Fast copper-, ligand- and solvent-free Sonogashira coupling in a ball mill

Article abstract of DOI:10.1039/c000674b

A solvent-free method for the Sonogashira coupling reaction was established under ball milling conditions without the use of copper or additional ligands. Pd(OAc)₂ or Pd(PPh₃)₄ in combination with 1,4-diazabicyclo[2.2.2]octane (DABCO) were chosen as catalysts and base, respectively. The reaction was investigated using a variety of aryl halides and acetylenes and with different amounts of the Pd-catalyst and DABCO. Results indicated that the employment of Pd(OAc)₂ in combination with SiO₂ as a grinding auxiliary preferentially induces the transformation of aryl iodides to the corresponding Sonogashira coupling products. In contrast, both the substitution of SiO₂ by Al ₂O₃ or replacement of Pd(OAc)₂ with Pd(PPh ₃)₄ enable the reaction of aryl bromides with phenylacetylenes. The selective reaction of bis-ethynyl compounds to double-coupled products and the influence of further common bases on the reaction was also scrutinized, confirming the high reactivity of DABCO as a base for solvent-free transformations.

Full text of DOI:10.1039/c000674b

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PAPER
www.rsc.org/greenchem | Green Chemistry
Fast copper-, ligand- and solvent-free Sonogashira coupling in a ball mill†
Rico Thorwirth, Achim Stolle* and Bernd Ondruschka
Received 12th January 2010, Accepted 19th March 2010
First published as an Advance Article on the web 29th April 2010
DOI: 10.1039/c000674b
A solvent-free method for the Sonogashira coupling reaction was established under ball milling
conditions without the use of copper or additional ligands. Pd(OAc)2 or Pd(PPh3)4 in combination
with 1,4-diazabicyclo[2.2.2]octane (DABCO) were chosen as catalysts and base, respectively. The
reaction was investigated using a variety of aryl halides and acetylenes and with different amounts
of the Pd-catalyst and DABCO. Results indicated that the employment of Pd(OAc)2 in
combination with SiO2 as a grinding auxiliary preferentially induces the transformation of aryl
iodides to the corresponding Sonogashira coupling products. In contrast, both the substitution of
SiO2 by Al2O3 or replacement of Pd(OAc)2 with Pd(PPh3)4 enable the reaction of aryl bromides
with phenylacetylenes. The selective reaction of bis-ethynyl compounds to double-coupled
products and the influence of further common bases on the reaction was also scrutinized,
confirming the high reactivity of DABCO as a base for solvent-free transformations.
The reaction is normally carried out in organic solvents
Introduction
under inert conditions.4a,b Besides the countless numbers of
Green chemistry and sustainability are becoming more and
publications dealing with the development of new catalytic
more important in everyday organic synthesis.1 Within this
systems, a few more recent articles report experimental protocols
subject, the elimination of solvents is advantageous, since supply,
under solvent-free conditions.6 Compared to other Pd-catalyzed
purification, and disposal of these can be omitted. The accom-
cross-coupling reactions, like the Suzuki–Miyaura or Mizoroki–
panying reduction of solvent waste is the major motivation for
Heck reactions,7,8 only one very recent implementation in a ball
the development of a broad variety of solvent-free synthetic
mill has been published to date for the Sonogashira reaction.9
reaction protocols.2 While reactions are often carried out in
In that work, Pd(PPh3)4 + CuI was used as the catalytic system
a solvent-free manner using classical laboratory equipment or
and the reactions were accomplished with distinctly longer
microwave heating, the application of ball milling is a rather
reaction times than described in the current work, as will be
small, but strongly emerging field of research. Ball milling was
reported below.
found to be an excellent method for some organic reactions: e.g.
aldol-type reactions, oxidation or reduction.2e,g,3 Besides these
stoichiometric reactions, metal-catalyzed and organocatalytic
protocols have also been proven to work.
Results and discussion
Reactions were performed under aerobic conditions using air-
stable Pd(II) acetate (Pd(OAc)2) and 1,4-diazabicyclo[2.2.2]-
octane (DABCO) as the catalyst and basic component respon-
sible for the deprotonation of alkynes, respectively. DABCO
has been found to be an excellent base for the Sonogashira
reaction,10 and it is a solid, which is a major advantage for
an implementation of the reaction in a ball mill (compared
to other commonly used amine bases like triethylamine or
diisopropylamine). In addition, fused quartz sand (SiO2) was
used as an inert filling material for the milling beakers to enable
work with small batch sizes. In contrast to the work of Mack
and coworkers,9 no copper co-catalyst has been employed and
the reaction time was restricted to 20 min of ball milling.
Within these investigations, a fast, copper-, ligand-, and
solvent-free protocol for the Sonogashira coupling of aryl
halides with aryl- and alkylacetylenes using a commercial
planetary ball mill is described. The Sonogashira reaction is
an important C–C cross-coupling reaction between sp- (aryl-,
alkenyl- and alkylacetylenes) and sp2-hybridized carbon atoms
(aryl halides or triflates) catalyzed by transition metals (Pd, Au,
Cu, Ni).4 The coupling products are widely used as starting
materials for the synthesis of molecular organic systems (e.g.
electro-optical switches, conducting polymers), pharmaceuticals
or natural products.4c–g Additionally, this synthetic transfor-
mation is the tool of choice for the construction of carbon-
rich materials (e.g. radialenes, graphenes) from simple building
blocks.5
Sonogashira reaction between aryl iodides and phenylacetylenes
Institute for Technical Chemistry and Environmental Chemistry,
Friedrich-Schiller University Jena, Lessingstraße 12, D-07743, Jena,
Germany. E-mail: Achim.Stolle@uni-jena.de; Fax: +49 364 194 8402;
Tel: +49 364 194 8413
† Electronic supplementary information (ESI) available: Experimental
details and characterization data for the coupling products. DOI:
10.1039/c000674b
Reaction screening of different aryl iodides (1a–f) and con-
jugated acetylene derivatives (2a–d; Table 1) was carried out
using constant reaction parameters to investigate the influence
of substituents on the acetylene derivatives and aryl halides on
the course of reaction.
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Table 1 Sonogashira reactionsa of aryl iodides (1) with substituted
phenylacetylenes (2)
Certain combinations of aryl halides and acetylenes tested
(1a–f with 2a–d) showed high selectivities for the Sonogashira
coupling product related to the employed aryl halide (Table 1).
Also the reproducibility was quite good; the deviation of the
values of conversion and selectivity did not exceed 1–2%. Using
agate, which is a relatively light-weight material, as the material
for milling beakers and balls led to medium and high conversions
of the aryl iodides. A more heavy-weight milling material, such
as ZrO2, resulted in significantly higher conversions for the
same reaction conditions, caused by the higher energy input
of the milling balls (3a,c,g,h; Table 1).7d,11 Conversions were
significantly higher for aryl iodides with electron-withdrawing
substituents (p-iodoacetophenone, 1f) and neutral substituents
(iodobenzene 1a) than for those with electron-donating sub-
stituents (p-iodotoluene and p-iodoanisole, 1c and 1e). The
electron-poor 2-iodothiophene (4) showed high conversion and
selectivity (98%) in the reaction with phenylacetylene (2a;
Scheme 1) under the reaction conditions reported for examples
listed in Table 1.
Product
Aryl iodide (R1) Acetylene (R2) X(1) [%]b S(3) [%]b
3a
1a (H)
2a (H)
68
80
54
47d
74c
51
58d
98
67
83c
55
77c
53
95
61
99
53
93
99
99
98
>99
>99
98
98
99
97
98
98
97
98
92
>99
>99
96
3a (ZrO2)c 1a (H)
2a
3b
3c
1b (o-Me)
1c (p-Me)
2a
2a
3c (ZrO2)c 1c (p-Me)
2a
3d
3e
3f
1d (o-MeO)
1e (p-MeO)
1f (p-Ac)
1a (H)
2a
2a
2a
3g
2b (p-Me)
3g (ZrO2)c 1a (H)
2b
3h
1c (p-Me)
2b
Scheme 1 Coupling reaction of 2-iodothiphene (4) and phenylacetylene
(2a; for conditions see Table 1).
3h (ZrO2)c 1c (p-Me)
2b
3j
3k
3l
3m
3n
3o
1e (p-MeO)
1f (p-Ac)
1e (p-MeO)
1f (p-Ac)
1e (p-MeO)
1f (p-Ac)
2b
2b
2c (p-MeO)
2c
2d (p-F)
2d
Sonogashira reaction between aryl iodides and alkynes
99
The variation of the acetylene seems to have little influence on the
conversion of the aryl iodides. This suggests that the oxidative
addition of the aryl iodide to the Pd-catalyst, which is faster for
electron-poor aryl iodides with a weaker carbon–halogen bond
than for electron-rich aryl iodides, could be the rate-determining
step within the catalytic cycle of this solvent-free method. This
dependency could be confirmed by employing decyne (6a) and
dodecyne (6b) as the coupling component (Table 2). Sonogashira
coupling of 6 with p-iodoanisole (1e) and 1f furnished coupling
products 7a–d (Table 2) in similar yields as demonstrated in
the corresponding reactions with phenylacetylenes 2a–d (see
Table 1). The treatment of alkynes 6 under the described
experimental conditions did not afford any destructive bond
breakage in the alkyl chain, which is due to the employment
of mild reaction conditions. The application of milling materials
with a higher density (steel, copper, tungsten carbide) resulted in
destructive shortening of the alkyl substituents by the occurrence
of stronger frictional forces and higher reaction temperatures.
In addition to alkynes 6 bearing an alkyl chain as a substituent
only, three acetylenes containing an OH-group at carbon atom
3 (8a–c; Scheme 2) were employed in the Sonogashira coupling
with 1f. After ball milling (agate) in the presence of 5 mol%
Pd(OAc)2 and 2.5 mmol of DABCO, the products (9a–c) were
isolated in acceptable yields. The selectivities for the Sonogashira
coupling products were as high as reported for the previous
examples (> 98%; Tables 1 and 2). The successful coupling of 8a
is remarkable, since the 2-hydroxyprop-2-yl group is an excellent
protecting group. In contrast to TMS or TIPS this end group
is tolerable to fluoride ions and can easily be removed in the
a Reaction conditions: 2 mmol aryl iodide (1a–f), 2.5 mmol acetylene
compound (2a–d), 2.5 mmol DABCO, 5 mol% Pd(OAc)2, 5 g SiO2, 800
rpm, 20 min, agate beaker (45 ml), 6 ¥ agate milling balls (15 mm).
b Determined with GC-FID measurements of extracted products in
relation to 1. c ZrO2 milling beakers and balls were used instead of
agate ones. d No change in conversion was observed when PdCl2 was
used instead of Pd(OAc)2 in the same molar amount.
It was found that only aryl iodides 1a–f showed noticeable
conversions, whereas in the case of aryl bromides, none or
only traces of the Sonogashira coupling product were found
under the reaction conditions employed (Pd(OAc)2 + DABCO).
Similar behaviour was reported for a solvent-free microwave-
assisted attempt using KF–alumina and Pd–CuI–PPh3 as the
base and catalyst system, respectively.6a No coupling product
was found if either Pd(OAc)2 or DABCO were absent, or if
Pd(OAc)2 was substituted by palladium powder. This suggests
that either Pd(II) is the active species in the catalytic cycle,
or that in situ reduction of Pd(II) to Pd(0) furnishes more
active Pd species. The latter way may be supported by the fact
that small amounts of 1,4-diarylbuta-1,3-diyne (homocoupling
product of 2) have been identified in the reaction mixture,
whose concentration was independent of conversion. For some
examples the application of PdCl2, instead of the acetate,
yielded products with similar yields and identical selectivities
(3c,e; Table 1). Employment of Pd(PPh3)4 as a catalyst was
investigated, enabling the transformation of aryl bromides (1g–l;
see Tables 6 and 7 and the following text) as indicated recently
by Mack and coworkers.9
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Table 2 Sonogashira reactionsa of aryl iodides (1) with alkynes (6)
Product
Aryl iodide
Acetylene
X(1) [%]b
S(7) [%]b
7a
p-Iodoanisole (1e)
Decyne (6a)
48
93
7b
7c
7d
p-Iodoacetophenone (1f)
p-Iodoanisole (1e)
Decyne (6a)
92
50
92
93
Dodecyne (6b)
Dodecyne (6b)
>99
>99
p-Iodoacetophenone (1f)
a Reaction conditions: 2 mmol aryl iodide (1e,f), 2.5 mmol alkyne (6), 2.5 mmol DABCO, 5 mol% Pd(OAc)2, 5 g SiO2, 800 rpm, 20 min, agate beaker
(45 ml), 6 ¥ agate milling balls (15 mm). b Determined with GC-FID measurements of extracted products in relation to 1.
Table 3 Double Sonogashira reactionsa of p-iodoacetophenone (1f) with bis-ethynyl compounds (10)
Bis-ethynyl compound
Sonogashira coupling product
Yield [%]b
63
10a
11a
10b
10c
11b
11c
69
75
10d
11d
74
a Reaction conditions: 2 mmol p-iodoacetophenone (1f), 1 mmol bis-ethynyl compound (10a–d), 2.5 mmol DABCO, 5 mol% Pd(OAc)2, 5 g SiO2, 800
rpm, 20 min, ZrO2 beaker (45 ml), 6 ¥ ZrO2 milling balls (15 mm). b Determined with 1H-NMR measurements of extracted products in relation to 1f.
presence of alkali hydroxides (retro-Favorski elimination). In
the case of 8b, the possible competing Mizoroki–Heck coupling
reaction on the terminal double bond did not occur.
Sonogashira reaction with bis-ethynyl compounds
Surprisingly, only di-coupled products could be isolated when
1f was applied in the Sonogashira reaction with bis-ethynyl
compounds (10; Table 3). ZrO2 beakers and milling balls were
used, instead of agate ones, to achieve satisfactory results.
Furthermore, the conversions of p-iodoacetophenone 1f were
limited by side reactions of the bis-ethynyl compounds, assumed
to be oligomerization reactions. The products were not suitable
for GC-FID analysis so 1H-NMR analysis of the crude reaction
mixture was used to determine the conversion and selectivity.
Since 1H-NMR spectra revealed a highly symmetrical peak
distribution and there were no signals for acetylenic protons,
Scheme
2
Reaction of p-iodoacetophenone (1f) and 3-hydroxy-
1
it was clear that mono-coupled products were absent. The H-
NMR spectra of the crude and isolated products revealed no
acetylenes (8; for conditions see Table 1).
differences, apart from the absence of signals for non-converted
1f.
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Scheme 3 Sonogashira model reaction of p-iodoanisole (1e) with phenylacetylene (2a).
Influence of catalyst, base and grinding auxiliary
The reaction between p-iodoanisole (1e) and phenylacetylene
(2a; Scheme 3) was taken as a model reaction for investigation of
the influence of the amounts of catalyst Pd(OAc)2 and DABCO
on the conversion of 1e. This reaction shows medium conversion
under screening reaction conditions (Table 1), assuming that
influences of the above-mentioned variations should be easily
recognizable by changes in conversion.
The amount of Pd(OAc)2 was varied in the range of 1–5 mol%
related to p-iodoanisole (1e), whilst keeping other reaction
parameters constant (Fig. 1). A nearly linear dependence of the
conversion and the amount of Pd(OAc)2 can be observed, while
the selectivity is unaffected. The turnover-frequencies (TOF) for
the coupling reactions of aryl iodides 1a–f with phenylacetylene
listed in Table 1 range from 28 to 59 h-1. Compared to
previous studies of solvent-free Sonogashira reactions in ball
mills (TOF: ~2 h-1)9 the herein-reported reaction conditions are
advantageous due to short reaction times. Decreasing the Pd-
concentration to 1 mol% (Fig. 1) resulted in an increase of TOF
to 110 h-1, which is remarkable considering the fact that the
reaction has a strongly heterogeneous nature.
Fig. 2 Conversion of p-iodoanisole (1e; 2 mmol) in the coupling
reaction with phenylacetylene (2a; 2.5 mmol) for different amounts of
DABCO (reaction conditions: 5 mol% Pd(OAc)2, 5 g SiO2; ball milling:
agate beaker (45 ml), 6 ¥ agate balls (15 mm) per beaker, 800 rpm,
20 min).
this reaction, since no further increase of conversion for higher
amounts of DABCO were noticed.
Compared to other common amine bases like triethylamine
or diisopropylamine and inorganic bases, DABCO afforded
the highest conversions for the model reaction of 1e with 2a
(Table 4), which is in fact proof that DABCO is the best
choice for the Sonogashira coupling reaction under solvent-
free conditions.10 Only quinuclidine (1-azabicyclo[2.2.2]octane)
showed slightly higher conversion, which is a stronger base than
DABCO (pKa 11.0 compared to 8.8 and 3.0 for DABCO) and
has a similar chemical structure (Scheme 4). But compared
to DABCO, quinuclidine is much more expensive and toxic,
therefore DABCO is more applicable, particularly with regard
Table 4 Sonogashira reactiona in the presence of different bases for the
reaction of p-iodoanisole (1e) and phenylacetylene (2a)
Base
X(1e) [%]b
S(3e) [%]b
Fig. 1 Conversion of p-iodoanisole (1e; 2 mmol) in the coupling
reaction with phenylacetylene (2a; 2.5 mmol) for different amounts
of Pd(OAc)2 (reaction conditions: 2.5 mmol DABCO, 5 g SiO2; ball
milling: agate beaker (45 ml), 6 ¥ agate balls (15 mm) per beaker, 800
rpm, 20 min).
DABCO
66
27
12
73
13
28
—
—
—
—
98
99
99
97
99
99
—
—
—
—
Triethylamine
Diisopropylamine
Quinuclidine
K2CO3
KOH
TBAB
Triphenylamine
Tribenzylamine
4-Phenylmorpholine
Next, the amount of DABCO was varied between 0.5–3 molar
equivalents (1.25–7.5 mmol) relative to phenylacetylene (2a;
Fig. 2). The relationship to 2a was chosen as the determinant
parameter, because the base is responsible for abstraction of
the propargylic hydrogen from 2, 6, 8 or 10 (Schemes 1–3,
Tables 1–3). Similar to the effect described in Fig. 1, a nearly
linear dependence of conversion and amount of DABCO is
apparent, though the selectivities remain high. A 1.5-fold molar
excess (3.75 mmol) of DABCO seems to be an upper limit for
a Reaction conditions: 2 mmol p-iodoanisole (1e), 2.5 mmol phenyl-
acetylene (2a), 3.75 mmol base, 5 mol% Pd(OAc)2, 5 g SiO2, 800 rpm,
20 min, agate beaker (45 ml), 6 ¥ agate milling balls (15 mm).
b Determined with GC-FID measurements of extracted products in
relation to 1e.
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Table 6 Screening reactionsa of aryl halides (1) and phenylacetylene
(2a) using Pd(PPh3)4 as catalyst
Scheme 4 Structures of 1,4-diazabicyclo[2.2.2]octane (DABCO) and
of 1-azabicyclo[2.2.2]octane (quinuclidine).
to the principles of green chemistry (avoiding toxicity)1a,b,d,11 and
green engineering (avoiding high costs).1c,11
Furthermore, sterically hindered bases like triphenylamine or
tribenzylamine did not initiate any reaction. The inactivity of
these bases may be an indication that the base is intermittently
coordinated to the catalyst. Considering the fact that o- and
p-iodotoluene (1b,c) resulted in similar product yields upon
coupling with 2a (Table 1), the independence of the experimental
outcomes on the variation of substituents at 2a supports the
fact that the oxidative addition of the aryl iodide is the rate-
determining step. This step is obviously independent from the
nature of the base, allowing the conclusion that the latter
is responsible for the activation of the acetylene coupling
partner. However, an acetylene–DABCO adduct could not be
identified in the reaction mixture, but it could be concluded that
DABCO forms an addition product (probably DABCO·HI) at
the end of the reaction. The low conversions resulting from the
employment of bases other than DABCO (Table 4) emphasizes
its special role in Sonogashira reactions. In the case of other
Pd-mediated cross-coupling reactions, the main function of the
base is the interception of the HI molecules. In contrast, in
the case of the Sonogashira coupling a Lewis or Brønsted
basicity is essential for the abstraction of the acidic proton
in 2a.
Different grinding auxiliaries were tested for their influence
on the reaction of p-iodoanisole (1e) and phenylacetylene (2a;
Table 5). The use of CeO2 and TiO2 led to the same conver-
sions as for SiO2, whereas both neutral (g-modification) and
basic alumina (a-Al2O3) significantly increased the conversion.
The application of silica gel and KF–Al2O3 (32 wt% KF)
revealed an opposite trend concerning the transformation to
product 3e. This negative effect is in contrast to the results
reported for the solvent-free Suzuki–Miyaura reaction per-
formed using KF–alumina as a base and under ball milling
conditions.7c–e
Agate:
ZrO2:
Product Aryl halide (R)
Y
X(1) b[%] S(3) b X(1) b[%] S(3) b
3c
3e
3f
3a
3cc
3e
3f
1c (Me)
1e (MeO)
1f (Ac)
I
I
I
Br
Br
Br
24
26
35
4
1
3
99
98
99
98
98
99
99
98
99
99
99
99
71
61
52
97
99
99
98
98
99
98
99
98
98
97
98
1g (H)
1h (Me)
1i (MeO)
1j (Ac)
Br 34
3p
3q
1k (CF3)
1l (NO2)
Br 26
Br 94 (32)c
a Reaction conditions: 2 mmol aryl halide (1c,e–l), 2.5 mmol phenyl-
acetylene (2a), 2.5 mmol DABCO, 5 mol% Pd(PPh3)4, 5 g a-Al2O3
(basic), 800 rpm, 20 min, beaker (45 ml), 6 ¥ milling balls (15 mm).
b Determined with GC-FID measurements of extracted products in
relation to 1. c Pd(OAc)2 was used instead of Pd(PPh3)4.
Influence of copper, Pd(0) and grinding auxiliary
A very interesting result was obtained when the Sonogashira
reaction between 1e and 2a was performed in the presence of
5 mol% CuI in addition to the Pd(OAc)2. The conversion of
1e decreased by 10%, caused by the increasing conversion of
2a to the homo-coupling product 1,4-diphenylbuta-1,3-diyne
(Glaser reaction). Obviously, CuI has no positive influence on
the Sonogashira coupling mechanism itself under solvent-free
reaction conditions. It is also worth mentioning that only traces
of the coupling product 3e were achieved if 20 mol% of PPh3
was added to the reaction mixture (5 mol% Pd(OAc)2, 2.5 mmol
DABCO). However, only the respective phosphine oxide could
be detected after ball milling. Apparently, in situ formation of
Pd(PPh3)4 had not occurred. In contrast, the application of
5 mol% Pd(PPh3)4 (also containing 20 mol% of PPh3) instead of
Pd(OAc)2 resulted in the formation of the Sonogashira coupling
products, as indicated in Table 6. Bromides (1g–l) were also
suitable for coupling reactions when using this Pd-complex
in combination with basic a-Al2O3 as a grinding auxiliary, as
demonstrated by Mack and co-workers, before performing the
reaction in a 8000M SpexCertiprep (vibration ball mill).9 The
herein-presented reaction is also advantageous with respect to
the fact that no additional copper was required, and milling balls
or containers made of copper were not needed. Remarkably p-
nitro-bromobenzene (1l) showed the highest conversion under
the given conditions and was also suitable for coupling with
Pd(OAc)2, but with lower conversion than for Pd(PPh3)4.
Table 5 Sonogashira reactiona between p-iodoanisole (1e) and phenyl-
acetylene (2a) in the presence of different grinding auxiliaries
Base
X(1e) [%]b
S(3e) [%]b
SiO2 (fused quartz sand)
SiO2 (silica gel)
CeO2
58
25
58
59
83
85
45
99
99
98
99
99
99
99
TiO2
g-Al2O3 (neutral)
a-Al2O3 (basic)
KF–Al2O3 (32 wt% KF)
a Reaction conditions: 2 mmol p-iodoanisole (1e), 2.5 mmol phenyl-
acetylene (2a), 2.5 mmol DABCO, 5 mol% Pd(OAc)2, 5 g grinding
auxiliary, 800 rpm, 20 min, agate beaker (45 ml), 6 ¥ agate milling
balls (15 mm). b Determined with GC-FID measurements of extracted
products in relation to 1e.
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Table 7 Reactiona of p-iodobromobenzene (12) and phenylacetylene (2a)
Pd-source
Milling material
X(12) [%]b
S(13a) [%]b
S(13b) [%]b
S(13c) [%]b
S(13d) [%]b
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(PPh3)4
Agate
Agate
ZrO2
ZrO2
87
39
91
99
81
100
78
19
0
20
2
0
0
1
1
0
0
1
3
94
a Reaction conditions: 2 mmol p-iodobrombenzene (12), 2.5 mmol phenylacetylene (2a), 2.5 mmol DABCO, 5 mol% Pd, 5 g Al2O3 (basic), 800 rpm,
20 min, beaker (45 ml), 6 ¥ milling balls (15 mm). b Determined by GC-FID measurements of extracted products in relation to 12.
The application of milling tools made of copper or tungsten
carbide for Sonogashira reactions, as used in the literature,
would certainly enhance the energy required, due to the higher
kinetic energy of the milling balls. Indeed, the presence of
ZrO2 or agate is preferable, due to lower thermal stress which
could cause side reactions especially at longer reaction times,
e.g. dehalogenation of aryl halides. The data shown in Table 6
reveals the dependence of conversion on the density (weight)
of the milling material. ZrO2 milling balls again afforded
higher conversions, whereas the selectivity remained unchanged
compared to the employment of agate.
If the results for the aryl iodides with agate milling material
are compared with those of the screening reactions (Table 1), it
can be seen that Pd(OAc)2 is more effective for the coupling of
iodo-aromatics via ball milling than Pd(PPh3)4; not only with
respect to the reaction itself but also regarding economic (price)
and environmental issues (no bulky ligands).1a–d,11
Using this approach to perform an asymmetric coupling of
p-iodobromobenzene (12) with phenylacetylene (2a; Table 7),
the selectivity for the product 13a was significantly higher
for Pd(PPh3)4, but the conversion of 12 was distinctly lower
than with the application of Pd(OAc)2 as catalyst with agate
milling equipment. Surprisingly, the double-coupled product
1,4-bis(phenylethynyl)benzene (13b) is only formed with the use
of Pd(OAc)2 although Pd(PPh3)4 should be more reactive for the
conversions of aryl bromides, as shown for the conversion of p-
nitro-bromobenzene (3q, Table 6). As indicated in Tables 1 and
6, switching to higher-weight milling equipment (ZrO2) afforded
higher conversions of 12,7d,12 accompanied by a decreased
selectivity for 13a. Instead, noticeable amounts of de-iodinated
starting material (13c) and the corresponding Sonogashira
coupling product of 13c (13d) were found.
tion with 1,4-diazabicyclo[2.2.2]octane as a catalyst and base,
respectively, allowed for the chemoselective trasformation of
aryl iodides. All coupling reactions showed high selectivities
according to the desired Sonogashira products. Conversions of
aryl iodides were controllable via variation of either the amount
of Pd(II)-acetate or DABCO and showed good reproducibility.
Furthermore, DABCO showed higher efficiency than other
commonly used bases. Modification of the standard reaction
procedure by three different methodologies also allowed the
transformation of aryl bromides: i) substitution of Pd(OAc)2 by
Pd(PPh3)4, ii) replacement of agate milling beakers and balls by
higher-weight equipment made of ZrO2 or/and iii) employment
of alumina as filling material instead of fused quartz sand.
The avoidance of organic solvents and the easy, fast and
energy-saving accomplishment of the reaction makes this
method a real alternative to conventional reaction protocols,
especially in regard to the concept of green chemistry. This
was proven by the employment of unusual, but synthetically
important, substrates like 3-hydroxyalkynes or bis-ethynyl com-
pounds. The presence of terminal carbon–carbon triple and
double bonds in one molecule chemoselectively afforded the
Sonogashira coupling product, instead of the Mizoroki–Heck
coupling product.
Experimental
General
All chemicals were purchased from Sigma Aldrich or Alfa Aesar
and were used as received. Reactions were accomplished in
a Fritsch “Pulverisette 7 classic line” (Fritsch GmbH, Idar-
Oberstein, Germany) planetary ball mill using 45 ml grinding
beakers (agate, ZrO2) and milling balls (6 ¥ 15 mm; agate or
ZrO2). All reaction vessels were cleaned with aqua regia prior to
use to avoid any contamination or memory effects.
GC-FID measurements were performed on a 6890-GC and
GC-MSD measurements were accomplished with a 6890N-GC-
MS, both from Agilent Technologies. Measurement conditions
GC◦-FID: HP 5, 30 m ¥ 0.32 mm ¥ 0.25 mm, H2 10 psi, program:
70 C (hold for 3 min), 15 K min-1 up to 280 ◦C (hold for
Conclusions
An improved copper-, ligand-, and solvent-free experimental
protocol for the Sonogashira coupling of aryl halides with aryl-
and alkyl-substituted acetylenes in a planetary ball mill was
developed. The employment of air-stable Pd(OAc)2in combina-
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10 min), injector temperature: 280 ◦C, detector temperature:
300 ◦C. Measurement conditions GC-MSD: HP 5, 30 m ¥
0.32 mm ¥ 0.25 mm, He 10 psi, program: 70 ◦C (hold for 3 min),
15 K min-1 up to 280 ◦C (hold for 7 min), injector temperature:
280 ◦C, detector: EI (70 eV). NMR spectra were recorded with
a Bruker Avance 200 MHz system at room temperature in
deuterochloroform (CDCl3) as a solvent, using tetramethylsilane
as internal standard.
All product yields reported herein are calculated from GC-
data and are comparable with the isolated ones. Nevertheless,
the reported yields were corrected by means of different FID-
sensitivity for substrate and product. The reported yields are
mean values from at least two independent experimental runs.
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Typical reaction procedure for the Sonogashira coupling
The grinding beakers (45 ml; agate or ZrO2) were equipped
with 6 milling balls of the same material (d = 15 mm).
Afterwards SiO2 (= fused quartz sand; 5 g), the acetylene com-
pound (2.5 mmol), 1,4-diazabicyclo[2.2.2]octane (= DABCO;
2.5 mmol, 280 mg), the aryl halide (2 mmol) and Pd(OAc)2
(5 mol%, 25 mg) were added in the given order. Milling was
carried out at 800 rpm for 20 min. After cooling of the grinding
beakers to room temperature (10 min), the crude products were
extracted on a frit with a thin silica layer using chloroform
(3 ¥ 10 ml). The solvent was evaporated in vacuum, the crude
products were dried, re-dissolved in 1.5 ml of chloroform and
analyzed by GC-FID and GC-MS.
Analytical samples for NMR investigations were isolated
by column chromatography using a n-hexane–toluene mixture
(1 : 1) as the eluent. Products were identified according to the
literature data. For the analytical details of the isolated products,
see the ESI.†
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The Royal Society of Chemistry 2010
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