Rapid, easy copper-free Sonogashira couplings using aryl iodides and activated aryl bromides

Article abstract of DOI:10.1016/j.tetlet.2003.09.159

We present here an easy, rapid copper-free methodology for the Sonogashira coupling reaction. It works well for a range of aryl iodides and activated aryl bromides.

Full text of DOI:10.1016/j.tetlet.2003.09.159

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8653–8656
Rapid, easy copper-free Sonogashira couplings using aryl iodides
and activated aryl bromides
Nicholas E. Leadbeater* and Bonnie J. Tominack
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
Received 23 July 2003; revised 12 September 2003; accepted 19 September 2003
Abstract—We present here an easy, rapid copper-free methodology for the Sonogashira coupling reaction. It works well for a
range of aryl iodides and activated aryl bromides.
© 2003 Elsevier Ltd. All rights reserved.
The Sonogashira reaction (palladium and copper co-
catalyzed coupling of terminal alkynes with aryl and
vinyl halides) is one of the most widely used C–C bond
forming reactions.1,2 It provides an efficient route to
aryl alkynes, which are interesting intermediates for the
preparation of a variety of target compounds with
applications ranging from natural products3 and
pharmaceuticals4 to molecular organic materials5 Due
to the use of the products, the development of new
catalyst systems has received considerable attention.
The reaction is generally carried out in organic solvents
such as benzene, toluene, THF, DMF and dioxane. It
requires a base, which is usually an amine such as
triethylamine, diethylamine, diisopropylethylamine.
The most widely used catalysts are Pd(PPh3)2Cl2 or
Pd(PPh3)4 in conjunction with copper(I) iodide. The
reaction has been applied to vinyl halides, aryl iodides
and bromides and, exceptionally, aryl chlorides.
also be adapted to use in conjunction with aqueous
solvent mixtures by using an ammonium salt as a
phase-transfer agent.13,14 A copper-free coupling of aryl
iodides with terminal alkynes has also been reported
using an ionic liquid as a solvent.15 This enables easy
separation of the product from the catalyst-ionic liquid
system, which could then be reused. Recently, an amine
and copper free methodology for the Sonogashira reac-
tion has been presented.16 A palladacycle catalyst and
an additive, tetrabutylammonium acetate, are
employed.
The problems with many of these copper-free method-
ologies however are that either high palladium catalyst
loadings have to be used or else the reaction has to be
performed under anaerobic conditions using palladium
complexes or ligands that are expensive or hard to
make. We wanted to develop an easy, quick copper-free
methodology for the Sonogashira reaction that uses
readily available palladium complexes and can be run
in air and without having to pre-dry reagents and
without the need for any solvent.
In the case of aryl iodides and vinyl halides, the Sono-
gashira reaction can sometimes be carried out under
mild conditions, possibly at room temperature, but
generally the reaction times are relatively long.6 The use
of higher temperatures and the presence of copper
favours side reactions of the terminal acetylenes.7,8 One
way around this problem is to develop a copper-free
methodology. There have been a number of recent
reports of this, most involving the use of an amine,
such as piperidine, triethylamine or pyrrolidine, as a
solvent,9,10 or in large excess.11,12 These methods can
As a starting point for the development of the method-
ology we chose to study the coupling of phenyl-
acetylene with 4-iodoanisole. Our optimisation data are
shown in Table 1. We found that using 4 mol%
Pd(PPh3)2Cl2 as the catalyst and 3.0 equiv. of piperidine
as a base it was possible to obtain a quantitative yield
of product within 10 min by dipping the reaction
mixture into an oil bath pre-heated to 70°C (Table 1,
entry 1). We then varied the base and catalyst loading.
Triethylamine and pyrrolidine gave good product yields
(Table 1, entries 2 and 3). No product was obtained
using mineral bases with or without the use of water
Keywords: Sonogashira; palladium; aryl iodides; aryl bromides; cop-
per-free.
* Corresponding author. Tel.: +44 20 7848 1147; fax: +44 20 7848
2810; e-mail: nicholas.leadbeater@kcl.ac.uk
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.159

8654
N. E. Leadbeater, B. J. Tominack / Tetrahedron Letters 44 (2003) 8653–8656
Table 2. Screening of conditions for the Sonogashira cou-
and a phase-transfer catalyst (Table 1, entries 4 and 5).
We found that when using piperidine the catalyst load-
ing can be lowered to 2 mol% without any significant
decrease in product yield in the 10 min reaction time
but this could be lowered further to 1 mol% if the time
was extended to 15 min and to 0.5 mol% of the time
was extended to 20 min (Table 1, entries 6–8). As an
extension of our studies, we tried using phosphine-free
sources of palladium as catalysts in conjunction with
our copper-free conditions but had no success with
palladium acetate or palladium on charcoal. We also
tried using palladium on charcoal in the presence of
triphenylphosphine, a catalyst system known to work in
the presence of copper,17 but found that it does not
work in the absence of copper.
pling of bromoarenes with phenylacetylenea
Having optimized the reaction conditions for aryl
iodides we turned our attention to aryl bromides.
Results are shown in Table 2. From a screen of the
reaction between phenylacetylene and 4-bromoace-
tophenone, 4-bromotoluene and 4-bromoanisole with 4
mol% Pd(PPh3)2Cl2 as the catalyst and 3.0 equiv. of
piperidine as the base, it was possible to see that the
copper-free conditions worked only for the case of the
activated substrate (Table 2, entries 1–3). A 99% yield
of the desired product was formed within 10 min using
4-bromoacetophenone. With this in mind, we focused
on the coupling of phenylacetylene and 4-bromoace-
tophenone and investigated the effects of decreasing the
catalyst loading. We found that reduction of the cata-
lyst loading to 3 mol% led to a product yield of 82%,
increasing the reaction time to 15 min increased the
yield to 91% (Table 2, entries 4 and 5). A 96% yield of
product was obtained after 20 min using 2 mol% cata-
lyst and a yield of 73% obtained after 30 min using 1
mol% (Table 2, entries 6 and 7). Using 0.5 mol%
catalyst gave only a 46% yield after 1 h (Table 2, entry
8).
We screened a representative range of aryl iodides and
activated bromides in the reaction, the results being
shown in Table 3. For the aryl iodides we used 2 mol%
of catalyst, piperidine as the base and a reaction time of
10 min.18 We chose aryl iodides from across the spec-
trum of those bearing electron-donating and electron-
withdrawing substituents (Table 3, entries 1–8). For the
aryl bromides we focused on activated examples and
used the same conditions but increased the catalyst
loading to 4 mol% (Table 3, entries 9–12).19 All the
reactions were performed in air and using reagents
without any further purification. As there is no copper
present, we do not have the problems often encoun-
tered of homo-coupling of the alkyne substrate and
hence do not need to take any particular precautions in
this regard such as, for example, running the reactions
under a hydrogen atmosphere.20
Table 1. Screening of conditions for the Sonogashira cou-
pling of 4-iodoanisole with phenylacetylenea
Entry
Base
Catalyst
loading
(mol%)
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
Piperidine
NEt3
4
4
4
4
4
2
1
0.5
10
10
10
10
10
10
15
20
>99
>99
>99
0
Pyrrolidine
Na2CO3
c
Na2CO3
0
Piperidine
Piperidine
Piperidine
>99
>99
>99
The results show that the methodology is applicable to
a range of aryl iodide and activated aryl bromide
substrates with good product yields being obtained.
The exception to this is 2-iodotoluene (Table 3, entry 4)
where we believe that steric congestion may be a prob-
lem although this is somewhat surprising in light of the
fact that 2-iodobenzylalcohol couples smoothly (Table
3, entry 8). We also screened representative aryl iodide
a Reactions were run using 1 mmol 4-iodoanisole, 1 mmol phenyl-
acetylene and 3 mmol base. The reaction mixture was placed in a
pre-heated oil bath at 70°C and held there for the allotted time.
b Not isolated.
c With 0.2 mL water and 1 mmol tetrabutylammonium bromide.

N. E. Leadbeater, B. J. Tominack / Tetrahedron Letters 44 (2003) 8653–8656
8655
Table 3. Screening of conditions for the Sonogashira coupling of 4-iodoanisole with phenylacetylenea
with phenylacetylene was repeated on a 10 mmol scale
with a product yield of 99% being obtained (Table 3,
entry 22).21
substrates using the lower catalyst loading of 0.5 mmol
and a reaction time of 20 min to show that this is
applicable to the range of aryl iodides from those
bearing electron-donating substituents through to those
containing electron-withdrawing ones (Table 3, entries
13–15). We then wanted to expand the methodology for
use with aliphatic alkynes so screened as examples
trimethylsilylacetylene and 1-hexyne. With these we
found that the higher catalyst loading is required in
order for the reaction to reach completion within a
short time (Table 3, entries 16–21).
The closest similar methodology to ours (and indeed
the one on which ours builds) is that of Linstrumelle
and co-workers.10 In their paper they present the cop-
per-free coupling of iodobenzene, bromobenzene and
two vinyl halides with a number of alkynes. They use a
high palladium loading (5 mol% Pd(PPh3)4) and the
reactions are run under anaerobic conditions. They also
use the base as a solvent and reaction times for the
arene substrates vary from 2 to 25 h. We repeated their
methodology but using 4-iodoacetophenone and phenyl-
To show that the reaction can be scaled up without
compromising the yield, the reaction of 4-bromotoluene

8656
N. E. Leadbeater, B. J. Tominack / Tetrahedron Letters 44 (2003) 8653–8656
acetylene as substrates. We obtained a 79% yield of
product after 18 h. Our methodology is certainly easier,
faster and requires less catalyst. Although the substrate
scope of aryl bromides is not as wide as that of Bohm
and Herrmann11 or Najera and co-workers,16 compari-
son shows that for aryl iodide substrates our method is
certainly faster and easier.
9. Pal, M.; Parasuraman, K.; Gupta, S.; Yeleswarapu, K. R.
Synlett 2002, 1976.
10. Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett.
1993, 34, 6403.
11. Bo¨hm, W. P. W.; Herrmann, W. A. Eur. J. Org. Chem.
2000, 3679.
12. Heidenreich, R. G.; Ko¨hler, K.; Krauter, J. G. E.;
Pietsch, J. Synlett 2002, 1118.
In conclusion, we have developed a methodology for
easy and rapid copper-free Sonogashira couplings. The
methodology has the advantage of short reaction times,
ease of reaction and the use of a readily available
palladium complex. The quantity of amine used is
much less than previously reported for copper-free pro-
tocols. Attempts to develop the methodology further
and increase its scope are currently underway in our
laboratory.
13. Nguefack, J.-F.; Bolitt, V.; Sinou, D. Tetrahedron Lett.
1996, 37, 5527.
14. Uozumi, Y.; Kobayashi, Y. Heterocycles 2003, 59, 71.
15. Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.;
Ryu, I. Org. Lett. 2002, 4, 1691.
16. Alonso, D. A.; Na´jera, C.; Pacheco, M. C. Tetrahedron
Lett. 2002, 43, 9365.
17. Nova´k, Z.; Szabo´, A.; Re´pa´si, J.; Kotschy, A. J. Org.
Chem. 2003, 68, 3327.
18. Procedure for coupling aryl iodides to alkynes: In a 10 mL
glass tube was placed aryl iodide (1.0 mmol), alkyne (1.0
mmol), piperidine (0.3 mL, 3 mmol), PdCl2(PPh3)2 (14
mg, 0.02 mmol) and a magnetic stir bar. The vessel was
sealed with a septum and placed in an oil bath pre-heated
to 70°C and held there for 10 min. After this time, the
reaction vessel was opened and the contents poured into
a separating funnel and the tube washed with water and
then with ether, these washings being added to the sepa-
rating funnel. Further water and diethyl ether (20 mL of
each) were added and the organic material extracted and
then washed with acid (15% v/v HCl) until the washings
were neutral. The organic layer was again washed with
water (40 mL) before being dried over MgSO4 and the
ether removed under vacuum leaving the crude product.
Products were characterized by comparison of 1H and
13C NMR spectra with those of authentic samples or in
the literature and yields determined by NMR with refer-
ence to a known quantity of an internal standard.
19. Procedure for coupling aryl bromides to alkynes: In a 10
mL glass tube was placed aryl bromide (1.0 mmol),
Acknowledgements
The Royal Society is thanked for a University Research
Fellowship (NEL).
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