Sonogashira coupling of aryl halides catalyzed by palladium on charcoal

Article abstract of DOI:10.1021/jo034149f

With the proper choice of solvent, palladium on charcoal acts as an efficient catalyst in the Sonogashira cross-coupling reaction of aryl bromides. The catalytically active species in the process is probably palladium, which leaches into the solution but

Full text of DOI:10.1021/jo034149f

palladium and the active species is a dissolved pal-
ladium-triphenylphosphane complex. There are also a
number of papers that report the use of Pd/C as a catalyst
in singular reactions, but they are usually limited to the
more reactive aryl iodides and 2-halopyridines.5,6
The potential advantages of the Pd/C catalyst system,
the ease of separation and facile recycling of the metal
and the low level (usually below 1 ppm) of metal
contamination3d in the product, suggest that an efficient
Sonogashira coupling protocol based on the use of the
Pd/C catalyst system and utilizing aromatic halides other
than iodides would be of major interest for both industrial
and academic applications.
Son oga sh ir a Cou p lin g of Ar yl Ha lid es
Ca ta lyzed by P a lla d iu m on Ch a r coa l
Zolta´n Nova´k,† Andra´s Szabo´,‡ J o´zsef Re´pa´si,‡ and
Andra´s Kotschy*,†
Department of General and Inorganic Chemistry,
Eo¨tvo¨s University, Pa´zma´ny Pe´ter s. 1/ A,
H-1117 Budapest, Hungary, and Ubichem Research, Plc.,
Pusztaszeri u. 59-67, H-1025 Budapest, Hungary
kotschy@para.chem.elte.hu
Received February 3, 2003
Of the factors governing the catalytic efficiency of the
Pd/C system in coupling reactions, the choice of solvent
was found to be crucial,3d,5e although its influence was
not examined in detail; therefore, our first reactions were
designed to study the effect of the solvent on the Pd/C-
catalyzed Sonogashira coupling. Electron-rich 4-bromo-
toluene (1) and the more reactive 3-bromopyridine (2)
were chosen as aryl halides,7 and the acetylene deriva-
tives included 3-butyne-1-ol (3a ), 1-hexyne (3b), and
2-methyl-3-butyn-2-ol (3c). The solvents used ranged
from the apolar toluene through dioxane to water, and
our base of choice was diisopropylamine. The aryl halide,
1.2 equiv of the alkyne, 5 mol % Pd (10 wt % on charcoal),
10 mol % PPh3,8 10 mol % CuI, and 1.2 equiv of
diisopropylamine were heated in an 80 °C oil bath for 24
h, and the conversions were determined by GC analysis
(Table 1).
The results clearly demonstrate the expected reactivity
difference between 4-bromotoluene (1) and 3-bromo-
pyridine (2), where the latter reached high conversion
in most cases. The comparison of the results in the
bromotoluene (1) series, on the other hand, shows some
interesting trends. The polarity of the solvent seems to
play an important role in the process. Addition of 5%
water to dioxane led to a significant increase in the
conversion, while in the dimethyl acetamide (DMA)
series, the effect was similar but less marked. It is also
interesting to note that reasonable conversions were
achieved also in water, except for the apolar 1-hexyne,
where the limited solubility of the reagent might hinder
Abstr a ct: With the proper choice of solvent, palladium on
charcoal acts as an efficient catalyst in the Sonogashira
cross-coupling reaction of aryl bromides. The catalytically
active species in the process is probably palladium, which
leaches into the solution but returns onto the surface of the
charcoal at the end of the reaction.
The palladium-catalyzed coupling of terminal acet-
ylenes with aryl and vinyl halides (the Sonogashira
reaction) is one of the important and widely used carbon-
carbon bond-forming reactions in organic synthesis.1 The
reaction generally proceeds in the presence of a homo-
geneous palladium catalyst, which makes the recovery
of the metal tedious if not impossible and might result
in high palladium contamination of the product. A way
to overcome these difficulties would be the use of a
heterogeneous palladium catalyst such as a solid-sup-
ported metal. The most readily available form of sup-
ported catalyst is palladium on charcoal, which is widely
used in heterogeneous hydrogenation processes and also
has a growing importance in carbon-carbon bond-form-
ing reactions.2,3 To the best of our knowledge, there is
only one comprehensive publication on the use of pal-
ladium/charcoal in the Sonogashira coupling,4 where the
authors claim that Pd/C serves only as a source of soluble
* Fax: +36-1-209-0602.
† Eo¨tvo¨s University.
‡ Ubichem Research, Plc.
(1) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467-4470. (b) Sonogashira, K. Comprehensive Organic Syn-
thesis; Trost, B. M., Fleming, I., Eds; Pergamon Press: Oxford, 1991;
Vol. 3, Chapter 2.4, pp 521-549 and references therein. (c) Bumagin,
N. A.; Sukhomlinova, L. I.; Luzikova, E. V.; Tolstaya, T. P.; Beletskaya,
I. P. Tetrahedron Lett. 1996, 37, 897-900. (d) Hundertmark, T.; Littke,
A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729-1731. (e)
Erdelyi, M., Gogoll, A. J . Org. Chem. 2001, 66, 4165-4169.
(2) Heck reaction: (a) Mehnert, C. P.; Weaver, D. W.; Ying, J . Y. J .
Am. Chem. Soc. 1998, 120, 12289-12296. (b) Khan, S. I.; Grinstaff,
M. W. J . Org. Chem. 1999, 64, 1077-1078. (c) Whitcombe, N., J .; Hii,
K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449-7476. (d) Hagiwara,
H.; Shimizu, Y.; Hoshi, T.; Suzuki, T.; Ando, M.; Ohkubo, K.; Yokoya-
ma, C. Tetrahedron Lett. 2001, 42, 4349-4351. (e) Djakovitch, L.;
Koehler, K. J . Am. Chem. Soc. 2001, 123, 5990-5999.
(5) Other examples of singular Pd/C-catalyzed Sonogashira reactions
based on ref 4 are: (a) Potts, K. T.; Horwitz, C. P.; Fessak, A.;
Keshavarz-K, M.; Nash, K. E.; Toscano, P. J . J . Am. Chem. Soc. 1993,
115, 10444-10445. (b) Bleicher, L.; Cosford, N. D. P. Synlett 1995,
1115-1116. (c) Cosford, N. D. P. et al. J . Med. Chem. 1996, 39, 3235-
3237. (d) Bleicher, L. S.; Cosford, N. D. P.; Herbaut, A.; McCallum, J .
S.; McDonald, I. A. J . Org. Chem. 1998, 63, 1109-1118. (e) Felpin,
F.-X.; Vo-Thanh, G.; Villie´ras, J .; Lebreton, J . Tetrahedron: Asymmetry
2001, 12, 1121-1124. (f) Bates, R. W.; Boonsombat, J . J . Chem. Soc.,
Perkin Trans. 1 2001, 654-657. (g) Heidenreich, R. G.; Ko¨hler, K.;
Krauter, J . G. E.; Pietsch, J . Synlett 2002, 1118-1122. (h) Mori, Y.;
Seki, M. J . Org. Chem. 2003, 68, 1571-1574.
(6) For a solvent-free Sonogashira reaction catalyzed by Pd on
alumina, see: Kabalka, G. W.; Wang, L.; Namboodiri, V.; Pagni, R.
M. Tetrahedron Lett. 2000, 41, 5151-5154.
(7) Reagents were selected to provide a representative example both
in terms of reactivity and utility. Although aromatic iodides react more
readily under the applied conditions, aryl bromides are available in
far greater numbers and their use is more economical.
(3) Pd on charcoal in the Suzuki reaction: (a) Marck, G.; Villiger,
A.; Buchecker, R. Tetrahedron Lett. 1994, 35, 3277-3280. (b) Gala,
D.; Stamford, A.; J enkins, J .; Kugelman, M. Org. Process Res. Dev.
1997, 1, 163-164. (c) Ennis, D. S.; McManus, J .; Wood-Kaczmar, W.;
Richardson, J .; Smith, G. E.; Carstairs, A. Org. Process Res. Dev. 1999,
3, 248-252. (d) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J . R.,
J r. Org. Lett. 2001, 3, 1555-1557. (e) Sakurai, H.; Tsukuda, T.; Hirao,
T. J . Org. Chem. 2002, 67, 2721-2722.
(8) Preliminary screening of common phosphorous-based ligands
showed that the catalytic system containing triphenylphosphine is not
inferior in terms of activity to phosphites, dppe, dppp, dppb, or dppf.
(4) De la Rosa, M. A.; Velarde, E.; Guzman, A. Synth. Commun.
1990, 20, 2059-2064.
10.1021/jo034149f CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/13/2003
J . Org. Chem. 2003, 68, 3327-3329
3327

TABLE 1. Solven t-Dep en d en t Con ver sion s in th e
P d /C-Ca ta lyzed Son oga sh ir a Cou p lin g of Ar yl Br om id es
(1, 2) a n d Acetylen es 3a -c
isolated by column chromatography. The isolated yields
varied considerably from good in the case of 3-pyridyl-
acetylenes (5a -c)10 to moderate to poor in the case of
tolylacetylenes. The change of 2-bromopyridine to 2-chlo-
ropyridine led only to a minor decrease in the isolated
yields (cf. entries 1, 3, 13, and 14). This result suggests
that the significant difference between conversions and
yields in the bromotoluene series might be attributed to
the enhanced lability of the intermediate arylpalladium
species rather than the decomposition of the product on
elongated heating. Despite its presence and identification
by GC-MS, we were unable to isolate any of the 4-cy-
anophenyl-acetylene 12b (entry 15).
After the demonstration of the applicability of pal-
ladium on charcoal in the Sonogashira coupling of aryl
bromides, there are still a number of questions to be
answered about the process. (i) Can we recycle the
catalyst without the deterioration of its activity? (ii) What
is the optimal palladium-to-ligand ratio? (iii) Where does
the catalytic cycle work, on the surface or in solution?
aqueous
aqueous
DMA
toluene dioxane dioxane DMA
H2O
1
1
1
2
2
2
3a
3b
3c
3a
3b
3c
74
16
4
100
100
46
20
13
6
99
53
15
44
39
34
100
93
97
85
73
76
86
90
84
71
100
100
84
69
37
98
96
54
92
100
92
TABLE 2. P d /C-Ca ta lyzed Son oga sh ir a Cou p lin g of Ar yl
Ha lid es a n d Acetylen es in DMA-Wa ter
2-Bromopyridine (6) and 2-methyl-3-butyn-2-ol (3c)
were reacted for 24 h using the standard conditions,11
and after the reaction mixture was allowed to cool to
ambient temperature, the amount of the palladium in
the solution was established as only 1.8% of the original
by atomic absorption measurements.12 After filtration,
washing with water, acetone, and DCM, and drying, the
catalyst was mixed with the reagents, base, ligand, and
cocatalyst and the process was repeated four more times
giving 100, 86, 82, 72, and 68% conversions, respectively.
Another question we addressed is the optimal ligand-
to-catalyst ratio in the process. Study of the reaction of
6 and 3c under standard conditions demonstrated, that
the conversion depends markedly on the amount of ligand
added: from the 0.5, 1, 2, 3, 4, and 5 equiv of PPh3 to Pd
used, the first three runs (0.5, 1, and 2 equiv) gave
significantly higher rates with the maximal efficiency
observed with a P:Pd ratio of 1:1. Increasing the phos-
phine level above a certain “saturation” limit (P:Pd > 2:1)
leads to no major change in the activity; only the “free
phosphine” concentration of the solution increases sharply,
as observed by the increase of its GC signal.
The mechanism of catalytic processes utilizing a het-
erogeneous palladium source has frequently been dis-
puted in the literature recently.12,13 The central question
of the debate is whether the palladium stays on the
support or dissolves before the catalytically active species
is formed. Examination of the homogeneous equivalent
of our process by changing Pd/C to palladium acetate
under the same reaction conditions shows a similar
behavior: variation of the amount of phosphine between
0 and 5 equiv leads to a maximum in efficiency at a P:Pd
a
b
Isolated yields are given in parenthesis. 0.6 equiv of alkyne
added after 24 h.
the process. Our solvent of choice for further studies was
DMA containing 5% water, in which the observed reac-
tion rates were comparable to the analogous homoge-
neous reactions.
To check the applicability of the DMA-water solvent
system, a range of aromatic halides, from the highly
reactive 2-bromopyridine (6) to the least reactive 4-chloro-
benzonitrile (9), were reacted with simple alkynes (3a -
c) (Table 2). The reactions were run on a 10 mmol scale
and driven to (near) completion. In cases where conver-
sion did not reach 90% after 24 h (entries 8, 10, 11, and
14), another 0.6 equiv of the alkyne was added,9 which
achieved the desired effect in all but one case (entry 15).
Following an aqueous workup, the desired products were
(9) In slower reactions, the competing copper-catalyzed dimerization
of the alkyne consumes the reagent before the completion of the
Sonogashira coupling.
(10) In certain cases, the reactions were also repeated on a 100 mmol
scale and the products were isolated in similar yield using distillation.
(11) For details, see Supporting Information.
(12) Recent results suggest that the amount of palladium in solution
might further be reduced by the addition of sodium formate at the
end of the process. For details, see: Ko¨hler, K.; Heidenreich, R. G.;
Krauter, J . G. E.; Pietsch, J . Chem. Eur. J . 2002, 8, 622-631.
(13) (a) Zhao, F.; Shirai, M.; Ikushima, Y.; Arai, M. J . Mol. Catal.
A: Chem. 2002, 180, 211-219. (b) Augustine, R. L.; O’Leary, S. T. J .
Mol. Catal. A: Chem. 1995, 95, 277-285 and references therein.
3328 J . Org. Chem., Vol. 68, No. 8, 2003

ratio of 2, and reactions run with a higher phosphine
ratio than 2 are significantly slower.11 Contrary to the
Pd/C-catalyzed processes, we see a slow coupling in the
absence of phosphine, too.
reuse the catalyst (although with limited success). Our
studies also revealed that the catalytic cycle runs in the
solution and that Pd/C acts most likely only as a source
of palladium in the process. These findings suggest that
by using solid-supported palladium in coupling reactions,
one might be able to exploit the benefits of homogeneous
catalysis but still retain the ease of heterogeneous
catalyst separation.
A series of experiments were run using 5 mol % Pd/C
and 10 mol % PPh3, and the solids in the reaction
mixtures were separated from the hot solutions by
filtration under argon after 1, 4, and 10 min reaction
times, respectively. The filtrates were returned to the oil
bath, while a mixture of starting materials, base, cocata-
lyst, and ligand was added to each filtered sample.11,14
All of the isolated Pd/C samples showed catalytic activity,
although slightly smaller than the original catalyst,
showing that minor amounts of palladium might have
leached from the support.11 The catalytic activity of the
filtrates, on the other hand, was not affected by the
removal of the solid-supported palladium. The reactions
proceeded uninterrupted, although they stopped at around
80% conversion.11
These results unambiguously prove that the palladium
that leaches into the solution is catalytically active, which
means that Pd/C is most likely not the active form but
the source of palladium in the process. The comparable
catalytic activity of the filtered Pd/C and the solution also
suggests that only a minor portion of the bound pal-
ladium is released into the solution.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P d /C-Ca ta lyzed Son oga sh ir a
Cou p lin g of Ar yl Ha lid es. A dry Schlenk flask was charged
with 0.512 g of Pd/C (0.5 mmol Pd), 0.192 g (1 mmol) of CuI,
and 0.262 g (1 mmol) of PPh3, followed by 9.5 mL of DMA and
0.5 mL of water. After the addition of 10 mmol of aryl halide,
2.1 mL of diisopropylamine, and 12.8 mmol of the appropriate
acetylene, the reaction mixture was purged with argon, sealed,
and placed in an 80 °C oil bath for 24 h. After the mixture was
cooled to ambient temperature, the charcoal was filtered off and
water was added to the solution. The aqueous phase was
extracted with diethyl ether, and the combined organic phases
were dried over magnesium sulfate. After removal of the solvent
in a vacuum, the crude products were purified by column
chromatography.
Ack n ow led gm en t. The authors thank Dr. K. Tor-
kos for providing the necessary analytical background.
The financial support of the Hungarian Ministry of
Education (FKFP-0125/2001) and Ubichem Research,
Plc., is gratefully acknowledged.
In summary, we established that palladium on char-
coal is an efficient catalyst in the Sonogashira coupling
of aryl bromides in polar solvents. By using this sup-
ported form of palladium, the metal contamination of the
reaction mixture was less than 2% and we were able to
Su ppor tin g In for m ation Available: Details of the mecha-
nistic studies as well as characterization data and literature
references for the products illustrated in Table 2. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) Sheldon, R. A.; Wallau, M.; Arends, I. W. C. E.; Schuchardt, U.
Acc. Chem. Res. 1998, 31, 485-493.
J O034149F
J . Org. Chem, Vol. 68, No. 8, 2003 3329