benzyl chlorides with aryl boronic acids in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2010.09.078

A novel chemoselective protocol for the carbonylative Suzuki coupling of benzyl chlorides with aryl boronic acids at low pressure of carbon monoxide has been developed. Applying a commercially available palladium acetate/PCy ₃ catalyst system in the presence of potassium phosphate as the base and water as the solvent the coupling reactions proceeded smoothly. To demonstrate the general applicability 12 different α-arylated acetophenones have been synthesized in moderate to good yields (41-78%) under mild conditions.

Full text of DOI:10.1016/j.tetlet.2010.09.078

Tetrahedron Letters 51 (2010) 6146–6149
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed carbonylative coupling of benzyl chlorides with aryl
boronic acids in aqueous media
⇑
Xiao-Feng Wu, Helfried Neumann, Matthias Beller
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel chemoselective protocol for the carbonylative Suzuki coupling of benzyl chlorides with aryl boro-
nic acids at low pressure of carbon monoxide has been developed. Applying a commercially available
palladium acetate/PCy3 catalyst system in the presence of potassium phosphate as the base and water
as the solvent the coupling reactions proceeded smoothly. To demonstrate the general applicability 12
Received 12 August 2010
Accepted 17 September 2010
Available online 24 September 2010
different
mild conditions.
a-arylated acetophenones have been synthesized in moderate to good yields (41–78%) under
Keywords:
Palladium
Ó 2010 Elsevier Ltd. All rights reserved.
Carbonylation
Benzyl chlorides
Aryl boronic acids
Suzuki reaction
Water
Palladium-catalyzed coupling reactions have become a true
power tool for advanced organic chemistry.1,2 In particular, the for-
mation of C–C-, C–O-, and C–N-bonds of aryl, heteroaryl, benzyl,
and vinyl halides in the presence of homogeneous palladium com-
plexes is frequently applied for the synthesis of pharmaceuticals,
agrochemicals, as well as advanced materials. Due to the impor-
tance of these reactions both academic as well as industrial labora-
tories continuously investigate and develop new applications.
Among the different known palladium-catalyzed coupling pro-
cesses, reactions with carbon monoxide create interesting benzoic
acid-based building blocks. Already in the mid-1970s, Heck and
co-workers described pioneering work on the alkoxy-, hydroxyl-,
and aminocarbonylation of aryl iodides and bromides.3 Since then,
numerous applications in organic synthesis have been reported
and even industrial processes were developed.4 As an example,
the more challenging reductive carbonylation of aryl halides form-
ing aldehydes has become an industrial process in 2006.5 Herein,
the key to success is the employed ligand (n-butyl-diadamantyl-
phosphine, cataCXium AÒ), which has also been applied success-
fully in alkoxycarbonylations6 and in the aminocarbonylation of
aryl halides with ammonia gas to give primary amides.7
Based on this work, we got attracted by related carbonylations
of benzyl halides. While the carbonylative coupling of benzyl
halides in the presence of O- and N-nucleophiles is well known,11,12
apart from only two examples similar reactions of benzyl chlorides
with phenyl boronic acid in the presence of carbon monoxide are
not described.8c This is somewhat surprising considering the
importance of the resulting 1,2-diarylethanone motif in known
pharmaceuticals and biologically active compounds.13 Hence, there
is still a need to develop convenient and more general methodolo-
gies for the synthesis of this class of compounds.
Herein, we present a novel procedure for carbonylative coupling
reactions of benzyl chlorides with phenyl boronic acids under mild
conditions in aqueous media. Initially, the carbonylation of inexpen-
sive benzyl chloride with phenyl boronic acid in the presence of
different palladium catalysts was tested as a benchmark reaction.
Selected results are shown in Table 1. In general, catalytic experi-
ments were performed in toluene using K3PO4 as the base at low
carbon monoxide pressure (10 bar). Applying Pd(OAc)2/PPh3 as the
catalyst system 26% of the desired carbonylative product 1 was
formed together after 20 hours along with 12% of the non-desired
Suzuki coupling by-product 2 (Table 1, entry 1). Employing PCy3 as
the ligand, an improved yield and chemoselectivity is obtained
(Table 1, entry 2). On the other hand using sterically more hindered
alkylphosphines such as n-butyl-diadamantylphosphine or tri-
tert-butylphosphine gave only low yields of carbonylation products
(Table 1, entries 6 and 7). Similarly, various bidentate phosphines as
well as one example of a carbene ligand [1,3-bis(2,6-diisopropyl-
phenyl) imidazolium chloride] led to significantly lower activity in
this reaction.
More recently, we became interested in three component
carbonylation reactions, such as the carbonylative Suzuki,8 car-
bonylative Sonogashira,9 and carbonylative Heck reactions,10
which allow for a significant increase in molecular complexity.
⇑
Corresponding author. Tel.: +49 381 1281 5000; fax: +49 381 4669 324.
E-mail address: matthias.beller@catalysis.de (M. Beller).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.078

X.-F. Wu et al. / Tetrahedron Letters 51 (2010) 6146–6149
6147
Table 1
Carbonylative Suzuki coupling of benzyl chloride: variation of ligandsa
B(OH)2
1
2
Pd(OAc)2/L
O
toluene
Cl
CO
K3PO4
CO 10 bar
80 oC, 20 h
Entry
Ligand
Conv.b (%)
Yield 1b (%)
Yield 2b (%)
1
2
3
4
5
6
7
8
PPh3
PCy3
TFP
DPPF
85
70
84
15
20
80
18
50
26
38
26
1
1
19
0
12
2
10
3
2
5
DPPP
BuPAd2
PtBu3ÁHBF4
Me(tBu)2PÁHBF4
0
0
27
N
PAd2
iPr
N
9
10
0
0
iPr
10
11
P(o-Toyl)3
IPrÁHCl
50
9
1
0
8
0
a
Pd(OAc)2 (2 mol %), L (4 mol %), K3PO4 (2 mmol), toluene (2 ml), benzyl chloride (1 mmol), phenyl boronic acid
(1.5 mmol), CO (10 bar), 80 °C, 20 h.
b
Conversion and yields were determined by GC using hexadecane as internal standard. TFP = tri-2-furylphos-
phine; IPrÁHCl = 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride.
Next, we tested different bases and solvents using Pd(OAc)2/
PCy3 as our standard catalyst system (Table 2). While K3PO4 and
K2CO3 gave comparable results (Table 1, entry 2 and Table 2, entry
1; 35–38%), Na2CO3 and Cs2CO3 resulted in lower yields (Table 2,
entries 2 and 3; 3–10%).
In the presence of organic bases such as DMAP and DABCO no
product was observed at all; instead only trimerization of phenyl
boronic acid was detected (Table 2, entries 4 and 5). Among the dif-
ferent organic solvents, dioxane proved to be the best giving 95%
conversion and 68% yield of product 1 (Table 2, entries 6–11). To
our delight only 2% of the direct coupling product was obtained
(Table 2, entry 6). Notably, running the model reaction in water
gave an even better yield (Table 2, entry 11; 73%). Clearly, water
is the most abundant, green, cheap, and environmental benign sol-
vent, which has attracted significant attention in the last decade.14
However, the use of water as solvent in carbonylation reactions has
Table 2
Carbonylative Suzuki coupling of benzyl chloride: testing of solvents and basea
B(OH)2
1
Pd(OAc)2
PCy3
O
Cl
CO
CO 10 bar
80 oC, 20 h
2
Entry
Solvent
Base
Conv.b (%)
Yield 1b (%)
Yield 2b (%)
1
2
3
4
5
6
7
8
9
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
THF
Heptane
DMF
NMP
K2CO3
Na2CO3
Cs2CO3
DMAP
DABCO
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
85
78
75
0
35
10
3
0
0
68
39
27
16
21
73
48
2
1
1
0
0
2
2
5
6
0
95
88
86
96
90
100
100
10
11
12c
10
7
24
H2O
H2O
a
Pd(OAc)2 (2 mol %), PCy3 (4 mol %), base (2 mmol), solvent (2 ml), benzyl chloride (1 mmol), phenyl boronic acid
(1.5 mmol), CO (10 bar), 80 °C, 20 h.
b
Conversion and yield were determined by GC using hexadecane as internal standard.
CO (5 bar).
c

6148
X.-F. Wu et al. / Tetrahedron Letters 51 (2010) 6146–6149
been largely neglected because it reacts preferentially as a nucleo-
phile forming the corresponding carboxylic acids. To the best of
our knowledge this is the first example using water as the single
solvent in carbonylative Suzuki reactions.
In the presence of quaternary ammonium salts, for example,
TBAF or TBAB the direct Suzuki coupling is favored. Similarly,
addition of 18-crown-6 led preferentially to the direct coupling
by-product 2.
Once optimized reaction conditions were identified, we investi-
gated the influence of substituted benzyl chlorides and aryl
boronic acids in this reaction.15 As shown in Table 3 the palla-
dium-catalyzed carbonylative Suzuki reaction took place under
Table 3
Palladium-catalyzed Suzuki carbonylation of different benzyl chloridesa
Pd(OAc)2/PCy3
K3PO4
B(OH)2
Cl
CO
R''
CO 10 bar, H2O
80 oC, 20 h
O
R'
R''
R'
Entry
1
Product
Yieldb (%)
73
O
2
3
4
78
47
58
O
O
F
O
O
5
6
54
55
O
O
OMe
MeO
7
8
41
58
53
58
69
50
OMe
O
O
F3C
OMe
9
O
10
11
12
Cl
O
Cl
O
S
O
a
Pd(OAc)2 (2 mol %), PCy3 (4 mol %), K3PO4 (2 mmol), H2O (2 ml), benzyl chlorides (1 mmol),
phenyl boronic acids (1.5 mmol), CO (10 bar), 80 °C, 20 h.
b
Isolated yields.

X.-F. Wu et al. / Tetrahedron Letters 51 (2010) 6146–6149
6149
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W. A., Eds., 2nd ed.; Wiley-VCH: Weinheim, 2002; pp 145–156; (d) Skoda-
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mild conditions (80 °C, 10 bar CO) in water. Ortho-, meta-, and para-
substituted aryl boronic acids gave the corresponding products in
moderate to good yields (Table 3, entries 4–11; 41–69%). There is
no problem using sterically hindered 2,6-dimethyl phenyl boronic
acid (Table 3, entry 4). In addition, 3-thiophenyl boronic acid as an
example for a heterocyclic substrate works equally well in this
system yielding 50% of the desired product (Table 3, entry 12).
It should be noted that in some cases (Table 3, entries 3–10) a
significant amount of the direct Suzuki product was formed
(30–45%) parallel to the carbonylation reaction. Especially, for
activated benzyl chlorides, for example, para-nitro-substituted
benzyl chloride, the direct coupling with phenyl boronic acid pre-
vailed. In contrast more difficult coupling substrates, for example,
ortho-substituted aryl boronic acids hampered the Suzuki reaction
due to steric reasons and favored the desired carbonylation
reaction.
In conclusion, we have developed novel carbonylative Suzuki
reactions of benzyl chlorides and aryl boronic acids. This methodol-
ogy allows for the straightforward synthesis of 1,3-diarylethanones,
which represent useful building blocks for organic synthesis.
Starting from inexpensive and easily available benzyl chlorides
the corresponding ketones are obtained in moderate to good yields.
Notably, these carbonylations can be performed in water as the
solvent.
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Acknowledgments
The authors thank the state of Mecklenburg-Vorpommern, the
Bundesministerium für Bildung und Forschung (BMBF) and the
DFG (Leibniz price) for the financial support. The authors thank
Drs. W. Baumann and C. Fischer (LIKAT) for the analytical support.
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15. General reaction procedure for model reaction: A 12 ml vial was charged with
Pd(OAc)2 (2 mol %), PCy3 (4 mol %), K3PO4 (2 mmol), PhB(OH)2 (1.5 mmol) and
a stirring bar. Then, 2 ml H2O (distilled, then degassed with argon within 1 h)
and 1 mmol of benzyl chloride were injected by syringe. The vial (or several
vials) was placed in an alloy plate, which was transferred into a 300 ml
autoclave of the 4560 series from Parr InstrumentsÒ under argon atmosphere.
After flushing the autoclave three times with CO and adjusting the pressure to
10 bar, the reaction was performed for 20 h at 80 °C. After the reaction is
finished, the autoclave was cooled down to room temperature and the pressure
was released carefully. The solution was extracted 3–5 times with 2–3 ml of
ethyl acetate. After evaporation of the organic solvent the residue was
adsorbed on silica gel and the crude product was purified by column chro-
matography using n-heptane/AcOEt (50:1) as eluent. White solid (143 mg) was
obtained as product, Rf = 0.27. 1H NMR (300 MHz, CDCl3): d 7.91–7.98 (m, 2H),
7.44–7.52 (m, 1H), 7.34–7.42 (m, 2H), 7.13–7.30 (m, 5H), 4.21 (s, 2H); 13C NMR
(75 MHz, CDCl3): d 197.7, 136.6, 134.6, 133.2, 129.5, 128.73, 128.69, 128.67,
126.9, 45.6; GC–MS (EI, 70 eV): m/z(%) = 196 (M+5), 105 (100), 91 (10), 77 (20),
65 (5), 51 (10).
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Beller, M. Carbonylation of Benzyl- and Aryl-X Compounds. In Applied