A straightforward copper-free palladium methodology for the selective alkynylation of a wide variety of S-, O-, and N-based mono- and diheterocyclic bromides and chlorides

Article abstract of DOI:10.1016/j.tet.2009.06.009

High-yield alkynylations are successfully achieved by a simple and widely accessible catalytic system for an unprecedented variety of heterocyclic bromides and chlorides in position -2, -3 or -5: pyridine, quinoline, thiophene, furan, thiazole, benzothiazole, pyrimidine, pyridazine, pyrazine, dioxepin halides are efficiently functionalized in short time reactions. This copper-free methodology employs 1 mol % palladium only, with inexpensive PPh₃ and amine base. The ionic liquid solvent allows a straigtforward separation of products and recycling opportunity. Unsuitable substrates and secondary reactions are also reported in order to point out further progress in cross-coupling using ionic liquids.

Full text of DOI:10.1016/j.tet.2009.06.009

Tetrahedron 65 (2009) 7146–7150
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Tetrahedron
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A straightforward copper-free palladium methodology for the selective
alkynylation of a wide variety of S-, O-, and N-based mono- and
diheterocyclic bromides and chlorides
*
Samer Saleh, Michel Picquet, Philippe Meunier, Jean-Cyrille Hierso
Universite´ de Bourgogne, Institut de Chimie Mole´culaire de l’Universite´ de Bourgogne UMR-CNRS 5260, 9 avenue Alain Savary 21078 Dijon, France
a r t i c l e i n f o
a b s t r a c t
Article history:
High-yield alkynylations are successfully achieved by a simple and widely accessible catalytic system for
an unprecedented variety of heterocyclic bromides and chlorides in position -2, -3 or -5: pyridine,
quinoline, thiophene, furan, thiazole, benzothiazole, pyrimidine, pyridazine, pyrazine, dioxepin halides
are efficiently functionalized in short time reactions. This copper-free methodology employs 1 mol %
palladium only, with inexpensive PPh3 and amine base. The ionic liquid solvent allows a straigtforward
separation of products and recycling opportunity. Unsuitable substrates and secondary reactions are also
reported in order to point out further progress in cross-coupling using ionic liquids.
Received 13 May 2009
Accepted 4 June 2009
Available online 10 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
hydroboration, cyclization, etc.).1,3i Another limitation comes from
a disinclination to employ sophisticated ligands, which are gen-
The palladium-catalyzed cross-coupling between sp2-hybrid-
ized carbon atoms (Csp2) of aryl, heteroaryl, and vinyl halides and
sp-hybridized carbon atoms of terminal acetylenes (Csp) pertains
to the family of powerful synthetic methods for the convergent
synthesis of important organic intermediates.1,2 The attractiveness
of these cross-coupling reactions has led to successful methodol-
ogy development for enynes, enediynes, polyynes, ynones, car-
bocycles, heterocycles, natural products and even nanostructured
macromolecule synthesis.3 In the last years, much work has been
done on metal/ligand catalytic systems with notable success using
tandem palladium/copper catalysts (Sonogashira reaction),4 or
palladium/copper-free systems (Heck alkynylation, often called
copper-free Sonogashira),5 and even copper/palladium-free sys-
tems (inspired by Ullmann’s chemistry).6 Despite these consider-
able improvements obtained by employing a great variety of new
catalysts and conditions, it remains surprising that practical ap-
plications of these procedures are still limited. A thorough analysis
of the literature shows, for instance, that no general and accessible
procedure dedicated especially to heterocycle alkynylation is
available.1,7 It is all the more unexpected that a substantial number
of current pharmaceutical drugs and agrochemicals are based on
heterocyclic scaffolds.3j Moreover, the reactivity of the alkyne
function opens the way to many valuable subsequent chemical
transformations (hydrogenation, oxydation, hydroamination,
erally more efficient but less accessible in terms of cost or han-
dling. Clearly, most of the practical catalyzed heterocycle
alkynylations are still effected and reported from aryl iodide
substrates in the presence of triphenylphosphine as auxiliary li-
gand.1 Sustainable extension of such kind of alkynylations is thus
directly concerned with a generalization of couplings from bro-
mide and chloride analogs,8 as well as the minimization of metal/
ligand catalysts amounts or its reuse.2 The methodology presented
herein describes a simple method for alkynylation of a variety of
S-, O-, and N-based heterocycles using a widely accessible system.
The choice of an ionic liquid as solvent is due to their potential as
valuable environmentally friendly alternative to conventional or-
ganic solvents, in part owing to their negligible vapor pressure.9
We chose 1-n-butyl-3-methylimidazolium tetrafluoroborate
[BMIM][BF4] as an efficient and ‘lowest-price’ ionic liquid10 to
anticipate further development in recycling or continuous-flow
processes.11 Another priority in the development of useful general
methodologies should be the systematic identification of side-
products formed and the determination of the scope of reaction
from problematic substrates;12a these tasks, which are usually not
necessarily addressed, are emphasized in the present report.
2. Results and discussion
We had previously explored the Heck alkynylation (copper-free
Sonogashira) with aryl halides (I, Br, Cl) by employing various
metallic precursors (palladium, nickel salts) and tertiary
* Corresponding author. Tel.: þ33 3 80 39 61 06; fax: þ33 3 80 39 36 82.
E-mail address: Jean-Cyrille.Hierso@u-bourgogne.fr (J.-C. Hierso).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.009

S. Saleh et al. / Tetrahedron 65 (2009) 7146–7150
7147
phosphines (PPh3, dppf, dppe, tri and tetraphosphines, ligand-free)
and bases (amines, carbonates) in [BMIM][BF4] as solvent.12b,c,4i As
a result, we provided the first method allowing to couple a large
array of unactivated and deactivated aryl bromides in ILs. The best
system was the simple and cheaper combination using [Pd/3PPh3]
at only 1 mol % loading with 1.2 equiv of base and in the absence of
copper salt. We thus decided to investigate the potential of this
system for heteroaromatics alkynylation. Preliminary results
revealed that both temperature and reaction time are crucial pa-
rameters that differ from our previous studies.12b Table 1 summa-
rizes the optimized conditions determined for the copper-free
alkynylation of a variety of five and six-membered heteroaryl
bromides incorporating one or two nitrogen, sulfur or oxygen
heteroatoms. 2-Bromopyridine is quantitatively coupled to phe-
nylacetylene in 2.75 h at 100 ꢀC (entry 1). At higher temperature
(130 ꢀC) or beyond 3 h of reaction time, the hydroamination of the
formed 2-(phenylethynyl)pyridine by the excess of pyrrolidine is
observed.13 3-Bromopyridine and 3-bromoquinoline are also effi-
ciently coupled to phenylacetylene in 4 h (entries 2, 3). Therefore,
the halogenated position is not specifically problematic and the
hindrance or electronic effect of quinoline fused-rings does not
limit the coupling.14
We were delighted to obtain clean and quantitative alkynylations
of the five-membered O- and S-heteroaromatic 3-bromofuran and 3-
bromothiophene with our system (entries 4, 5),13 since formerly
reported results underlined the failure of many systems involving
either PPh3 or more sophisticated ligands.7f,15 Higher temperature
and longer time are mandatory to couple 3-bromofuran. A first
genuine limitation appeared from the S,N-diheteroaromatic 2-
bromothiazole: in the presence of pyrrolidine, a coupling of this
base to thiazole was observed in majority. However, the selectivity
towards (phenylethynyl)thiazole, which is then obtained in 72%
yield, can be restored by using the tertiary base NEt3 (entry 6).16 The
coupling of N-diheteroaromatic pyrimidine bromides in position -2
and -5 is easier and proceeds smoothly in 4 h (entries 7, 8). For
a selective coupling of 2-bromopyrimidine, NEt3 is also required to
avoid the predominant coupling of pyrrolidine to pyrimidine.13 Our
system was also successfully employed for alkynylation of a dihy-
dro-2H-[1,5]benzodioxepin derivative as a much less studied sub-
strate of industrial interest (entry 9).17 Possibly due to basic
conditions or temperature, heterocyclic substrates such as bro-
molactone, bromoindole, bromopyrrazole, bromo-uracil and bro-
moisoxazole were found to be more challenging since either no
coupling or reagent decomposition was observed.
Table 1
Heteroaryl bromides alkynylation with phenylacetylene
0.5% [Pd(allyl)Cl]2
3% PPh3
1.2 equiv Base
HetAr
HetAr-Br +
[BF4]-
Me
N
N
Bu
100 °C
Entrya
1
Heteroaryl
bromide
Base/time (h)
Product
Yieldb
%
100 (95)c
100 (93)c
Br
Br
Pyrrolidine/2.75
Pyrrolidine/4
N
N
2
N
N
With regard to the relevant results obtained in alkynylation of
bromides, we decided to investigate the alkynylation of heteroaryl
chlorides. Table 2 sums up the successful results obtained under
conditions similar to the ones optimized for bromides. As already
observed,7a,g and contrary to the case of bromides, the heteroaryles
halogenated in position -3 were found unreactive (3-chloropyr-
idine, 3-chlorothiophene). Conversely, the coupling of
3
4
5
Pyrrolidine/4
Pyrrolidine/4
Pyrrolidine/7d
98 (92)c
100 (95)c
100
Br
N
N
Br
Br
S
S
Table 2
Heteroaryl chlorides alkynylation with phenylacetylene
O
O
Entrya
Heteroaryl
chloride
Base
Product
Yield %
100
N
S
N
S
Cl
N
1
Pyrrolidine
6
7
8
NEt3/6.5
72
Br
Br
Br
N
N
N
Cl
2
3
4
5
NEt3
NEt3
NEt3
100 (95)
92 (68)
100
N
N
N
N
N
Pyrrolidine/4
98 (92)c
N
N
Cl
S
N
S
N
N
NEt3/4
99
N
N
N
S
N
S
Cl
O
O
9
Pyrrolidine/4.5
100 (80)c
N
N
Br
O
O
NEt3
NEt3
98 (73)
Cl
N
a
N
Reaction conditions: 0.5 mol % [Pd(allyl)Cl]2 catalyst, 3 mol % PPh3, 1.0 equiv aryl
bromide, 1.2 equiv of phenylacetylene, 1.2 equiv of base, 3 mL [BMIM][BF4], 100 ꢀC.
b
Me
N
N
N
N
Me
Yields based on aryl bromides (average of two runs), determined by GC (external
6
100 (95)
O
Cl
O
standard); isolated yields obtained after chromatography on silica column reach
80–95% of these values.
c
a
Isolated yield.
Same conditions as Table 1, 4 h, 1.0 equiv aryl chloride.
d
120 ꢀC.

7148
S. Saleh et al. / Tetrahedron 65 (2009) 7146–7150
Table 4
phenylacetylene to mono- and diheteroaromatics chlorinated in
a position adjacent to the heteroatom proceeds smoothly (entries
1–6).18 Thus, 2-chloropyridine and 2-chloropyrazine are quantita-
tively coupled (entries 1, 2). To our delight, the selectivity of
2-chlorothiazole coupling is much improved compared to the bro-
mide analogue (92% vs 72%), speculatively because of a less com-
petitive nucleophilic substitution of the halogenide by the amine,
and 2-chlorobenzothiazole19 is an even more suitable substrate
(entries 3, 4). N-Diheteroaromatics pyrimidine and pyridazine were
also very efficiently coupled (entries 5, 6) and we were very pleased
to obtain in a remarkably high yield and clean reaction, the elec-
tron-enriched 3-(phenylethynyl)-6-methoxypyridazine.20
Having demonstrated that a notable variety of heteroaryl bro-
mides and chlorides can be efficiently alkynylated with phenyl-
acetylene, we examined the scope of this methodology for other
terminal alkynes. Under identical conditions, a representative se-
lection of the previously used heterocycles was reacted with
a short chain and a long chain aliphatic acetylenic (respectively 1-
hexyne and 1-decyne); the excellent results obtained are reported
in Table 3.13
Alkynylations with subsequent recycling experiments
Entrya Heteroaryl halide
Product
Yieldb
100
%
Recycling
yieldb
%
Br
Br
1
2
98
N
N
100
98
99
98
N
N
3
Br
N
N
4
5
100
98
99
Br
Br
Cl
S
S
N
N
N
N
100
6
7
100
100
75
54
Table 3
N
N
Alkynylations with aliphatic short- or long-chain alkynes
Entrya
Heteroaryl
halide
Time (h)
Product
Yieldb
100
%
O
O
Br
O
O
1
4
Br
S
n-Bu
n-Bu
S
N
a
Same conditions as Table 1 for each run, including base and reaction time.
Yields determined by GC.
b
Br
2
10
45
N
3. Conclusion
3
4
5
10
4
100
100
98
Br
n-Bu
To conclude, the activation of more atom-economic halides in
replacement of iodides, combined with the use of recyclable non-
volatile ILs solvents may give a significant impetus towards a more
N
N
Br
S
n-Octyl
n-Octyl
n-Octyl
,
21
sustainable and cost-efficient chemical industry,9k especially if
reduced amounts of metal (1 mol % or less) are used in combination
with lower cost ligands and bases. The present catalytic system is
probably relevant in this concern.
S
4
Br
O
O
4. Experimental
4.1. Generality
Br
6
4
4
100
100
N
N
7
All reactions and workup procedures were performed under
inert atmosphere of argon using conventional vacuum-line and
glasswork techniques. The solids (catalyst and reagents) and the
ionic liquid (IL) were degassed under vacuum before use. The or-
ganic and organometallic products were received from commercial
sources and used without further purification. Chromatography
was performed on silica gel (230–400 mesh, Merck Kieselgel 60).
GC, GC–MS, and NMR experiments were performed on Shimadzu
GC-2014, Hewlett-Packard HP-6890 series and Bruker Avance 300,
respectively.
Br
n-Octyl
N
N
a
Same conditions as Table 1, pyrrolidine as base.
Yields based on aryl bromides (average of two runs) determined by GC.
b
Quantitative conversions were attained in 4 h with decyne,
while longer reaction times were needed to couple the more vol-
atile 1-hexyne, probably because of its tendancy to form a vapor
phase out of the IL. The only co-products detected in all cases are
the enyne dimerization products from the alkyne in excess,12c,13 yet
this reaction does not hamper in any manner the coupling of het-
eroaryl bromides. Finally, we decided to take profit of the
[BMIM][BF4] solvent to evaluate the recycling opportunities (Table
4) with excellent to moderate success since the recycling of chlo-
rides or bromobenzodioxepin was less effective. While the possi-
bility of recycling was proven, room for progress is still possible in
terms of ILs immobilized system, as shown by the detection from
GC–MS of O]PPh3 in the extracted organic phases, as already
reported by us.12b
4.2. Representative catalytic experiment for the Heck
alkynylation reaction in [BMIM][BF4]
The ionic liquid [BMIM][BF4] was synthesized following the
method described in the literature.22 This ionic liquid is also com-
mercially available (see for instance www.iolitec.de or www.sol-
vionic.com). The solid mixture of [Pd(allyl)Cl2] (4.5 mg,
0.0244 mmol of Pd), triphenylphosphine (19.1 mg, 0.0732 mmol)
was degassed for 15 min in a 20 mL Schlenk tube equipped with

S. Saleh et al. / Tetrahedron 65 (2009) 7146–7150
7149
Synthesis 2004, 1281; (l) Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett.
2004, 45,1603; (m) Lemhadri, M.; Doucet, H.; Santelli, M. Synthesis 2005, 1359; (n)
Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron 2005, 61, 9839; (o) Brenstrum,
T.; Clattenburg, J.; Britten, J.; Zavorine, S.; Dyck, J.; Robertson, A. J.; McNulty, J.;
Capretta, A. Org. Lett. 2006, 8,103; (p) Nagamochi, M.; Fang, Y.-Q.; Lautens, M. Org.
Lett. 2007, 9, 2955.
5. For selected representatives examples see: (a) Bo¨hm, V. P. W.; Herrmann, W. A.
Eur. J. Org. Chem. 2000, 3679; (b) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.;
Dormer, P. G.; Hughes, D. L. Org. Lett. 2003, 5, 4191; (c) Gelman, D.; Buchwald, S.
L. Angew. Chem., Int. Ed. 2003, 42, 5993; (d) Djakovitch, L.; Rollet, P. Adv. Synth.
Catal. 2004, 346, 1782; (e) McGuinness, D. S.; Cavell, K. J. Organometallics 2000,
19, 741; (f) Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411; (g) Ma, Y.;
Song, C.; Jiang, W.; Wu, Q.; Wang, Y.; Liu, X.; Andrus, M. B. Org. Lett. 2003, 5,
a magnetic stirrer bar and a reflux condenser. Under argon were
added 3 mL of [BMIM][BF4]. The mixture was then degassed under
reduced pressure for another 10 min, then under argon was added
0.218 mL of 2-chloropyrazine (279.5 mg, 2.44 mmol, d¼1.284). The
Schlenk tube was heated in an oil bath at 60 ꢀC to give a yellow
solution. To the ionic liquid solution was added, out of the oil bath,
0.415 mL triethylamine (301 mg, 2.93 mmol, d¼0.726) then
0.321 mL phenylacetylene (299 mg, 2.93 mmol, d¼0.93). The
resulting mixture was heated at 100 ꢀC for 4 h under argon. The
product was extracted from the ionic liquid phase by the addition of
diethylether (six times 5 or 10 mL) and decanting off the ether from
´
´
¨
3317; (h) Najera, C.; Gil-Molto, J.; Karlstrom, S.; Falvello, L. R. Org. Lett. 2003, 5,
1451; (i) Gil-Molto´, J.; Na´jera, C. Eur. J. Org. Chem. 2005, 4073; (j) Feuerstein, M.;
Doucet, H.; Santelli, M. Tetrahedron Lett. 2004, 45, 8443; (k) Alonso, D. A.;
Na´jera, C.; Pacheco, M. C. Tetrahedron Lett. 2002, 43, 9365; (l) Alonso, D. A.;
Na´jera, C.; Pacheco, M. C. Adv. Synth. Catal. 2003, 345, 1146; (m) Koma´romi, A.;
the ionic phase (GC yield 100%). After evaporation the residue was
1
purified by silica gel chromatography (ethyl acetate/heptane:
⁄
4
first, then pure ethyl acetate to recover pure product) to give
420 mg of 2-(phenylethynyl)pyrazine (2.33 mmol, isolated yield
95%).
´
Novak, Z. Chem. Commun. 2008, 4968.
6. For selected representatives examples see: (a) Okuro, K.; Furuune, M.; Miura,
M.; Nomura, M. Tetrahedron Lett. 1992, 33, 5363; (b) Okuro, K.; Furuune, M.;
Miura, M.; Nomura, M. J. Org. Chem. 1993, 58, 4716; (c) Gujadhur, R. K.; Bates,
C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315; (d) Bates, C. G.; Saejueng, P.;
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Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843; (f) Ma, D.; Liu, F. Chem.
Commun. 2004, 1934; (g) Kang, S.-K.; Yoon, S.-K.; Kim, Y.-M. Org. Lett. 2001, 3,
2697; (h) Li, J.-H.; Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.; Zhang, M.-B.; Hu,
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Zhang, M.-B. J. Org. Chem. 2007, 72, 6294; (j) Monnier, F.; Turtaut, F.; Duroure,
L.; Taillefer, M. Org. Lett. 2008, 10, 3203; (k) Plenio, H. Angew. Chem., Int. Ed.
2008, 47, 6954.
7. Efficient methodologies tested on a large variety of heteroaromatics are very
scarce and employ sophisticated ligands and/or copper co-catalyst, see: (a)
Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2005, 46, 1717; (b)
Feuerstein, M.; Doucet, H.; Santelli, M. J. Mol. Catal. A. 2006, 256, 75; (c) Yang, F.;
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P.; Sharma, A.; Van der Eycken, E. Org. Lett. 2008, 6, 1147; (e) Wu, M.; Mao, J.;
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Zapf, A.; Spannenberg, A.; Bo¨rner, A.; Beller, M. Chem.dEur. J. 2009, 15, 1329. see
also Ref. 2b.
4.3. Recycling experiment for the Heck alkynylation reaction
in [BMIM][BF4]
The reaction were carried out and worked-up under the same
conditions employed for the first runs. After extraction with
diethylether of the first run, the resulting dark colored ionic liquid
was recovered and reused without any pre-treatment (no water
washing), but degassed under reduced pressure for 1 h. The tube
was refilled with the heteroarylhalide, heated up to 60 ꢀC, then was
added the base and the alkyne. Same temperature and reaction
times were employed.
Acknowledgements
8. For instance, 2-iodopyridine (98%) is found around 45.5ꢁ102 V/mol, 2-bro-
mopyridine (99%) 0.9ꢁ102 V/mol, and 2-chloropyridine (99%) 0.2ꢁ102 V/mol,
from small-scale commercial sources (Sigma–Aldrich 2009 lowest prices).
9. (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b) Wasserscheid, P.; Keim, W. Angew.
Chem., Int. Ed. 2000, 39, 3772; (c) Sheldon, R. Chem. Commun. 2001, 2399; (d)
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We are grateful to CNRS and CP2D program ‘Chimie Pour le
De´veloppement Durable’ for financial support of this work. S.S.
´
thanks the Universite de Bourgogne and the Institute of Molecular
Chemistry (ICMUB) for a PhD grant. The authors are also grateful to
S. Royer and M. Beauperin (ICMUB) for their help in daily work.
Supplementary data
1H NMR spectra, GC chromatograms and MS data of the cou-
pling products and of some relevant byproducts. Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2009.06.009.
10. [BMIM][BF4] is among the three cheapest ILs sold by Iolitec from a library of
500 ionic liquids of all current classes.
11. Relevant examples are described: (a) Fukuyama, T.; Shinmen, M.; Nishitani, S.;
Sato, M.; Ryu, I. Org. Lett. 2002, 4, 1691; (b) Park, S. B.; Alper, H. Chem. Commun.
2004, 1306; (c) Kroon, M. C.; Hartmann, D.; Berkhout, A. J. Ind. Eng. Chem. Res.
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2006, 3283.
13. See GC and mass spectrum in Supplementary data.
14. In Ref. 7e this coupling of 3-bromoquinoline is specially tricky (23% yield of
3-(phenylethynyl)quinoline in 24 h at 130 ꢀC).
15. (a) In Ref. 7f the alkynylation of 3-bromofuran with the activated TMSacetylene
from Pd/PPh3 in TMEDA as base and solvent in the presence of CuI is prob-
lematic (65% yield in 20 h at 80 ꢀC). (b) Most often 2-halothiophenes couplings
are reported, in Ref. 7b is underlined that 3-halothiophenes are more chal-
lenging susbtrates since, as electron-excessive heterocycles, thiophenes are
more sensitive to halogen position.
16. Secondary products are thiazole dimerization and Et2N–thiazole coupling see
Supplementary data, possibly due to nucleophilic attack at the C2.
17. (a) Gobbi, L. C.; Gubler, M.; Neidhart, W.; Nettekoven, M. H. PCT Int. Appl., WO
2005044814, 2005, according to this report dihydro-2H-[1,5]benzodioxepin
derivatives would be useful as inhibitors of human acetyl-coenzyme A carb-
oxylase (ACC), and stimulate fatty acid oxidation in liver and muscle, which
might make them suitable as drugs for diabetes, obesity and dyslipidemia. (b)
In perfumery, 7-methyl-2H-benzo-[1,5]-dioxepin-3-one, by Pfizer, is a marine
4. For selected representative examples see: (a) Thorand, S.; Krause, N. J. Org.
Chem. 1998, 63, 8551; (b) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C.
Org. Lett. 2000, 2, 1729; (c) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295; (d)
Ko¨llhofer, A.; Plenio, H. Adv. Synth. Catal. 2005, 347, 1295; (e) Ko¨llhofer, A.;
Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed. 2003, 42, 1056; (f) Anderson, K.
W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44, 6173; (g) Adjabeng, G.;
Brenstrum, T.; Frampton, C. S.; Robertson, A. J.; Hillhouse, J.; McNulty, J.; Cap-
retta, A. J. Org. Chem. 2004, 69, 5082; (h) Hierso, J.-C.; Fihri, A.; Amardeil, R.;
Meunier, P.; Doucet, H.; Santelli, M. Tetrahedron 2005, 61, 9759; (i) Hierso, J.-C.;
Fihri, A.; Amardeil, R.; Meunier, P.; Doucet, H.; Santelli, M.; Ivanov, V. V. Org.
Lett. 2004, 6, 3473; (j) Feuerstein, M.; Berthiol, F.; Doucet, H.; Santelli, M. Org.
Biomol. Chem. 2003, 1, 2235; (k) Feuerstein, M.; Berthiol, F.; Doucet, H.; Santelli, M.
fragrance called Calone 1951Ò
.
18. See reference 6i, in this study an active and reusable system based on 10 mol %
[Cu2O/2PPh3] and excess of n-Bu4NBr gives only moderate yields of (phenyl-
ethynyl)-diheteroaromatics from bromides (43% from 2-Br-thiazole, 46% from 2-

7150
S. Saleh et al. / Tetrahedron 65 (2009) 7146–7150
Br-pyrimidine, 48% from 2-Br-pyrazine) or from some heteroaromatic chlorides
Igeta, H. Chem. Pharm. Bull. 1980, 28, 3488 (49% from chloride); (b) Draper, T. L.;
Bailey, T. R. J. Org. Chem. 1995, 60, 748 (67% from iodide).
21. Reinhardt, D.; Ilgen, F.; Kralisch, D.; Ko¨nig, B.; Kreisel, G. Green Chem. 2008,
10, 1170.
22. Suarez, P. A. Z.; Einloft, S.; Dullius, J. E. L.; de Souza, R. F.; Dupont, J. Polyhedron
1996, 15, 1271.
(19% from 2-Cl-pyridine), showing the challenges related to these couplings
19. From2-iodobenzothiazole onlya41% yieldwas reported forthis reactionwith Pd/
CuI: Kumar, D.; David, W. M.; Kerwin, S. M. Bioorg. Med. Chem. Lett. 2001, 11, 2971.
20. No system was reported, up to now, for this synthesis from aryl chloride in the
absence of Cu, and only moderate yield was obtained: (a) Osawa, A.; Abe, Y.;