Palladium- and solvent-free synthesis of ynones by copper(I)-catalyzed acylation of terminal alkynes with acyl chlorides under aerobic conditions

Article abstract of DOI:10.1002/hlca.201300023

Air-stable Cu^I/cryptand-22 complex was found to be a highly active catalyst for the solvent-free cross-coupling reaction of terminal alkynes with different acyl chlorides in the presence of Et₃N as base to give the corresponding ynon

Full text of DOI:10.1002/hlca.201300023

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Helvetica Chimica Acta – Vol. 97 (2014)
Palladium- and Solvent-Free Synthesis of Ynones by Copper(I)-Catalyzed
Acylation of Terminal Alkynes with Acyl Chlorides under Aerobic Conditions
by Elmira Mohammadi, Barahman Movassagh*, and Mozhgan Navidi
Department of Chemistry, K. N. Toosi University of Technology, P.O. Box 16315-1618, Tehran, Iran
(
phone: þ 98-21-22853650; e-mail: bmovass1178@yahoo.com)
I
Air-stable Cu /cryptand-22 complex was found to be a highly active catalyst for the solvent-free
cross-coupling reaction of terminal alkynes with different acyl chlorides in the presence of Et N as base to
3
give the corresponding ynones in quantitative yields.
Introduction. – Among several protocols for the synthesis of ynones [1 – 3], the
reaction of acyl chlorides with alkynyl organometallic reagents, based on copper [4],
zinc [5], tin [6], silver [7], lithium [8], and silicon [9], is arguably one of the most
versatile and efficient methods. Recently, the coupling reaction of terminal alkynes and
acyl chlorides catalyzed by Pd catalysts has received much attention [10]; but, on the
other hand, efficient Pd-free systems would obviously be much more interesting for
economic reasons, regarding both the higher cost of Pd as well as the difficulties in
removing the metal (and its ligands) from the products. Indeed, it is a common
industrial practice to avoid, whenever possible, the use of Pd catalysts in the last steps of
the synthesis of complex molecules. Nevertheless, there are several other reports in
which coupling of acyl chlorides with terminal alkynes catalyzed by Pd(PPh ) Cl /CuI
3
2
2
provided ynones [11]. However, most of the reported methods require anhydrous
solvents, inert gas, long reaction times, and expensive and toxic reagents. Moreover, the
use of CuI has been avoided in many cases, because the in situ formed copper(I)
acetylides derived from CuI undergo homocoupling upon exposure to air, yielding side
products (Glaser coupling) [12]; moreover, the copper(I) acetylides formed show an
extremely high reactivity and may explode in open air [13].
In practice, from an ecological point of view, ꢀthe best solvent is without doubt no
solventꢁ. There are, of course, many reactions which can already be carried out without
solvent. Reports on solvent-free reactions have, indeed, become increasingly frequent
and specialized over recent years. There are also reactions in which at least one reactant
is liquid under the conditions employed, implying that the solvent that would normally
be used can simply be left out.
I
Results and Discussion. – The traditional Cu -catalyzed cross-coupling between
terminal alkynes and acyl chlorides require long reaction times and an inert atmosphere
I
[
14]. In an effort to find an efficient Cu complex that could promote the mentioned
I
coupling, we investigated a class of Cu catalyst system based on a commercially
available azacrown ether, 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane (Kryptofix 22
ꢀ
or cryptand-22), which was first reported by Mꢁhle and Sheldrick [15]. This catalyst,
ꢂ 2014 Verlag Helvetica Chimica Acta AG, Zꢃrich

Helvetica Chimica Acta – Vol. 97 (2014)
71
CuI/cryptand-22 (or CuI/C22), was prepared in our laboratory by an easier method
than the previously reported one [15]. This catalytic system is an air-stable solid powder
and remains so for at least one month with no change in its catalytic activity. We
assumed that the flexible macrocyclic and chelating effect of such N- and O-containing
ligands may assist the stabilization of the reactive copper intermediates. To study the
coordination of the ligand, cryptand-22, to CuI, resulting in complex CuI/C22, the IR
spectrum of free ligand was compared with that of the complex. A medium intensity
ꢀ
1
n(
band was observed at 3327 cm in the IR spectrum of the ligand, whereas the
NꢀH)
ꢀ
1
same band was observed at 3264 cm of the complex, supporting the assumption that
the ligand coordinates to the metal ion through the N-atoms of the ligand.
Herein, we report a new homogeneous copper catalyst system, CuI/C22, that
I
suppresses the Cu -mediated homocoupling formation even in the presence of air. It is
an air-stable and highly efficient catalyst system for the ynone cross-coupling reaction
of terminal alkynes 2 with acyl chlorides 1. To optimize the reaction conditions with
respect to solvent, temperature, base, and the amount of the catalyst, the coupling
reaction between benzoyl chloride (1a; 1.4 equiv.), phenylacetylene (2a; 1.0 equiv.),
and a base (1.2 equiv.) was performed as a model reaction under aerial condition
(
Table 1). The best result was obtained when 2.6 mol-% of the catalytic system and
Et N, as base, were used under solvent-free conditions at 608 (Entry 5, Table 1). After
3
Table 1. Optimization of the CuI/C22-Catalyzed Reactiona)
Entry
Base
Temp. [8]
Solvent
Catalyst [mol-%]
Yield [%]b)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
Et N
25
25
25
40
60
70
60
60
60
60
60
60
60
60
–
–
–
–
–
–
–
–
2
2.6
3
73
81
64
85
93
94
32
N.R.
14
12
N.R.
37
N.R.
25
3
Et N
3
Et N
3
Et N
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
3
Et N
3
Et N
3
i
EtN Pr
2
Piperidine
K CO
–
2
3
1
1
1
1
1
Et N
THF
DMF
Toluene
NMP )
MeCN
3
Et N
3
Et N
3
c
Et N
3
Et N
3
a) Reaction conditions: benzoyl chloride (1a; 1.4 equiv.), phenylacetylene (2a; 1.0 equiv.), base
b
c
(
1.2 equiv.), 30 min, aerial conditions. ) Yields of isolated products; N.R., no reaction. ) 1-
Methylpyrrolidin-2-one.

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Helvetica Chimica Acta – Vol. 97 (2014)
optimization, the generality of this cross-coupling was demonstrated with a variety of
acyl chlorides 1 (aromatic, heteroaromatic, and aliphatic) and terminal alkynes 2.
Representative results are listed in Table 2. All products were fully characterized by
spectroscopic methods and compared with authentic spectra. As seen in Table 2,
generally, aliphatic terminal alkynes needed longer reaction times and afforded lower
yields (Entries 11 – 14, Table 2) than phenylacetylene (2a). Both aryl and alkyl acyl
chlorides coupled with alkynes in air.
The reaction was almost equally facile with both electron-withdrawing and
electron-donating substituents in the aroyl chlorides. Besides, no significant steric
effect was observed due to MeꢀC(2) of 2-methylbenzoyl chloride. Heteroaromatic acyl
chlorides, e.g., thiophene-2-carbonyl chloride (1g), also reacted with terminal alkynes
to give the corresponding ynones in good-to-high yields (Entries 7 and 12, Table 2).
Finally, we compared the performance of our catalyst with other catalytic systems
reported in the literature for the cross-coupling of benzoyl chloride (1a) with
phenylacetylene (2a; Table 3). The results established the superior catalytic activity of
CuI/C22 in this reaction.
Conclusions. – We have developed an easy, very efficient, and fast solvent-,
phosphorous-, and Pd-free protocol for the cross-coupling reaction of acyl chlorides
with terminal alkynes catalyzed by the air-stable CuI/C22 complex, affording almost
quantitative yields of the corresponding ynones. This reaction is very useful both from
economical and environmental point of view, displaying the advantages of i)
Table 2. CuI/C22-Catalyzed Cross-Coupling of Acyl Chlorides 1 with Terminal Alkynes 2a)
Entry
Acyl chloride
R1
Ph
Alkyne
R2
Product
Time [h]
Yield [%]b)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bu
Bu
Bu
Hexyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
0.5
0.75
1
0.75
0.25
0.25
5
93
91
92
92
90
91
87
88
81
82
68
63
35
52
4-MeꢀC H
6
4
2-MeꢀC H
6
4
4-ClꢀC H
6
4
4-NO ꢀC H
2
6
4
4-CNꢀC H
6
4
Thiophen-2-yl
Cyclohexyl
1
i
Pr
1.25
1.5
2.5
3
3
5.3
10
11
12
13
14
1j
Cyclopropyl
Ph
1a
1g
1k
1a
Thiophen-2-yl
4-MeOꢀC H
6
4
Ph
a) Reaction conditions: 1.0 mmol of 2, 1.4 mmol of 1, 1.2 mmol of Et N, 608, aerobic condition. ) Yields
b
3
of isolated products.

Helvetica Chimica Acta – Vol. 97 (2014)
73
Table 3. Comparison of Different Catalytic Systems for the Coupling Reaction of Benzoyl Chloride (1a)
with Phenylacetylene (2a)
Entry
Catalyst
Conditions
Time [h]
Yield a) [%]
Ref.
1
2
Pd(OAc)2
Pd(OAc)2
Palladacycle
Neat, r.t., Ar
Toluene, 1108
Toluene, 1108
0.17
1
1
93
70
75
98
96
93
78
93
[10c]
[16]
[16]
[11a]
[11b]
[17]
3
4
5
6
7
PdCl
2
(PPh
3
)/CuI
H
2
O, 658
4
PdCl (PPh )/CuI
THF, r.t.
0.17
36
30
0.5
2
3
NS-MCM-41-Pd/CuI
CuI
CuI/C22
Et N, 508, N
3
2
Neat, r.t., Ar
Neat, 608
[14a]
b
)
a) Yield of isolated product. b) This work.
operational simplicity, ii) mild reaction conditions, iii) avoidance of organic solvents,
and toxic and expensive reagents, iv) short reaction times, and v) high product yields.
We acknowledge financial support from the K. N. Toosi University of Technology Research Council.
We are also grateful to Professor J. Ghasemi for helpful discussions.
Experimental Part
Preparation of the Catalyst. Copper(I) iodide (76 mg, 0.4 mmol) was added into a soln. of cryptand-
2
2 (106 mg, 0.4 mmol) in MeCN (8 ml) under stirring. The mixture was refluxed for 45 min, during which
time the color of the mixture was turned from colorless to brown, and all the materials dissolved
thoroughly. Then, while the volume of the soln. was reduced to half, a cream-colored precipitate formed.
The precipitate was washed with MeCN and finally air-dried to give the complex CuI/C22 (142 mg, 78%).
M.p. 169 – 1708. The Cu content of the complex was determined by atomic absorption spectroscopy
(
14.52%), which was in good agreement with the calculated value (14.03%).
General Procedure for Preparation of Ynones. A test tube was charged with acyl chloride 1
(
1.4 mmol), the terminal alkyne 2 (1.0 mmol), CuI/C22 (12.0 mg, 2.6 mol%), and Et N (1.2 mmol). The
3
mixure was then stirred for 30 min at 608 under aerobic conditions. The progress of the reaction was
monitored by TLC. Upon completion of the reaction, the mixture was extracted with CHCl (2 ꢁ 5 ml).
3
The combined org. layers were washed with H O (2 ꢁ 10 ml). The org. layer was separated, dried
2
(
MgSO ), filtered, and concentrated in vacuo to give the crude product, which was further purified by
4
prep. TLC (silica gel; hexane/AcOEt 9 :1) to afford the desired pure product 3.
Large-Scale Cross-Coupling Reaction of Phenylacetylene (2a) with Benzoyl Chloride (1a) Catalyzed
by CuI/C22. In an oven-dried flask, a mixture of phenylacetylene (2a; 0.51 g, 5.0 mmol), Et N (0.61 g,
3
6
.0 mmol), benzoyl chloride (1a; 0.98 g, 7.0 mmol), and CuI/C22 (0.06 g, 2.6 mol%) was stirred for 40 min
at 608 under aerobic conditions. The progress of the reaction was monitored by TLC. Upon completion of
the reaction, the mixture was extracted with CHCl (2 ꢁ 15 ml). The combined org. layers were washed
3
with H O (2 ꢁ 15 ml). The org. layer was separated, dried (MgSO ), filtered and concentrated in vacuo to
2
4
give the crude product which was further purified by prep. TLC (silica gel; hexane/AcOEt 9 :1) to afford
1.0 g (98%) of pure 1,3-diphenylprop-2-yn-1-one (3a).
1
-(4-Methylphenyl)-3-phenylprop-2-yn-1-one (3b). Brown solid. M.p. 88 – 898. IR (neat): 2199
1
(
7
1
CꢂC), 1637 (C¼O). H-NMR (CDCl , 300 MHz): 8.13 (d, J ¼ 8.2, 2 H); 7.69 (dd, J ¼ 7.9, 1.6, 2 H);
3
13
.39 – 7.52 (m, 3 H); 7.32 (d, J ¼ 7.9, 2 H); 2.45 (s, 3 H). C-NMR (CDCl , 75 MHz): 177.7; 145.2; 134.6;
3
33.0; 130.6; 129.7; 129.3; 128.7; 120.2; 92.6; 86.9; 21.8.

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Helvetica Chimica Acta – Vol. 97 (2014)
1
-(2-Methylphenyl)-3-phenylprop-2-yn-1-one (3c). Yellow oil. IR (neat): 2196 (CꢂC), 1638 (C¼O).
1
H-NMR (CDCl , 400 MHz): 8.35 (d, J ¼ 7.6, 1 H); 7.69 (d, J ¼ 6.8, 2 H); 7.38 – 7.52 (m, 5 H); 7.29 – 7.32
3
13
(
m, 1 H); 2.72 (s, 3 H). C-NMR (CDCl , 100 MHz): 179.8; 140.5; 135.7; 133.3; 133.0; 132.9; 130.7; 128.7;
3
1
26.0; 120.4; 91.9; 88.4; 22.0.
3
-Phenyl-1-(thiophen-2-yl)prop-2-yn-1-one (3g). Brown solid. M.p. 56 – 588. IR (KBr): 2197 (CꢂC),
1
1
2
1
641 (C¼O). H-NMR (CDCl , 300 MHz): 8.02 (d, J ¼ 3.8, 1 H); 7.73 (d, J ¼ 5.4, 1 H); 7.67 (d, J ¼ 6.1,
3
13
H); 7.39 – 7.50 (m, 3 H); 7.19 (t, J ¼ 4.4, 1 H). C-NMR (CDCl , 75 MHz): 169.8; 144.9; 135.3; 135.1;
3
32.8; 130.9; 128.7; 128.2; 119.9; 91.8; 86.5.
1
1
-Cyclohexyl-3-phenylprop-2-yn-1-one (3h). Yellow oil. IR (neat): 2197 (CꢂC), 1658 (C¼O). H-
NMR (CDCl , 400 MHz): 7.61 (d, J ¼ 7.5, 2 H); 7.48 (t, J ¼ 7.6, 1 H); 7.41 (t, J ¼ 7.6, 2 H); 2.54 (tt, J ¼ 11.8,
3
2
(
.9, 1 H); 2.09 (d, J ¼ 10.7, 2 H); 1.83 – 1.87 (m, 2 H); 1.71 – 1.73 (m, 1 H); 1.50 – 1.55 (m, 2 H); 1.27 – 1.40
13
m, 3 H). C-NMR (CDCl , 100 MHz): 191.6; 133.0; 130.6; 128.6; 120.2; 91.4; 87.2; 52.3; 28.3; 25.8; 25.4.
3
1
4
-Methyl-1-phenylpent-1-yn-3-one (3i). Yellow oil. IR (neat): 2197 (CꢂC), 1668 (C¼O). H-NMR
(
6
CDCl , 300 MHz): 7.58 (d, J ¼ 8.0, 2 H); 7.35 – 7.48 (m, 3 H); 2.78 (sept., J ¼ 7.0, 1 H); 1.27 (d, J ¼ 7.0,
3
3
1
H). C-NMR (CDCl , 75 MHz): 192.2; 133.0; 131.5; 128.6; 128.1; 91.6; 85.8; 43.1; 18.1.
3
1
-Cyclopropyl-3-phenylprop-2-yn-1-one (3j). Yellow oil. IR (neat): 2197 (CꢂC), 1643 (C¼O).
1
H-NMR (CDCl , 300 MHz): 7.55 – 7.58 (m, 2 H); 7.35 – 7.49 (m, 3 H); 2.13 – 2.20 (m, 1 H); 1.31 – 1.39 (m,
H); 1.09 – 1.14 (m, 2 H). C-NMR (CDCl , 75 MHz): 188.4; 133.0; 130.6; 128.6; 120.0; 90.4; 86.2; 24.6;
1.2. EI-MS: 170 (5, M ), 167 (19), 149 (26), 129 (89), 105 (24), 75 (22), 69 (100), 57 (29). Anal. calc. for
3
13
2
1
3
þ
C H O: C 84.68, H 5.92; found: C 84.90, H 5.87.
12
10
1
1
-(Thiophen-2-yl)hept-2-yn-1-one (3l). Yellow oil. IR (neat): 2228 (CꢂC), 1623 (C¼O). H-NMR
(
CDCl , 400 MHz): 7.92 (d, J ¼ 3.6, 1 H); 7.70 (d, J ¼ 4.8, 1 H); 7.17 (t, J ¼ 4.8, 1 H); 2.51 (t, J ¼ 7.2, 2 H);
3
13
1
.67 (quint., J ¼ 7.2, 2 H); 1.52 (sext., J ¼ 7.2, 2 H); 0.98 (t, J ¼ 7.2, 3 H). C-NMR (CDCl , 100 MHz):
3
1
70.1; 145.1; 134.9 (2C); 128.2; 95.4; 79.3; 29.8; 22.1; 18.8; 13.5.
1
-(4-Methoxyphenyl)hept-2-yn-1-one (3m). Yellow oil. IR (neat): 2202 (CꢂC), 1632 (C¼O).
1
H-NMR (CDCl , 300 MHz): 8.08 – 8.13 (m, 2 H); 6.91 – 6.97 (m, 2 H); 3.88 (s, 3 H); 2.49 (t, J ¼ 7.1, 2 H ) ;
3
13
1
1
.66 (quint., J ¼ 7.0, 2 H); 1.51 (sext., J ¼ 7.1, 2 H); 0.96 (t, J ¼ 7.3, 3 H). C-NMR (CDCl , 75 MHz):
3
77.1; 164.3; 131.9; 113.7; 113.6; 95.9; 79.6; 55.6; 29.9; 22.1; 18.9; 13.5.
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Received January 13, 2013