Palladium-catalyzed carbonylative suzuki coupling of benzyl halides with potassium aryltrifluoroborates in aqueous media

Article abstract of DOI:10.1002/adsc.201000804

A general palladium-catalyzed carbonylative cross-coupling reaction of benzyl chlorides with potassium aryltrifluoroborates in water has been developed. Applying this improved methodology 16 different 1,2-diarylethanones have been synthesized in 40-89% yield. Copyright

Full text of DOI:10.1002/adsc.201000804

UPDATES
DOI: 10.1002/adsc.201000804
Palladium-Catalyzed Carbonylative Suzuki Coupling of Benzyl
Halides with Potassium Aryltrifluoroborates in Aqueous Media
a
a
a,
Xiao-Feng Wu, Helfried Neumann, and Matthias Beller *
a
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
Fax : (+49)-381-1281-5000; e-mail: matthias.beller@catalysis.de
Received: October 25, 2010; Revised: January 1, 2011; Published online: March 10, 2011
[
3]
Abstract: A general palladium-catalyzed carbonyla-
tive cross-coupling reaction of benzyl chlorides with
potassium aryltrifluoroborates in water has been
developed. Applying this improved methodology 16
different 1,2-diarylethanones have been synthesized
in 40–89% yield.
sis and organic synthesis. Among the different CÀC
cross-coupling reactions, also three component-type,
[4]
carbonylations have been developed in the past.[
5]
These reactions, for example, carbonylative Heck,
[
6]
[7]
Suzuki, and Sonogashira reactions allow for the
preparation of interesting (hetero)aromatic carbonyl
building blocks, which can be easily refined further
on.
While carbonylations of aryl halides are well estab-
lished, and even industrial processes are known, car-
bonylative coupling reactions of alkyl or benzyl hal-
Keywords: benzyl chlorides; carbonylation; palladi-
um; potassium aryltrifluoroborates; water
[8]
[
9,10]
ides have been much less investigated.
ple in the area of carbonylative Suzuki reactions, until
Palladium-catalyzed cross-coupling reactions have recently only two examples using benzyl halides have
become one of the most popular tools for the synthe- been published. This is somewhat surprising consid-
sis of novel bio-active compounds and advanced ma- ering the importance of the resulting 1,2-diaryletha-
For exam-
[
11]
[1,2]
terials.
Both academic as well as industrial labora- none motif in known pharmaceuticals and biologically
[
12]
tories continuously investigate new applications of the active compounds.
Hence, there is still a need to
different known methodologies. Thus, this area consti- develop convenient and more general methodologies
tutes one of the major topics in homogeneous cataly- for the synthesis of this class of compounds.
[a]
Table 1. Carbonylative Suzuki cross-coupling: model reaction.
[b]
[b]
[b]
Entry
Base
Conversion [%]
Yield 1 [%]
Yield 2 [%]
1
2
3
4
5
6
7
K PO
100
100
100
100
100
100
100
100
75
51
17
4
48
36
56
70
65
17
13
16
1
11
22
4
23
6
0
3
4
K HPO
2
4
4
KH PO
2
K CO
2
3
Na CO
2
3
NaHCO3
KHCO3
KHCO3
KHCO3
[
[
c]
1
1
4
5
d]
[
a]
Pd
10 bar), 1008C, 20 h.
Conversion and yields were determined by GC; with use of hexadecane as internal standard.
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (2 mol%), PCy (4 mol%), base (2 mmol), H O (2 mL), benzyl chloride (1 mmol), PhBF K (1 mmol), CO
2
3
2
3
(
b]
[
[
[
c]
8
5
08C.
08C.
d]
788
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 788 – 792

Palladium-Catalyzed Carbonylative Suzuki Coupling of Benzyl Halides with Potassium Aryltrifluoroborates
Based on our interest in novel and improved palla- is proven by synthesizing 16 different 1,2-diaryletha-
[
13]
dium-catalyzed carbonylations, very recently, we re- nones in moderate to good yields. More specifically, 9
ported the coupling of benzyl chlorides with arylbor- different benzyl halides were reacted with potassium
onic acids to 1,2-diarylethanones in moderate to good phenyltrifluoroborate to give the corresponding prod-
[14]
yields. Unfortunately, applying arylboronic acids as ucts in 55–89% yield (Table 2). Both electron-rich
transfer reagents, the unwanted non-carbonylative and electron-withdrawing substituted benzyl chlorides
coupling is comparably in rate to the carbonylative were successfully transformed (Table 2, entries 3–9).
coupling process. Hence, the substrate scope of this
reaction is limited.
Variations of the aryltrifluoroborates showed that
different functional groups are tolerated (Table 3).
Here, we report an improved and more general car-
bonylative coupling reaction of benzyl halides. Key to
success is the use of potassium aryltrifluoroborates as Table 2. Palladium-catalyzed carbonylative coupling of
[
15]
[a]
more selective nucleophilic coupling partners.
benzyl chlorides with potassium phenyltrifluoroborate.
In our initial experiments, we studied the reaction
of potassium phenyltrifluoroborate with benzyl chlo-
ride in the presence of carbon monoxide (Table 1).
At the start, we used similar reaction conditions,
which have been applied for the carbonylative cou-
[
14]
pling of benzyl chloride with phenylboronic acid
Table 1, entry 1). To our delight, 51% of 1,2-
diphenylethanone 1 was obtained together with 13%
[b]
Entry Benzyl chloride Product
1
Yield [%]
(
ACHTUNGTRENNUNG
[c}
[14]
of diphenylmethane 2. It should be noted that phenyl-
boronic acid only gave product 2 under these condi-
tions. We explain this difference due to the increased
70; 68; 73
stability of PhBF K, while PhB(OH)2 forms more
easily benzene.
Applying more acidic potassium phosphates as base
gave lower yields (4–17%; Table 1, entries 2 and 3).
On the other hand carbonates and bicarbonates led to
comparable results to potassium phosphate, and up to
3
2
3
62
[
[
14]
72; 78
85; 80
70% of product 1 is produced (Table 1, entries 4–7).
The use of potassium or sodium acetate resulted in
the formation of benzyl acetate, while benzyl alcohol
was formed as the major product when potassium hy-
droxide was employed as base. Notably, in the pres-
ence of organic bases (DABCO, DMAP, and pyri-
dine) no carbonylation product 1 is obtained, instead
homo-coupling of benzyl chloride took place. Among
c]
4
5
6
7
80
all tested bases, KHCO proved to be optimal yielding
3
[c]
89; 88
55; 47
70% of the desired product (Table 1, entry 7).
Next, several organic solvents (DMSO, DMF, and
NMP) were tested in the presence of KHCO as base.
3
Unfortunately, only traces of product 1 and 40–50%
of benzyl phenylacetate as a result of the correspond-
ing alkoxycarbonylation were detected. To our sur-
prise, running the model reaction in water worked
well, despite the potential formation of the corre-
sponding carboxylic acids.
[14]
8
63
With respect to the CO pressure, 10 bar of carbon
monoxide gave best results: Higher pressures (20 bar)
inhibited the reactivity of palladium catalyst; lower
pressures (5 bar) gave more non-carbonylation cross-
coupling product 2.
After having found suitable conditions for the
model reaction, we explored the scope and limitations
of our protocol. As shown in Table 2 and Table 3, the
generality and versatility of the current methodology
9
60
[a]
Pd
A
H
U
G
R
N
U
G
2
3
3
H O (2 mL), benzyl chlorides (1 mmol), PhBF K
2
3
(
1 mmol), CO (10 bar), 1008C, 20 h.
[
[
b]
c]
Yields were determined by GC.
Isolated yield.
Adv. Synth. Catal. 2011, 353, 788 – 792
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
789

Xiao-Feng Wu et al.
UPDATES
Table 3. Palladium-catalyzed carbonylative coupling of responding 1, 2-diarylethanones in moderate to good
[
a]
benzyl chloride with potassium aryltrifluoroborates.
yields.
Experimental Section
Typical Reaction Procedure for the Carbonylative
Cross-Coupling of Benzyl Chloride and Potassium
Phenyltrifluoroborate
[b]
Entry Arylborates
1
Product
Yield [%]
68
A 4-mL vial was charged with Pd
ACHTUNGTNERNUN(G OAc) (2 mol%), PCy
2 3
(
4 mol%), KHCO (2 mmol), PhBF K (1.0 mmol) and a stir-
3
3
ring bar. Then, 2 mL H O (distilled, then degassed with
2
argon within one hour) and 1 mmol of benzyl chloride were
injected by syringe. The vial (or several vials) was (were)
placed in an alloy plate, which was transferred into a 300ꢃ-
mL autoclave of the 4560 series from Parr Instruments
under an 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 1008C. After the re-
action had finished, the autoclave was cooled down to room
temperature and the pressure was released carefully. The so-
lution was extracted 3–5 times with 2–3 mL of ethyl acetate.
After evaporation of the organic solvent the residue was ad-
sorbed on silica gel and the crude product was purified by
column chromatography using n-heptane/AcOEt (50:1) as
[
c]
2
3
4
5
6
7
75; 75
48
55
[c]
eluent. The product was isolated as a white solid; yield:
88; 85
63
1
1
7
7
33 mg (68%); R =0.27. H NMR (300 MHz, CDCl ): d=
f
3
.91–7.98 (m, 2H), 7.44–7.52 (m, 1H), 7.34–7.42 (m, 2H),
.13–7.30 (m, 5H), 4.21 (s, 2H); C NMR (75 MHz,
1
3
CDCl ): d=197.7, 136.6, 134.6, 133.2, 129.5, 128.73, 128.69,
3
+
1
5
28.67, 126.9, 45.6; GC-MS (EI, 70 eV): m/z(%)=196 (M ,
), 105 (100), 91 (10), 77 (20), 65 (5), 51 (10).
40
Acknowledgements
[
a]
Pd ACHTUNGTRENNUNG( OAc) (2 mol%), PCy (4 mol%), KHCO (2 mmol),
2 3 3
H O (2 mL), benzyl chloride (1 mmol), ArBF K
2
3
The authors thank the State of Mecklenburg-Vorpommern
and the Bundesministerium fꢀr Bildung und Forschung
(1 mmol), CO (10 bar), 1008C, 20 h.
[
[
b]
c]
Yields were determined by GC.
Isolated yield.
(
BMBF) for financial support. We also thank Mrs. S. Lei-
minger, Dr. W. Baumann, and Dr. C. Fischer (all LIKAT) for
analytical support.
References
Hence, MeO, MeS, dioxole, F, and CF substituted
3
phenyltrifluoroborates gave the corresponding 1,2-di-
arylethanones in 48–88% yields (Table 3, entries 2–6).
Moreover, 2,5-dimethylthiophenetrifluoroborate as an
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sired coupling product (Table 3, entry 7).
In conclusion, an improved method for the palladi-
um-catalyzed carbonylative Suzuki coupling of benzyl
chlorides with potassium aryltrifluoroborates has
been developed. The reactions proceeds at low
carbon monoxide pressure in water as benign solvent.
Compared to previously known methods both elec-
tron-rich and electron-withdrawing substituted benzyl
halides and arylborates are transformed into the cor-
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Adv. Synth. Catal. 2011, 353, 788 – 792