Using Pd-salen complex as an efficient catalyst for the copper- and solvent-free coupling of acyl chlorides with terminal alkynes under aerobic conditions

Article abstract of DOI:10.1016/j.cclet.2010.01.010

The palladium-salen complex palladium(II) N,N′-bis{[5-(triphenylphosphonium)-methyl]salicylidene}-1,2-ethanediamine chloride was found to be a highly active catalyst for the copper- and solvent-free coupling reaction of terminal alkynes with different acy

Full text of DOI:10.1016/j.cclet.2010.01.010

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 656–660
www.elsevier.com/locate/cclet
Using Pd–salen complex as an efficient catalyst for the
copper- and solvent-free coupling of acyl chlorides with
terminal alkynes under aerobic conditions
*
*
Mohammad Bakherad , Amir Hossein Amin , Ali Keivanloo,
Bahram Bahramian, Mersad Raessi
School of Chemistry, Shahrood University of Technology, Shahrood, Iran
Received 9 October 2009
Abstract
0
The palladium–salen complex palladium(II) N,N -bis{[5-(triphenylphosphonium)-methyl]salicylidene}-1,2-ethanediamine
chloride was found to be a highly active catalyst for the copper- and solvent-free coupling reaction of terminal alkynes with
different acyl chlorides in the presence of triethylamine as base, giving excellent ynones under aerobic conditions.
#
2010 Mohammad Bakherad. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Copper-free; Ynones; Pd–salen complex; Neat
Alkynyl ketones appear in many biologically active molecules [1], and play crucial roles as intermediates in the
synthesis of natural products [2] and drug-like molecules [3]. They have mainly been used in the preparation of
heterocyclic derivatives such as pyrroles [4], furans [5], and quinolines [6]. Their preparation typically involves
reaction of alkynyl organometallic reagents such as silver [7], and tin [8] with acyl chlorides. An alternative method for
the synthesis of alkynyl ketones is the transition metal-catalyzed coupling of terminal alkynes or metalated derivatives
with organic halides in the presence of carbon monoxide [9]. The direct coupling of alkynyl palladium reagents with
acyl chlorides is an important method for the preparation of alkynyl ketones. However, these methods require
anhydrous solvents and an inert atmosphere [10]. Moreover, these reactions need degassed organic solvents, and have
to be carried out under an inert atmosphere. This is particularly inconvenient when the reactions are carried out in
multiple vessels for library generation. Therefore, the development of a convenient method is an important objective in
this effort. Taking these into consideration, we decided to concentrate on developing a new palladium catalyst which is
highly active and air-stable. Our goal was to keep the reaction effective in the absence of solvent and copper salts as a
co-catalyst under aerobic conditions.
Palladium(II) salts with bidentate N,O-ligands have proven to be efficient catalysts for C–C bond-forming
reactions. [11] As part of our continuing interest in palladium catalyzed carbon–carbon cross-coupling reactions [12],
*
Corresponding authors.
E-mail addresses: m.bakherad@yahoo.com (M. Bakherad), amir_amin345@yahoo.com (A.H. Amin).
1001-8417/$– see front matter # 2010 Mohammad Bakherad. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.01.010

M. Bakherad et al. / Chinese Chemical Letters 21 (2010) 656–660
657
Fig. 1. The structure of compound 1.
we have recently reported a mild protocol for the copper-free Sonogashira coupling reactions catalyzed by the Pd–
salen complex under aerobic conditions [13].
In this paper, we wish to report the development of a mild protocol for the copper- and solvent-free coupling
0
reaction of terminal alkynes with various acyl chlorides under aerobic conditions with the Palladium(II) N,N -
bis{[5(triphenylphosphonium)methyl]salicylidene}-1,2-ethanediamine chloride 1 [13] as catalyst (Fig. 1).
1
. Experimental
A round-bottom flask was charged with acyl chloride (1.0 mmol), a terminal alkyne (1.0 mmol), Pd–salen complex
0.01 mmol), and Et N (1.0 mmol). The mixture was stirred at room temperature for 15 min under aerobic conditions.
3
(
Upon completion of the reaction, the reaction mixture was extracted with EtOAc (2 ꢀ 10 mL). The organic layer was
washed with water to remove the amine hydrochloride formed. The organic layer was separated, dried over MgSO ,
4
filtered, and concentrated under vacuum to obtain the crude product. The residue was purified by column
chromatography using hexane/ethyl acetate (20:1) as eluent to afford the product [14].
2
. Result and discussion
The catalytic activity of palladium–salen complex 1 (1 mol%) was studied at room temperature under aerobic
conditions in a copper- and solvent-free coupling reaction using acyl chlorides and terminal alkynes.
As a starting point for the development of the methodology, we chose to study the coupling of phenylacetylene with
benzoyl chloride. Our optimization data is shown in Table 1. First several bases were screened for the coupling
reaction in the presence of a catalytic amount of the Pd–salen complex. As shown in Table 2, dioxan proved to be a
good solvent for this coupling reaction, and among the bases tested, triethylamine was the most efficient (entry 10).
To our surprise, under solvent-free conditions, the highest yield of product was obtained when the reaction was
performed (Table 1). As shown in Table 1, when the reaction was performed with Et N as base, an excellent 97% yield
3
Table 1
a
Copper- and solvent-free coupling reaction of benzoyl chloride with phenylacetylene in the presence of different bases
.
b
Yield (%)
Entry
Base
Et
Pd–salen complex (mol%)
Time (min)
1
2
3
4
5
6
7
8
9
3
N
1
15
15
15
15
15
15
15
30
60
97
84
76
80
82
97
70
97
97
DIPEA
1
pyridine
1
Cs
2
CO
CO
3
1
K
2
3
1
Et
Et
Et
Et
3
N
N
N
N
2
3
3
3
0.5
1
1
a
Reaction conditions: benzoyl chloride (1.0 mmol), phenylacetylene (1.0 mmol), base (1.0 mmol), room temperature, aerobic conditions.
GC yield.
b

658
M. Bakherad et al. / Chinese Chemical Letters 21 (2010) 656–660
Table 2
Copper-free coupling reaction of benzoyl chloride with phenylacetylene in the presence of different base solvent
a
.
b
Yield (%)
Entry
Solvent
Base
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
Et
DIPEA
Pyridine
Et
3
N
63
54
46
48
42
35
70
54
46
78
75
64
73
69
61
52
c
CH
CH
CH
3
CN
3
CN
3
CN
3
N
DIPEA
Pyridine
THF
3
Et N
THF
DIPEA
THF
Pyridine
1
1
1
1
1
1
1
0
1
2
3
4
5
6
Dioxane
Dioxane
Dioxane
Toluene
Toluene
Toluene
Pyrrolidine
3
Et N
DIPEA
Pyridine
3
Et N
DIPEA
Pyridine
d
—
a
Reaction condition: benzoyl chloride (1.0 mmol), phenylacetylene (1.0 mmol), base (1.0 mmol), solvent (3 mL), room temperature, aerobic
conditions.
b
GC yield.
c
Diisopropylethylamine.
d
Solvent employed as base.
Table 3
a
Copper- and solvent-free coupling reactions of various acyl chlorides with terminal alkynes
.
1
2
b
Yield (%)
Entry
R
R
Product
1
2
3
4
5
6
7
8
9
Ph
Ph
4a
4b
4c
4d
4e
4f
97
85
93
98
87
88
92
75
80
85
69
75
79
76
4-Cl-C
6
H
4
-
Ph
4-MeO-C
4-Me-C
4-NO -C
Cyclohexyl
6
H
4
-
Ph
6
H
4
-
Ph
2
6
H
4
-
Ph
Ph
2-thiophene
Ph
Ph
4g
4h
4i
n-C
n-C
n-C
n-C
n-C
n-C
n-C
4
H
4
H
4
H
6
H
6
H
6
H
6
H
9
4-MeO-C
6
H
4
-
-
9
1
1
1
1
1
0
1
2
3
4
2-Me-C
Ph
6
H
4
-
9
4j
13
13
13
13
4k
4l
4-MeO-C
4-Me-C
4-Cl-C
6
H
4
6
H
4
-
4m
4n
6
H
4
-
a
3
Reaction conditions: 2 (1.0 mmol), 3 (1.0 mmol), Et N (1.0 mmol), room temperature, aerobic conditions.
b
GC yield.

M. Bakherad et al. / Chinese Chemical Letters 21 (2010) 656–660
659
of the product was obtained (entry 1). Increasing the amount of palladium catalyst (entry 6) and increasing the reaction
time (entry 8) did not increase the yield of product further. A low palladium concentration resulted in a decreased yield
(
entry 7). Using the optimized reaction conditions, we explored the general applicability of the Pd–salen complex 1
with various benzoyl chlorides 2 containing electron-withdrawing or electron-donating groups and different terminal
alkynes 3 (Table 3). Table 3 shows that the reaction is equally facile with both electron-donating and electron-
withdrawing substituents present on the aroyl chloride, resulting in excellent yields of the corresponding ynones.
Cyclohexane acid chloride also afforded the desired product in 88% yield (entry 6). A hetero-aryl acyl chloride such as
2
-thiophene carbonyl chloride (entry 7) reacted smoothly with phenyl acetylene to give the products in 92% yield. The
reaction was sluggish in the case of the aliphatic alkyne 1-octyne (entry 11), giving a relatively lower yield.
In conclusion, we showed that the air stable palladium–salen complex 1 efficiently catalyzed the copper- and
solvent-free coupling reaction of various acyl chlorides with terminal alkynes under aerobic conditions. The simple
procedure, short reaction time, high selectivity, and excellent isolated yields make this method well-suited for the
generation of a combinatorial library of ynones.
Acknowledgment
The authors would like to thank the Research Council of Shahrood University of Technology for the support of this
work.
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1
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3
ꢁ1
1
(
(
(
m, 5H), 7.62–7.70 (m, 2H), 8.20 (d, 2H, J = 8.6 Hz). 4c: MP 98–99 8C (Lit. [16]) 99 8C; IR (KBr) (max cm ): 2200, 1635. H NMR
500 MHz, CDCl ): d 3.85 (s, 3H), 6.95 (d, 2H, J = 9.0 Hz), 7.41–7.51 (m, 3H), 7.65–7.69 (m, 2H), 8.18 (d, 2H, J = 8.9 Hz). 4d: MP 69–70 8C
Lit. [17]) 70 8C; IR (KBr) (max cm ): 2203, 1640, 1610, 1570. H NMR (500 MHz, CDCl
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ꢁ1
1
3
): d 2.43 (s, 3H), 7.30-7.42 (m, 5H), 7.68 (d, 2H,
ꢁ
1
1
J = 8.6 Hz), 8.15 (d, 2H, J = 8.7 Hz). 4e: MP 160–162 8C (Lit. [16]) 162–163 8C; IR (KBr) (max cm ): 2200, 1650, 1510, 1340. H NMR
ꢁ
1
1
(500 MHz, CDCl ): d 7.49–7.83 (m, 5H), 8.42 (s, 4H). 4f: Colorless oil; [16] IR (neat (max cm ): 2200, 1660. H NMR (500 MHz, CDCl ): d
3 3
ꢁ1
1
3
.20–2.14 (m, 10H), 2.42–2.55 (m, 1H), 7.30–7.42 (m, 3H), 7.57–7.60 (m, 2H). 4g: MP 54–55 8C (Lit. [18]) 53–54 8C; IR (KBr) (max cm ):
1
3
010, 2200, 1622, 1410. H NMR (500 MHz, CDCl ): d 7.18–7.22 (m, 1H), 7.35–7.50 (m, 3H), 7.64–7.72 (m, 3H), 8.03 (d, 1H, J = 2.9 Hz). 4h:
ꢁ1
1
3
Colorless oil; [19] IR neat (max cm ): 2950, 2200, 1645. H NMR (500 MHz, CDCl ): d 0.95 (t, 3H, J = 7.2 Hz), 1.44–1.54 (m, 2H), 1.60–
ꢁ1
1.70 (m, 2H), 2.50 (t, 2H, J = 7.2 Hz), 7.46–7.52 (m, 2H), 7.55–7.60 (m, 1H), 8.12–8.15 (m, 2H). 4i: Colorless oil; [20] IR neat (max cm ):
1
2930, 2850, 2200. H NMR (500 MHz, CDCl ): d 0.97 (t, 3H, J = 6.3 Hz), 1.44–150 (m, 2H), 1.56–1.67 (m, 2H), 2.44 (t, 2H, J = 6.2 Hz), 3.88
3
ꢁ1
1
(
s, 3H), 6.94 (d, 2H, J = 8.3 Hz), 8.16 (d, 2H, J = 6.6 Hz). 4j: Colorless oil; [21] IR neat (max cm ): 2955, 2860, 2202, 1645. H NMR
500 MHz, CDCl ): d 0.95 (t, 3 H, J = 6.1 Hz), 1.42–1.52 (m, 2H), 1.61–1.66 (m, 2H), 2.46 (t, 2H, J = 6.8 Hz), 2.65 (s, 3H), 7.21–7.26 (m, 1H),
.34–7.43 (m, 2H), 8.20–8.24 (m, 1H). 4k: Colorless oil; [16] IR neat (max cm ): 2230, 2200, 1650. H NMR (500 MHz, CDCl
m, 11H), 2.55(t, 2H, J = 7.2 Hz), 7.45–7.52 (m, 2H), 7.55–7.61 (m, 1H), 8.12–8.16 (m, 2H). 4l: Colorless oil; [17] IR neat (max cm ): 2930,
(
3
ꢁ1
1
7
3
): d 0.82–1.75
ꢁ1
(
1
2
850, 2199, 1640. H NMR (500 MHz, CDCl
3
): d 0.96 (t, 3H, J = 6.4 Hz), 1.32–1.68 (m, 8H), 2.45 (t, 2H, J = 6.9 Hz), 3.83 (s, 3H), 6.92 (d, 2H,
ꢁ1
1
J = 8.2 Hz), 8.11 (d, 2H, J = 6.6 Hz). 4m: Colorless oil; [17] IR neat (max cm ): 2950, 2940, 2198, 1640. H NMR (500 MHz, CDCl
3
): d 0.90
t, 3H, J = 7.1 Hz), 1.23–1.78 (m, 8H), 2.52 (t, 2H, J = 7.4 Hz), 7.26 (d, 2H, J = 8.3 Hz), 8.05 (d, 2H, J = 7.2 Hz). 4n: Colorless oil; [17] IR neat
(
(
ꢁ1
1
3
max cm ): 2930, 2855, 2240, 2200, 1642, 1595, 1576. H NMR (500 MHz, CDCl ): d 0.92 (s, 3H), 1.22–1.75 (m, 8H), 2.54 (t, 2H,
J = 7.2 Hz), 7.42 (d, 2H, J = 8.2 Hz), 8.10 (d, 2H, J = 8.2 Hz).

660
M. Bakherad et al. / Chinese Chemical Letters 21 (2010) 656–660
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