Palladium-catalyzed carbonylative coupling of benzyl chlorides with terminal alkynes to give 1,4-diaryl-3-butyn-2-ones and related furanones

Article abstract of DOI:10.1039/c1ob06345f

A general palladium-catalyzed carbonylative Sonogashira coupling of benzyl chlorides with terminal acetylenes has been established. Depending on the alkyne 1,4-diaryl-3-butyn-2-ones or substituted furanones are obtained in moderate to good yields. Best catalytic performance is achieved applying a mixed Pd(PPh ₃)Cl₂/P(OPh)₃ catalyst system. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06345f

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Palladium-catalyzed carbonylative coupling of benzyl chlorides with terminal
alkynes to give 1,4-diaryl-3-butyn-2-ones and related furanones†
Xiao-Feng Wu, Helfried Neumann and Matthias Beller*
Received 8th August 2011, Accepted 5th September 2011
DOI: 10.1039/c1ob06345f
Table 1 Carbonylative coupling of benzyl chloride with phenyl acetylene:
A general palladium-catalyzed carbonylative Sonogashira
coupling of benzyl chlorides with terminal acetylenes has been
established. Depending on the alkyne 1,4-diaryl-3-butyn-2-
ones or substituted furanones are obtained in moderate to
good yields. Best catalytic performance is achieved applying
a mixed Pd(PPh3)Cl2/P(OPh)3 catalyst system.
testing of palladium sourcesa
Entry
Pd [2 mol%]
Conv [%]b
Yield [%]b
Palladium-catalyzed coupling reactions have become an indis-
pensable tool in modern organic synthesis. These methodologies
are of significant value for the preparation of pharmaceuticals
and agrochemicals, as well as advanced materials.1 Hence, both
academic as well as industrial laboratories constantly explore
new applications of the different coupling reactions.2 Clearly, this
area constitutes one of the major topics in homogeneous catalysis
and organic synthesis, which is also demonstrated by the recent
Nobel Prize in 2010.3 Along with the different coupling reactions,
palladium-catalyzed carbonylative-coupling reactions are also
attracting increasing attentions within the last decade.4 They allow
for the direct incorporation of CO, the most inexpensive and
readily available C1-source, into parent molecules. The resulting
building blocks can be easily refined further on.5 One of the
notable examples of CO-incorporating coupling reactions is the
carbonylative Sonogashira reaction.6 While the coupling of aryl
halides with carbon monoxide and alkynes has been well explored,
carbonylative reactions of benzyl halides with terminal acetylenes
to produce alkynones and furanones are scarcely known. In fact,
to the best our knowledge, only two reports deal with the synthesis
of 1,4-diarylbutynones using such a methodology.6i,10
In 2011, we described an improved protocol for the synthesis
of furanones starting from aryl bromides/triflates and benzyl
acetylenes.7 In that work we failed to perform similar carbony-
lations using inexpensive benzyl chlorides as starting material.
Based on our continuous interest in palladium-catalyzed carbony-
lation reactions6o,7,8 here we wish to report novel carbonylative
Sonogashira reactions of benzyl chlorides with aryl acetylenes as
well as the carbonylative coupling with benzyl acetylenes to give
furanones.9
1
2
3
4
5
6
7
8
PdCl2
PdBr2
Pd(OAc)2
Pd(TFA)2
Pd(PhCN)2Cl2
Pd(MeCN)2Cl2
Na2PdCl4
K2PdCl4
[Pd(cinnamyl)Cl]2
Pd(PPh3)2Cl2
6
19
1
15
10
16
20
10
0
6
10
1
10
10
9
13
8
0
9
10
50
42
a Benzyl chloride (1 mmol), phenyl acetylene (1 mmol), CO (10 bar),
toluene (2 ml), NEt3 (2 mmol), [Pd] (2 mol%), P(OBu)3 (4 mol%), 100 ◦C,
16 h. b Conversion and yield were determined by GC-MS using hexadecane
as internal standard.
At the start of our investigations, we reacted benzyl chloride
with phenyl acetylene under 10 bar of CO pressure in the presence
of a PdCl2/P(OBu)3 catalyst system. Despite some conversion, the
product yield was disappointingly low (only 6% yield of the desired
product) (Table 1, entry 1). Testing different palladium precur-
sors gave no considerable improvement of yield and conversion
(Table 1, entries 2–9). However, applying Pd(PPh3)2Cl2 led to a
significant improvement in yield of the desired product (Table 1,
entry 10). Interestingly, no reaction took place when the reaction
was performed without P(OBu)3 as ligand.
In order to improve the product yield further, the influence
of different reaction parameters such as pressure, temperature,
ligand, and base was tested (Table 2). Unfortunately, the addition
of different phosphine ligands resulted in a low yield of the target
product (Table 2, entries 1–4). On the other hand, in the presence
of P(OPh)3 the product was obtained in 72% yield (Table 2, entries
5–7). Next, we attempted to improve the yield by changing the
base (Table 2, entries 8–11). Here, NEt3 proved to be optimal.
Finally, the best yield (85%) was realized by increasing the amount
of phenyl acetylene to 1.2 equiv (Table 2, entry 12). Notably, at
a lower pressure of CO (5 bar), 68% of 1,4-diphenylbutynone
was still achieved (Table 2, entry 13). In the case of high
Leibniz-Institut fu¨r Katalyse e.V. an der Universitu¨t Rostock, Albert-
Einstein-Strasse 29a, 18059 Rostock, Germany. E-mail: matthias.beller@
catalysis.de; Fax: (+49)381-1281-5000
† Electronic supplementary information (ESI) available: General re-
action procedures and NMR datas for model systems. See DOI:
10.1039/c1ob06345f
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Table 2 Testing of ligands and basesa
Table 3 Palladium-catalyzed synthesis of 1,4-diaryl-3-alkyn-2-onesa
Entry
Ligand [4 mol%]
Base [2 mmol]
Conv [%]b
Yield [%]b
1
2
3
BuPAd2
PCy3
NEt3
NEt3
NEt3
1
20
19
0
17
10
4
NEt3
15
6
5
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
NEt3
NEt3
NEt3
DABCO
DMAP
NBu3
DBU
NEt3
70
84
77
100
75
22
100
99
60
72
50
0
0
1
0
6c
7d
8c
9c
10c
11c
12e
13f
85 (80g)
68
a Benzyl chlorides (1 mmol), terminal acetylenes (1.2 mmol), CO (10 bar),
toluene (2 ml), NEt3 (2 mmol), Pd(PPh3)2Cl2 (2 mol%), P(OPh)3 (8 mol%),
100 ◦C, 20 h. b Yields were determined by NMR. c Isolated yield.
NEt3
90
a Benzyl chloride (1 mmol), phenyl acetylene (1 mmol), CO (10 bar),
toluene (2 ml), base (2 mmol), Pd(PPh3)2Cl2 (2 mol%), ligand (4 mol%),
100 ◦C, 16h. b Conversion and yield were determined by GC-MS using
hexadecane as internal standard. c P(OPh)3 (8 mol%). d P(OPh)3 (20 mol%).
e P(OPh)3 (8 mol%), phenyl acetylene (1.2 mmol), 20 h. f P(OPh)3 (8 mol%),
phenyl acetylene (1.2 mmol), CO (5 bar), 20 h. g Isolated yield.
conversion but low or no desired product yield, benzyl chloride
was decomposed and phenyl acetylene was still detected as it
is.
With the best conditions in hand, we studied the scope and
limitations of this methodology (Table 3). Methyl-, tert-butyl-,
and fluoro-substituted benzyl chlorides successfully gave the
corresponding products with phenyl acetylene in 50–80% yield
(Table 3, entries 1–5).
Scheme 1 Proposed reaction mechanism.
Not only aromatic acetylenes, but also cyclopentyl acetylene as
an example of an aliphatic alkyne worked in this reaction (Table 3,
entry 8). On the other hand, activated benzyl chlorides such as 4-
nitrobenzyl chloride and acetylenes, e.g. 4-bromophenylacetylene,
did not work and gave mainly the non-carbonylative
products.
Using benzyl acetylenes instead of aryl acetylenes resulted
in the formation of potentially bio-active furan-2(3H)-ones11
in moderate yields (Table 4). Both electron-withdrawing and
electron-donating functionalized benzyl chlorides can be used in
the coupling with benzyl acetylene and furnished the correspond-
ing 5-benzyl-3-benzylidenefuran-2(3H)-ones in moderate to good
yields.
tion of the acylpalladium complex takes place by CO inser-
tion. Base-induced substitution of the chloride by the acetylide
occurs and the alkynone is formed via reductive elimination.
After the carbonylative Sonogashira coupling took place with
benzyl acetylene, further reaction with hydridopalladiumchloride,
which is generated within the first cycle (see Scheme 1), results
in the formation of the isomerized complex 1. Subsequent
second carbonylation and final reductive elimination led to
furanone 2.
In conclusion, novel protocols for the carbonylation of benzyl
chlorides and alkynes have been established. Applying an unusual
Pd(PPh3)2Cl2/P(OPh)3 catalyst system eight different alkynones
are produced in moderate to good yields (45–80%). Benzyl
acetylene gave the corresponding furanones in moderate yield
(45–68%) via palladium-catalyzed domino double carbonylation
reactions.
The different reactivity of aromatic and benzylic alkynes is
explained by a subsequent carbonylation in the case of the
latter substrates. As shown in Scheme 1, we propose an initial
oxidative addition of the benzyl chloride to Pd(0) to give the
corresponding benzylpalladium(II) complex. Subsequent forma-
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Table 4 Palladium-catalyzed synthesis of furanonesa
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Entry
1
Furanones
Yield [%]b
68c
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2
3
4
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6
7
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65
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50
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45
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a Benzyl chlorides (1 mmol), terminal acetylenes (1.2 mmol), CO (10 bar),
toluene (2 ml), NEt3 (2 mmol), Pd(PPh3)2Cl2 (2 mol%), P(OPh)3 (8 mol%),
100 ◦C, 20 h. b Yields were determined by NMR. c Isolated yield.
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Org. Biomol. Chem., 2011, 9, 8003–8005 | 8005
©