Synthesis of ynones via recyclable polystyrene-supported palladium(0) complex catalyzed acylation of terminal alkynes with acyl chlorides under copper- and solvent-free conditions

Article abstract of DOI:10.1055/s-0030-1259322

Herein, a highly efficient method for the copper- and solvent-free coupling reaction of acyl chlorides and terminal alkynes catalyzed by 1-phenyl-1,2-propanedione-2-oxime thiosemicarbazone-functionalized polystyrene resin-supported Pd(0) complex is descri

Full text of DOI:10.1055/s-0030-1259322

LETTER
311
Synthesis of Ynones via Recyclable Polystyrene-Supported Palladium(0)
Complex Catalyzed Acylation of Terminal Alkynes with Acyl Chlorides under
Copper- and Solvent-Free Conditions
Synthesisof
Ynones ohammad Bakherad,* Ali Keivanloo, Bahram Bahramian, Saeideh Jajarmi
School of Chemistry, Shahrood University of Technology, Shahrood, Iran
Fax +98(273)3395441; E-mail: m.bakherad@yahoo.com
Received 31 August 2010
bipyridyl complex in the presence of Ph3P and CuI at
50 °C in Et3N as solvent.
Abstract: Herein, a highly efficient method for the copper- and sol-
vent-free coupling reaction of acyl chlorides and terminal alkynes
catalyzed by 1-phenyl-1,2-propanedione-2-oxime thiosemicarba-
zone-functionalized polystyrene resin-supported Pd(0) complex is
described. Acyl chlorides are easily coupled with terminal alkynes,
giving good to high yields in the presence of a low catalyst loading
(1 mol% Pd) in Et3N at room temperature under aerobic conditions.
After centrifugation, the supported catalyst can be recycled and re-
used several times with only a slight decrease in activity.
Very recently, we have reported the synthesis of the poly-
styrene-supported bidentate phosphine palladium(0) com-
plex [PS-dpp-Pd(0)] and found that this complex is a
highly active and recyclable catalyst for acylation of ter-
minal alkynes with acid chlorides.13 However, to the best
of our knowledge, no Sonogashira coupling reaction of
acyl chlorides with terminal alkynes catalyzed by polysty-
rene-supported palladium(0) complex has been reported.
Key words: copper-free, solvent-free, supported catalyst, Sono-
gashira coupling, acyl chloride, ynone
Our approach was guided by three imperatives: (1) the
support should be easily accessible; (2) the reaction
should be carried out using readily available and cheap re-
agents; and (3) the ligand anchored on the support should
be air-stable at room temperature, which should allow its
storage in normal bottles with unlimited shelf-life.
The synthesis of ynones has attracted considerable inter-
est because of their appearance in a wide variety of bio-
logically active molecules1 and their utility as synthetic
intermediates, particularly for the synthesis of natural
products2 and pharmaceutical molecules.3 A common
route to ynones involves the acylation of alkynyl organo-
metallic reagents based on silver,4 copper,5 lithium,6 zinc,7
silicon,8 and tin9 with acid chlorides. The coupling reac-
tion of acyl chlorides and terminal alkynes catalyzed by
palladium catalysts has received much attention of late.
This reaction can be achieved under mild conditions with
a wide range of functional groups on alkynes and en-
hanced chemoselectivity.10
In this paper, we wish to report the synthesis of the poly-
styrene-supported palladium(0) 1-phenyl-1,2-propanedi-
one-2-oxime thiosemicarbazone complex [abbreviated as
PS-ppdot-Pd(0)] and its catalytic properties in the copper-
and solvent-free Sonogashira reaction of acyl chlorides
with terminal alkynes catalyzed under aerobic conditions.
The ease of preparation of the complex, its long shelf-life,
stability toward air, and compatibility with a wide variety
of aryl halides and alkynes make it ideal for the above-
mentioned reactions.
In spite of the synthetic elegance of the construction of
synthetically useful ynones, these palladium-catalyzed re-
actions are usually carried out in a homogeneous phase,
which makes the catalysts difficult to recover and reuse in
subsequent reactions.
We used a well-known chloromethylated polystyrene (2%
DVB) as catalyst support because it is still one of the most
popular polymeric materials used in synthesis due to its
inexpensive, ready availability, mechanical robustness,
and facial functionalization.
The use of heterogeneous catalysts for the synthesis of
ynones has paid much attention to reducing waste, thus
working toward an environmentally benign chemical pro-
cess. Likhar and co-workers have reported that acyl chlo-
rides could be coupled with terminal alkynes in the
presence of 1 mol% of Pd/C under refluxing toluene, and
the catalyst could be reused for five cycles with a 15%
leaching of Pd.11
Recently, Chen et al.12 have described the synthesis of
ynones by coupling acyl chlorides with terminal alkynes
catalyzed by a nanosized MCM-41 anchored palladium
The immobilized Schiff base palladium PS-ppdot-Pd(0)
can be prepared easily from a commercially available
polymer. In this approach, the Schiff base palladium com-
plex is attached, via a covalent bond, to a pendant chlo-
romethyl group on the surface of the polymer resin
particles. Reaction of polystyrene resin with 1-phenylpro-
pane-1,2-dione-2-oxime thiosemicarbazone PPDOT14 (1)
in DMF at 100 °C and then treatment of the PPDOT-func-
tionalized polymer 2 with a solution of PdCl2(PhCN)2 in
ethanol under reflux resulted in covalent attachment of the
palladium complex. Reduction with hydrazine monohy-
drate gave the polystyrene-supported palladium(0)-com-
plex catalyst [PS-ppdot-Pd(0)] 4 (Scheme 1).
SYNLETT 2011, No. 3, pp 0311–0314
x
x.
x
x.
2
0
1
1
Advanced online publication: 13.01.2011
DOI: 10.1055/s-0030-1259322; Art ID: D23310ST
© Georg Thieme Verlag Stuttgart · New York

312
M. Bakherad et al.
LETTER
Ph
N
Ph
N
+
DMF, 100 °C, 20 h
Cl
H2NSCHN
HNSCHN
N OH
N
OH
1
2
Ph
[PdCl2(PhCN)2]
EtOH, reflux, 12 h
NH2NH2⋅H2O
EtOH, 50 °C, 5 h
PS-PPdot-Pd(0
HNSCHN
N
N
OH
Pd
4
Cl
Cl
3
Scheme 1
Table 1 Copper- and Solvent-Free Coupling Reaction of Benzoyl
Successful functionalization of the polymer was con-
firmed by elemental analysis. The N content of the resin
was found to be 4.77% (0.82 mmol/g), which indicates
that only 60% of total chlorine is substituted by amine.
The metal loading of the polymer-supported palladium
complex, determined by inductively coupled plasma
(ICP), was found to be 4.38% (0.41 mmol/g). In the IR
spectrum of the polymer-bound PPDOT obtained, the
sharp C–Cl peak (due to CH2Cl groups) at 1264 cm–1 in
the starting polymer was practically omitted or was seen
as a weak band after introduction of PPDOT and palladi-
um on the polymer. In addition, the IR spectrum of the
polymer-anchored PPDOT showed new absorption bands
at 3400 (OH), 3340 (NH), and 1678 cm–1 (C=N), which
were absent in the IR spectrum of the pure polymer beads.
This confirms the formation of the metal complex on the
surface of the polymer.
Chloride with Phenylacetylenea
Entry Base
Catalyst (mol%) Time (h)
Yield (%)b
1
2
DIPEA
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
98
99
95
50
85
68
92
10
5
Et3N
3
pyrrolidine
pyridine
Et2NH
4
5
6
morpholine
piperidine
K2CO3
7
8
9
Cs2CO3
Et3N
The catalytic activity of the PS-ppdot-Pd(0) complex 4 (1
mol%) was studied at room temperature under aerobic
conditions in a copper-free coupling reaction using phe-
nylacetylene and benzoyl chloride. As shown in Table 1,
our initial goal was to optimize the reaction conditions for
a copper- and solvent-free coupling of benzoyl chloride
5a (1 mmol) and phenylacetylene 6a (1 mmol) in the pres-
ence of 1 mol% Pd [as in PS-ppdot-Pd(0)]. When the re-
action was performed with Et3N as base, an excellent 99%
yield of the product was obtained (entry 2). When the re-
action was conducted with common inorganic bases such
as K2CO3 and Cs2CO3, low GC yields were obtained (en-
tries 8 and 9). Using lower palladium loadings mostly led
to a longer reaction time, which was consistent with our
experimental results (entries 10 and 11).
10
11
87
80
Et3N
5
a Reaction conditions: benzoyl chloride (1.0 mmol), phenylacetylene
(1.50 mmol), base (1.0 mmol), r.t., aerobic conditions.
b GC yield.
with phenylacetylene under similar conditions to afford
the corresponding products 7d,e in excellent yield (99%),
respectively (entries 4 and 5).
The Sonogashira coupling reaction of ortho-substituted
electron-rich benzoyl chlorides with terminal alkynes
gave the corresponding coupling products in high yields
despite the steric hindrance of the ortho substituents (en-
tries 3 and 13).
After optimized conditions were found, a variety of acyl
chlorides were coupled with terminal alkynes in the pres-
ence of 1 mol% of PS-ppdot-Pd(0) under copper- and sol-
vent-free conditions (Table 2). These results show that the
reaction is equally facile with both electron-donating and
electron-withdrawing substituents present on the aroyl
chloride and the terminal alkyne resulting in excellent
yields of ynones.
When the less reactive acetylenes 1-hexyne and 1-pentyne
were used, the coupling products were produced efficient-
ly. The coupling of para-substituted benzoyl chlorides
having methyl-, methoxy-, and chloro-substituents took
place with 1-hexyne to give the corresponding products
7j–l in 98%, 98%, and 99% yields, respectively (entries
10–12). Coupling reaction of 1-pentyne with more reac-
tive electron-deficient p-chlorobenzoyl chloride or the
less reactive electron-rich p-methyl- and p-methoxyben-
zoyl chlorides gave excellent yields of the coupled prod-
ucts (entries 17–19). Copper-free coupling reactions of
aroyl halides with trimethylsilylacetylene also took place
The coupling reaction of phenylacetylene with p-methyl
and p-methoxy benzoyl chlorides bearing electron-donat-
ing groups at their para positions gave the corresponding
products 7b and 7f in 98% yield (entries 2 and 6). p-Nitro-
and p-chlorobenzoyl chlorides having electron-deficient
aromatic rings also underwent the Sonogashira coupling
Synlett 2011, No. 3, 311–314 © Thieme Stuttgart · New York

LETTER
Synthesis of Ynones
313
chloride with phenylacetylene. The catalyst was separated
from the reaction mixture by filtration after each experi-
ment, washed with water and acetonitrile, and dried care-
fully before use in subsequent runs. Thus after the first
reaction, which gave a quantitative yield of the coupling
product 7a (Table 2, entry 1), the catalyst beads were re-
covered and successively subjected to four further runs
under the same conditions to afford 5a in 99–90% yields
(Table 3).
Table 2 Copper- and Solvent-Free Sonogashira Reactions of Acid
Chlorides with Terminal Alkynesa
[PS-ppdot-Pd(0)]
ArCO
R
ArCOCl
5
R
+
Et3N, r.t., 0.5 h
6
7
Entry
1
Ar
Ph
R
Product
7a
7b
7c
Yield (%)b
Ph
99
2
4-MeC6H4
2-MeC6H4
4-O2NC6H4
4-ClC6H4
4-MeOC6H4
cyclohexyl
2-thienyl
Ph
Ph
98
3
Ph
97
Table 3 Copper-Free Coupling Reaction of Benzoyl Chloride with
Phenylacetylene Catalyzed by the Recycled Catalysta
4
Ph
7d
7e
99 (95)
99
Entry
Cycle
1st
Yield (%)b
5
Ph
1
2
3
4
99
97
93
90
6
Ph
7f
98 (93)
99
2nd
3rd
7
Ph
7g
7h
7i
8
Ph
99
4th
9
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
TMS
TMS
TMS
TMS
99
a Reaction conditions: benzoyl chloride (1.0 mmol), phenylacetylene
(1.0 mmol), catalyst (0.01 mmol), Et3N (1 mmol), r.t., 0.5 h, aerobic
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-MeC6H4
cyclohexyl
2-thienyl
Ph
7j
98
conditions.
7k
7l
98
b GC yield.
99 (94)
97
In conclusion, we have shown that PS-ppdot-Pd(0) is a
highly efficient and recyclable catalyst for the copper- and
solvent-free coupling reaction of a variety of acyl chlo-
rides and terminal alkynes leading to the formation of
ynones. The catalyst can be easily recycled by centrifuga-
tion and reused several times with only a slight decrease
in activity.
7m
7n
7o
7p
7q
7r
99
99
99
4-ClC6H4
4-MeC6H4
4-MeOC6H4
cyclohexyl
Ph
99
98
Preparation of Polymer-Anchored PS-ppdot-Pd(0) 4
7s
98 (93)
99
To a 250 mL round-bottom flask equipped with a magnetic stirrer
bar, and containing DMF (100 mL), were added chloromethylated
polystyrene (2 g, 1.25 mmol/g of Cl) and PPDOT (7.5 mmol), and
the reaction mixture was stirred for 24 h at 100 °C. The reaction
mixture was filtered and washed thoroughly with DMF, and dried
in vacuo for 12 h. The PPDOT-functionalized polymer 2 (1.5 g) was
treated with EtOH (50 mL) for 30 min. An ethanolic solution of
PdCl2(PhCN)2 (0.12 g) was added, and the resulting mixture was
heated to 70 °C for 6 h. The resulting bright yellow colored poly-
mer, impregnated with the metal complex, was filtered and washed
with EtOH, and then stirred with hydrazine monohydrate (2 g) and
EtOH (20 mL) at 50 °C under Ar for 5 h. The resulting product was
filtered, washed with EtOH, and dried at 50 °C to give PS-ppdot-
Pd(0) (Scheme 1).
7t
7u
7w
7x
7y
99
4-MeOC6H4
4-O2NC6H4
2-thienyl
98
99 (95)
98
a Reaction conditions: 5 (1.0 mmol), 6 (1.0 mmol), [PS-dppot-Pd(0)]
(0.01 mmol), Et3N (1.0 mmol), 0.5 h, r.t., aerobic conditions.
b GC yield. Numbers in parentheses are isolated yields.
under similar conditions to give products 7u, 7w, and 7x
in excellent yields (entries 21–23).
General Procedure for the Coupling Reaction of Acid Chlorides
with Terminal Alkynes Catalyzed by PS-ppdot-Pd(0)
A round-bottom flask was charged with an acid chloride (1.0
mmol), a terminal alkyne (1.0 mmol), [PS-ppdot-Pd(0)] (0.01
mmol), and Et3N (1.0 mmol). The mixture was stirred at r.t. for 30
min under aerobic conditions. Upon completion of the reaction, the
A heteroaryl acyl chloride such as 2-thiophene carbonyl
chloride also reacted with terminal alkynes to give the
products in near quantitative yields (entries 8, 15, and 24).
Under the same conditions as above, cyclohexane carbo- mixture was extracted with EtOAc (2 × 10 mL). The organic layer
was washed with H2O to remove the amine hydrochloride byprod-
nyl chloride also afforded the desired coupling products in
uct. The organic layer was separated, dried over MgSO4, filtered,
excellent yield (entries 7, 14, and 20).
and concentrated in vacuo to afford the crude product. The residue
was purified by column chromatography using CHCl3–MeOH
(98:2) as eluent to afford the pure product.
The recyclability of the PS-ppdot-Pd(0) catalyst 4 was ex-
amined in the Sonogashira coupling reaction of benzoyl
Synlett 2011, No. 3, 311–314 © Thieme Stuttgart · New York

314
M. Bakherad et al.
LETTER
(9) Logue, M. W.; Teng, K. J. Org. Chem. 1982, 47, 2549.
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The authors are grateful to the Research Council of Shahrood Uni-
versity of Technology for the financial support of this work.
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