A general cyclocarbonylation of aryl bromides and triflates with acetylenes: Palladium-catalyzed synthesis of 3-alkylidenefuran-2-ones

Article abstract of DOI:10.1002/chem.201101083

Making use of CO: An improved efficient synthesis of 5-aryl-3- alkylidenefuran-2-ones has been developed (see scheme). Starting from readily available (hetero)aryl bromides or aryl triflates and alkynes, furanones were produced in good yields through a do

Full text of DOI:10.1002/chem.201101083

DOI: 10.1002/chem.201101083
A General Cyclocarbonylation of Aryl Bromides and Triflates with
Acetylenes: Palladium-Catalyzed Synthesis of 3-Alkylidenefuran-2-ones
Xiao-Feng Wu,[a] Basker Sundararaju,[b] Pazhamalai Anbarasan,[a] Helfried Neumann,[a]
Pierre H. Dixneuf,[b] and Matthias Beller*[a]
Furanones represent an important family of organic com-
pounds that are present in several natural products and bio-
active derivatives.[1] More specifically, this structural motif is
found in a wide variety of therapeutically interesting drug
candidates that have anti-inflammatory,[2] cardiotonic,[3] an-
algesic,[4] anticancer,[5] anticonvulsant,[6] antimicrobial,[7] and
antiviral activities[8] (Figure 1). Selected examples of cur-
rently marketed drugs with the furanone scaffold are Basi-
dalin, Ascorbic acid, Narthogenin, Butalactin, and Rofecox-
ib.
lyzed cyclization of appropriately functionalized acetylenic
substrates (Scheme 1).[9]
Although several strategies are known for the preparation
of a variety of furanone derivatives,[1] the synthesis of 3-al-
kylidenefuran-2-ones is less well studied. Aside from the tra-
ditional cyclodehydration of g-keto acids and subsequent
aldol condensation with aromatic aldehydes, few routes
have been reported by means of the transition-metal-cata-
Scheme 1. Synthetic strategies towards the formation of 3-alkylidenfura-
nones.
On the other hand, palladium-catalyzed carbonylative
coupling reactions have been demonstrated to be powerful
tools for the synthesis of substituted aromatic carboxylic
acid derivatives by using CO as a cheap and readily avail-
able C1 source.[10] During the last few years, we have dis-
closed a number of novel or improved palladium-catalyzed
carbonylations.[11] Examples include the aminocarbonylation
of aryl halides to form primary amides,[11b,c] the carbonyla-
tive Heck reactions of aryl/vinyl triflates to give chalco-
nes,[11d] and the reductive carbonylation of aryl bromides to
form aldehydes, which is also applied on an industrial
scale,[11f] among others. During the course of our studies on
palladium-catalyzed carbonylative Sonogashira coupling re-
actions,[11g] we observed the formation of (E)-3-benzylidene-
5-phenylfuran-2ACTHNUTRGNEUNG(3H)-one as a minor product in the reaction
Figure 1. Selected examples of bio-active furanones.
of bromobenzene with benzyl acetylene. This unusual
double carbonylation process interested us because there is
limited precedent for this type of carbonylation, with only
one publication to date. Therein, Alper and Huang describe
the reaction of aryl iodides with 1-aryl-3-propynes to give
[a] X.-F. Wu, Dr. P. Anbarasan, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
furanones.[12a] More specifically, they used Pd
ACHTUNGTRENNUNG(OAc)2
E-mail: matthias.beller@catalysis.de
(5 mol%) as the catalyst system at relatively high pressures
of carbon monoxide (20–80 bar). Unfortunately, only limited
functional group tolerance was demonstrated and no exam-
ples of the use of heterocycles were included. Therefore, the
need to develop a general procedure for the carbonylation
of available aryl-X derivatives to give furanones under mild
conditions still exists.
[b] B. Sundararaju, Prof. Dr. P. H. Dixneuf
Catalyse et Organomꢂtalliques
Institut Sciences Chimiques de Rennes
UMR 6226-CNRS-Universitꢂ de Rennes
Av. Gꢂnꢂral Leclerc, 35042 Rennes (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101083.
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Chem. Eur. J. 2011, 17, 8014 – 8017

COMMUNICATION
Herein, we report the first general catalytic double car-
bonylation process of aryl bromides and alkynes that also
allows for the carbonylation of aryl triflates. These processes
proceed at 80–1108C and 5–10 bar of carbon monoxide. In
exploratory experiments on the carbonylation of bromoben-
zene with benzylacetylene, it turned out that a catalyst
system consisting of [{(cinnamyl)PdCl}2] with Xantphos[13] as
the ligand in toluene worked well (88% yield of (E)-3-ben-
Scheme 2), should result in the formation of isomerized
complex 2. A subsequent second carbonylation reaction
leads to furanone 3.
After having found suitable conditions for the double car-
bonylation of bromobenzene (Table 1, entry 7), we explored
the scope and limitations of this methodology. As shown in
Table 2 and Scheme 3, the generality and versatility of the
current methodology is proved by synthesizing more than 20
different furanone derivatives in good to excellent yields.
In addition to aryl bromides, aryl triflates were examined
in this type of reaction.[15] To our delight, this catalytic
system worked well in the cyclocarbonylation of several aryl
zylidene-5-phenylfuran-2ACHTNUTRGNE(NUG 3H)-one; Table 1, entry 7). Other
commonly used bidentate ligands, such as 1,2-bis(diphenyl-
Table 1. Palladium-catalyzed cyclocarbonylation of bromobenzene.[a]
Table 2. Palladium-catalyzed cyclocarbonylation of aryl bromides/trifla-
tes.[a]
Entry
Ligand ([mol%])
Conversion
[%][b]
Yield
[%][b]
1
2
3
4
5
6
7
PCy3 (4)
PPh3 (4)
35
80
93
29
35
100
100
77
28
62
85
15
19
82
88
60
76
BuPAd2 (4)
DPPE (2)
DPPB (2)
DPPF (2)
Xantphos (2)
Xantphos (2)
Xantphos (2)
Entry
ArX
Furanone
Yield
[%][b]
1
2
X=OTf
X=Br
68
83
8[c]
9[d]
100
[a] Bromobenzene (1.0 mmol), benzyl acetylene (1.0 mmol), CO (10 bar),
[{(cinnamyl)PdCl}2] (1 mol%), ligand, toluene (2 mL), NEt3 (2.0 mmol),
1108C, 20 h. [b] Conversion and yield were determined by GC by using
hexadecane as the internal standard. [c] 808C. [d] CO (5 bar).
3
4
X=OTf
X=Br
78
75
phosophino)ethane (DPPE) and 1,4-(diphenylphosphino)bu-
tane (DPPB), resulted in low conversion and yield (15 and
19%, respectively; Table 1, entries 4 and 5). However, the
use of BuPAd2 (cataCXium A; Ad=adamantyl), a versatile
ligand in palladium-catalyzed coupling reactions,[14] also
gave 85% of the desired furanone. Lowering the pressure
(5 bar) or temperature (808C) in the presence of Xantphos
also resulted in good yields of the furanone (60 and 76%
yield, respectively; Table 1, entries 8 and 9).
5
85
6
7
X=OTf
X=Br
50
73
The possible reaction mechanism for the formation of
(E)-3-benzylidene-5-phenylfuran-2ACTHNUTRGNE(NUG 3H)-one is shown in
8
9
X=OTf
X=Br
78
85
Scheme 2. Initially, a carbonylative Sonogashira reaction
takes place between bromobenzene and benzyl acetylene to
afford alkynone 1.[11g] Next, reaction of 1 with hydridopalla-
diumbromide, which is generated within the first cycle (see
10
60
11
12
85
81
Scheme 2. Proposed reaction mechanism.
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M. Beller et al.
Table 2. (Continued)
Entry
ArX
Furanone
Yield
[%][b]
13
88
14
85
15
16
X=OTf
X=Br
67
85
Scheme 3. Palladium-catalyzed cyclocarbonylation of 3-aryl-1-propynes
with PhX (reaction conditions: PhX (1.0 mmol), 3-aryl-1-propyne
(1.0 mmol), CO (10 bar), [{(cinnamyl)PdCl}2} (1 mol%), Xantphos
(2 mol%), toluene (2 mL), NEt3 (2.0 mmol), 1108C, 20 h, isolated yield).
[a] Yield determined by NMR spectroscopy. [b] Yield determined by GC.
17
91
18
19
54
79
ed kinase inhibitor BE-23372M. Treatment of 3,4-
dimethoxyACTHNUTRGNEUGbN romobenzene with 3-(3’,4’-dimethoxyphenyl)-
prop-1-yne in the presence of [{(cinnamyl)PdCl}2] (1 mol%)
and Xantphos (2 mol%) under carbon monoxide (10 bar)
afforded the desired product in 65% yield (Scheme 4).
In conclusion, a general and efficient method for the syn-
thesis of 5-aryl-3-alkylidenfuranones has been developed.
For the first time it has been demonstrated that readily
available (hetero)aryl bromides and aryl triflates can be
doubly carbonylated with benzyl acetylenes and also aliphat-
ic alkynes. The generality of this methodology is proven by
more than 30 examples that proceed in good yields. Notably,
the straightforward synthesis of permethylated BE-23372M,
a kinase inhibitor, is achieved. Further developments of the
present catalytic system, as well as for propargylic deriva-
tives, are currently underway.
20
21
56
66
[a] ArX (1.0 mmol), benzyl acetylene (1.0 mmol), CO (10 bar), [{(cinna-
myl)PdCl}2] (1 mol%), Xantphos (2 mol%), toluene (2 mL), NEt3
(2 mmol), 1108C, 20 h. [b] Isolated yield.
triflates to give the corresponding furanones in good to ex-
cellent yield (Table 2, entries 1, 3, 6, 8, and 15).
Next, different 1-aryl-3-propynes were synthesized[16] and
subjected to the cyclocarbonylation reaction with bromo-
benzene. As shown in Scheme 3, five different furanones
were obtained in good isolated yields (61–88%) irrespective
of the electronic nature of the substrate. More interestingly,
aliphatic 3-propynes also worked well in this system. Six fur-
anones resulting from the reaction of aliphatic alkynes are
shown in Scheme 3, and yields of 55–87% were achieved.
However, NO2-, CHO-, and CH3CO-substituted aryl bro-
mides and aromatic acetylenes failed to give the correspond-
ing products under these conditions.
Scheme 4. Synthesis of permethylated BE-23372M. a) see reference [1d].
Experimental Section
Typical procedure for the cyclocarbonylation of bromobenzene and
benzyl acetylene to form a furanone: [{(Cinnamyl)PdCl}2] (1 mol%) and
Xantphos (2 mol%) were transferred into a vial (4 mL reaction volume)
equipped with a septum, a small cannula, and a stirring bar. After the
vial was purged with argon, bromobenzene (1 mmol), benzyl acetylene
Finally, the usefulness of the presented methodology is il-
lustrated in the straightforward synthesis of the permethylat-
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Chem. Eur. J. 2011, 17, 8014 – 8017

Synthesis of 3-Alkylidenefuran-2-ones
COMMUNICATION
(1.2 mmol), toulene (2 mL), and NEt3 (2 mmol) were injected into the
vial by syringe. The vial was then placed in an alloy plate, which was
transferred into a 300 mL autoclave of the 4560 series from Parr Instru-
ments under an argon atmosphere. After flushing the autoclave three
times with CO, a pressure of 10 bar was established and the reaction was
performed for 20 h at 1108C. After the reaction, the autoclave was
cooled to room temperature and the pressure was carefully released.
Water (6 mL) was added to the reaction mixture and the solution was ex-
tracted with ethyl acetate (3–5ꢄ2–3 mL). The extracts were adsorped
onto silica gel and the crude product was purified by column chromatog-
raphy by using n-heptane and n-heptane/AcOEt (10:1) as the eluent. The
product was obtained in 206 mg (83% yields) as yellow solid.
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Acknowledgements
We thank the state of Mecklenburg–Vorpommern and the Bundesminis-
terium fꢀr Bildung und Forschung (BMBF) for financial support. We also
thank Dr. W. Baumann and Dr. C. Fischer (LIKAT) for analytical sup-
port.
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Keywords: alkynes
·
aryl triflates
·
carbonylation
·
furanones · homogeneous catalysis · palladium
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Received: April 8, 2011
Published online: June 7, 2011
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