On the catalytic duo PdCl2(PPh3)2/AuCl(PPh3) that cannot effect a Sonogashira-type reaction: a correction

Article abstract of DOI:10.1016/j.tetlet.2009.11.003

In contrast to the observation made by the Laguna group, we report that the combination of PdCl₂(PPh₃)₂ and AuCl(PPh₃) makes a unique catalytic system that allows Sonogashira-type cross-coupling of both aryl and alkyl alkynes with aryl halides in excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.11.003

Tetrahedron Letters 51 (2010) 301–305
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Tetrahedron Letters
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On the catalytic duo PdCl2(PPh3)2/AuCl(PPh3) that cannot effect
a Sonogashira-type reaction: a correction
*
Biswajit Panda, Tarun K. Sarkar
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2009
Revised 28 October 2009
Accepted 2 November 2009
Available online 5 November 2009
In contrast to the observation made by the Laguna group, we report that the combination of PdCl2(PPh3)2
and AuCl(PPh3) makes a unique catalytic system that allows Sonogashira-type cross-coupling of both aryl
and alkyl alkynes with aryl halides in excellent yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Among all the carbon–carbon bond forming reactions now in
use, the Sonogashira reaction undeniably occupies the numero
uno position in terms of its efficiency for accessing aryl alkynes
and conjugated enynes, which are prevalent intermediates for
the synthesis of a diverse array of natural products, pharmaceuti-
cals, and molecular organic materials.1 The traditional experimen-
tal procedure involves PdCl2(PPh3)2 as a Pd(0) precursor and CuI as
a co-catalyst in a solution containing amine bases.2 The CuI is re-
cally ineffective (<1% conversion) even in the case of an electron-
poor aryl iodide, namely 4-iodoacetophenone (Scheme 1). These
authors suggest that the inactivity of AuCl(PPh3) is due to its high
stability under the experimental conditions thus making it a poor
pre-catalyst, whereas AuCl(tht) displays its activity since it can
easily lose tht ligand and this may lead to the formation of the ac-
tive catalyst in solution.
As part of a broader program on the unique reactivity of Pd–Au
dual catalytic systems,8 we have had cause to reinvestigate the
Sonogashira-type cross-coupling of 4-iodoacetophenone with
phenylacetylene using a combination of PdCl2(PPh3)2 and AuCl
(PPh3) under strictly Laguna and co-worker’s conditions. The result
was dramatic (Scheme 1): the product alkyne was obtained in
excellent yield (92%) (96% conversion)!9 Equally surprising was
the observation that omission of the co-catalyst still gives the
product in 54% isolated yield. Our results are, therefore, in conflict
with those reported by the Laguna group. However, it is not easy to
explain the reason for this difference.
In order to probe the synthetic scope of this gold co-catalyzed
Sonogashira-type reaction, it was deemed important to optimize
the reaction conditions by using different bases and solvents, as
well as changing the reaction temperature. We chose the cross-
coupling of bromobenzene with phenylacetylene as the model
reaction and the results are presented in Table 1. Clearly, the cata-
lytic system is not powerful enough to allow the reaction in THF at
ambient temperature; heating to reflux was needed in this case
although prolonging the reaction time beyond 4 h did not show
any effect on the yield of the reaction. The reaction also takes place
in water or triethylamine, but the yields are unsatisfactory. Finally,
going from THF through MeCN, DMSO, and DMF, and changing
bases from Et3N to K2CO3 allowed identification of PdCl2(PPh3)2/
AuCl(PPh3) in DMF/DMA in the presence of Et3N as the efficient
catalytic system for the cross-coupling of bromobenzene
quired to activate the alkynes as p-acid. Over the years, some alter-
natives to the CuI co-catalyst have been developed in order to
overcome the problems emanating from competitive homocou-
pling to the diyne. These include employing stoichiometric
amounts of silver oxide or tetrabutylammonium salts3 as activa-
tors or use of palladium-only procedures.4 Clearly, the develop-
ment of a new co-catalyst other than CuI which will not allow
homocoupling as a side reaction is desirable.
During the last decade or so, cationic phosphine–gold(I) com-
plexes have found extensive use as versatile and selective catalysts
for a growing number of synthetic transformations.5,6 The alkyno-
philicity of cationic Au(I) species is superior to that of other coin-
age metals, for example, Cu and Ag. It is conceivable that
replacement of Cu(I) co-catalyst by cationic gold(I) would not only
promote the Sonogashira-type cross-coupling of aryl halides with
alkynes but due to extreme resistance of gold compounds to oxida-
tion, these reactions are unlikely to be accompanied by the usual
Hay/Glaser type products which are frequently observed in copper
co-catalytic processes. Indeed, very recently Laguna and co-work-
ers7 have demonstrated that the catalytic systems PdCl2(PPh3)2/
Na(AuCl4) and PdCl2(PPh3)2/AuCl(tht) (tht = tetrahydrothiophene)
can give good results (ꢀ95%) for electron-deficient aryl iodides
(two examples) and aryl bromides (two examples), but for bromo-
benzene yields drop to 5% and 26%, respectively. Furthermore, use
of a different gold co-catalyst AuCl(PPh3) was shown to be practi-
Under our optimized reaction conditions, we accomplished
Sonogashira-type cross-coupling of a wide array of electronically
and structurally diverse aryl halides (Table 2).10 With respect to
* Corresponding author. Tel.: +91 03222283330.
E-mail address: tksr@chem.iitkgp.ernet.in (T.K. Sarkar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.003

302
B. Panda, T. K. Sarkar / Tetrahedron Letters 51 (2010) 301–305
O
1% PdCl2(PPh3)2
H3C
1% AuCl(PPh3)
NH(i-Pr)2, THF
rt, 14h
<1% conversion ( Laguna et al.)7
96% conversion (this work)
O
I
+
H3C
54% (isolated yield) a
1% PdCl2(PPh3)2
NH(i-Pr)2, THF
rt, 14h
a
Scheme 1. ꢀ7% of Hay/Glaser-type homocoupling product was also formed in this reaction.
Table 1
Effect of reaction conditions on the cross-coupling of bromobenzene with phenylacetylenea
2 % PdCl2(PPh3)2 /
2 % AuCl(PPh3)
+
Br
Entry
Solvent
Base
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
THF
THF
H2O
Et3N
Toluene
MeCN
DMSO
DMF
DMF
DMA
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
Et3N
rt
Reflux
80
80
80
80
80
80
80
8
4
12
6
6
4
3
3
3
3
nr
81
40
67
33
84
89
96
79
96
10
80
a
Reactions were run in 3 ml solvent with 1 mmol bromobenzene, 1.1 mmol phenylacetylene, and 3 mmol base.
Isolated yield.
b
Table 2
Coupling of aryl halides with terminal alkynes
2% PdCl2(PPh3)2/
2% AuCl(PPh3)
Aryl
R
R
H
+
X
Aryl
Et3N, DMF
X= Br, I
Entry
1
ArX
Products
Temp (°C)
Time (h)
0.75
Yielda,b (%)
93
O
O
I
60
Me
Me
2
3
70
70
0.5
98
92
I
Me
I
Me
0.75
OH
Me
Me
I
4
80
1
98
Me
Me
Br
Br
5
6
80
80
3
3
91
96
OH

B. Panda, T. K. Sarkar / Tetrahedron Letters 51 (2010) 301–305
303
Table 2 (continued)
Entry
ArX
Products
Temp (°C)
Time (h)
3
Yielda,b (%)
Me
Br
Br
Me
7
8
80
80
91
94
OH
3
7
Me
Me
OMe
Br
OMe
9
80
91 (42)
Br
10
11
12
80
80
90
7
7
9
93
MeO
MeO
MeO
MeO
94
Br
MeO
MeO
Br
MeO
MeO
90(27)
OMe
OMe
Br
13
90
9
93(29)
MeO
Me
MeO
Me
14
15
80
80
5
4
70c,d
CO2Me
Br
NH2
Br
NH2
62
F
Br
16
17
18
19
80
80
80
80
3
3
4
4
92e,f
F
Br
Br
91
Br
OH
Ph
Ph
Ph
Ph
91
Br
Br
89
OH
Me
Me
Me
Me
Br
20
90
6
86
a
Isolated yield.
b
Yields in parentheses refer to those using CuI in place of AuCl(PPh3).
Cs2CO3 was used instead of Et3N.
60% of the coupled product was isolated when K2CO3 was used as a base.
Replacement of AuCl(PPh3) by (IPr)AuCl gives the product in 94% yield in 1.5 h.
1% PdCl2(PPh3)2/1% AuCl(PPh3) and a reaction time of 5 h gave the product in 89% yield.
c
d
e
f
the aryl bromides11 and iodides,12 both electron-neutral and elec-
tron-poor species react with alkynes to provide the products in
excellent yields (Table 2, entries 1, 2, 5, and 6). Electron-rich aryl
halides (Table 2, entries 3, 7, and 8) are amenable to this protocol;

304
B. Panda, T. K. Sarkar / Tetrahedron Letters 51 (2010) 301–305
Me
2%PdCl2(PPh3)2
DMF, 70 oC, 1h
Ph3PAu
Me
(
+
(
)
2
)
2
O
O
I
1
2
79%
Scheme 2.
however, more remarkable is that even extremely electron-rich
systems (Table 2, 9–13) couple efficiently with alkynes. This meth-
od is also tolerant of ortho-substitution in aryl bromides (Table 2,
entries 16–19). Even the highly sterically hindered aryl halides (Ta-
ble 2, entries 4 and 20) couple with alkynes without any difficul-
ties. Notably, amino groups are tolerated under these conditions
as shown by the reaction of 2-bromoaniline, which is converted
into the corresponding 2-substituted products (Table 2, entry
15). Alkynes containing an electron-withdrawing group (directly
attached with the ethynyl carbon) are usually poor substrates for
the coupling with aryl halides.13 It is gratifying to note that this
catalytic system allows such a coupling with methyl propiolate, al-
beit in modest yield (Table 2, entry 14). Incidentally, for this
reaction use of a carbonate base (e.g., K2CO3 and Cs2CO3) was
essential since in the presence of NEt3 complete destruction of
the acetylene source was observed. Interestingly, several examples
(Table 2, entries 3, 5, 7, 17, and 19) where alkyl alkynes are found
to couple efficiently with aryl halides are also in conflict with Lagu-
na and co-worker’s finding that the gold co-catalysts used in their
work are much more efficient in activating aryl alkynes than alkyl
alkynes.7
In conclusion, we have demonstrated that the reportedly inac-
tive dual catalytic system PdCl2(PPh3)2/AuCl(PPh3) allows efficient
Sonogashira-type cross-coupling of aryl bromides and iodides. Fur-
ther work is underway in this laboratory to investigate the full
scope of this dual catalytic process involving even the challenging
aryl chlorides as one of the partners and also to unveil the detailed
mechanism of alkyne activation in this reaction.
Acknowledgments
This work was supported by DST and CSIR, Government of India.
B.P. is grateful to CSIR, Government of India, for a Senior Research
Fellowship. The NMR facility was supported by the FIST program of
the DST.
Supplementary data
General experimental procedure and full spectroscopic data for
compounds 1 and 2 are available. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.11.003.
As previously noted by Laguna and co-workers.7 no traces of
Hay/Glaser type homocoupling of alkynes could be observed
(TLC) in any of the reactions described in Tables 1 and 2 which
were essentially clean. Furthermore, independent experiments
were carried out to see the role of Pd and Au separately in these
reactions. While the gold complex AuCl(PPh3) was found to be to-
tally inactive in the absence of the palladium complex
PdCl2(PPh3)2, the latter alone led to the formation of the coupled
product (Table 2, entry 5) in 18% yield. The Pd-Au dual catalytic
reactions are also possible with lower catalytic loadings, although
longer reaction times are needed for efficient conversions. For
example, in entry 16 (Table 2) with 1% Pd(PPh3)2Cl2/1%AuCl(PPh3)
the product was obtained in 89% isolated yield after a reaction time
of 5 h. Incidentally, the assumption made by Laguna and co-work-
ers7 to explain the inactivity of AuCl(PPh3) in terms of lesser pro-
pensity for the dissociation of the phosphine ligand seems
untenable in view of our observation that replacement of the phos-
phine ligand by strongly bonded N-heterocyclic carbene ligand (IPr
NHC) still gives the product (Table 2, entry 16) in high yield (94%).
It should be noted that the strong metal–carbenic bond of the NHC
complex favors tight-binding kinetics, therefore lessening ligand
dissociation.14 We have also compared the results of the Sonogash-
ira coupling in the presence of the Pd–Au catalytic system with
those obtained under classical conditions, that is, in the presence
of CuI, and amine (under identical conditions as in Table 2 with
the replacement of AuCl(PPh3) by CuI). In these cases (Table 2, en-
tries 9, 12, and 13) yields as given in parentheses are woefully low,
the predominant by-product being the Hay/Glaser type homocou-
pling product (31–44%).
References and notes
1. For recent reviews on Sonogashira reaction, see: (a) Doucet, H.; Hierso, J.-C.
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9365; (c) Mery, D.; Heuze, K.; Astruc, D. Chem. Commun. 2003, 1934; (d) Soheili,
A.; Albaneze-walker, J.; Murry, J. A.; Dormer, P. G.; Hughes, D. L. Org. Lett. 2003,
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2005, 3, 387; (b) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395; (c) Hashmi, A. S.
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Chem. Rev. 2008, 108, 3395; (h) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev.
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6. Salts or nano-particles of gold also promote Sonogashira-type reactions, see:
(a) Gonzalez-Arellano, C.; Abad, A.; Corma, A.; Garcla, H.; Iglesias, M.; Sanchez,
F. Angew. Chem., Int. Ed. 2007, 46, 1536; (b) Li, P.; wang, L.; Wang, M.; You, F.
Eur. J. Org. Chem. 2008, 35, 5946.
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2008, 130, 2168; (b) Duschek, A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2008, 47,
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9. Preparation of 1-(4-(phenylethynyl)phenyl)ethanone under strictly Laguna’s
condition:74-Iodoacetophenone
(369 mg,
1.5 mmol),
phenylacetylene
(0.25 mL, 2.25 mmol), and NH(i-Pr)2 (0.33 mL, 2.25 mmol) were stirred in
THF (3 mL) under argon. [PdCl2(PPh3)2] (10.5 mg, 0.015 mmol) was added and
the mixture was stirred for 10 min before the addition of [AuCl(PPh3)] (7 mg,
0.015 mmol). The mixture was stirred at room temperature for 14 h, then it
was diluted with diethyl ether (5 ml), and filtered through a small Celite bed.
The filtrate was poured into water and the aqueous layer was extracted with
diethyl ether (10 mL Â 3). The combined organic layer was dried over
anhydrous Na2SO4, and the solvent was evaporated under reduced pressure.
The product was isolated by chromatography on a silica gel column, 304 mg
(92%); also isolated was 4-iodoacetophenone, 17 mg (4%).
On the basis of the Pd–Ag catalyzed coupling reaction reported
by Pale and co-workers15 it may be assumed that gold acetylides
are intermediates in our case and these organogold compounds en-
ter into the Pd catalytic cycle. Indeed, preliminary work already fa-
vors this mechanism as we have found that the preformed gold
acetylide 1 gives the coupled product 2 in 79% isolated yield unac-
companied by any Hay/Glaser type product (Scheme 2).16,17
10. General procedure for the Pd–Au dual catalytic Sonogashira-type cross-
coupling.A flame-dried two-necked flask, equipped with a reflux condenser,

B. Panda, T. K. Sarkar / Tetrahedron Letters 51 (2010) 301–305
305
gas inlet/outlet, and rubber septum, was evacuated and backfilled with argon
(the cycle was performed twice) and then charged under a positive pressure of
argon with aryl halides (1 mmol), DMF(3 mL), PdCl2(PPh3)2 (14 mg,
0.02 mmol), base (3 mmol), followed by AuCl(PPh3) (10 mg, 0.02 mmol) and
terminal acetylenes (1.1 mmol). Then the reaction mixture was heated at
mentioned temperature and time. It was diluted by diethyl ether (3 ml) and
filtered through a small Celite bed. The filtrate was poured into water and the
aqueous layer was extracted with diethyl ether (10 mL Â 3). The combined
organic layer was dried (Na2SO4) and the solvent was evaporated under
reduced pressure. The product was isolated by chromatography on a silica gel
column.
12. (a) Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 3291; (b) Gil-
Molto, J.; Najera, C. Eur. J. Org. Chem. 2005, 19, 4073; (c) Alonso, D. A.; Najera, C.;
Pacheco, M. C. Adv. Synth. Catal. 2003, 345, 1146; (d) Mio, M. J.; Kopel, L. C.;
Braun, J. B.; Gadzikwa, T. L.; Hull, K. L.; Brisbois, R. G.; Mrkworth, C. J.; Grieco, P.
A. Org. Lett. 2002, 4, 3199.
13. Radhakrishnan, U.; Stang, P. J. Org. Lett. 2001, 3, 859.
14. Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290.
15. Halbes, U. L.; Pale, P.; Berger, S. J. Org. Chem. 2005, 70, 9185.
16. This work was presented in NOST conference on May 4, 2009 at Goa, India.
17. During the preparation of the revised manuscript, a similar coupling involving
transmetalation from organogold(I) compounds to palladium has come to our
notice: Hashmi, A. S. K.; Lothschutz, C.; Dopp, R.; Rudolph, M.; Ramamurthi, T.
D.; Rominger, F. Angew. Chem., Int. Ed. 2009, 48, 8243.
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1729; (b) Kollhofer, A.; Plenio, H. Adv. Synth. Catal. 2005, 347, 1295; (c) der
Heiden, M. A.; Plenio, H. Chem. Commun. 2007, 972; (d) Batey, R. A.; Shen, M.;
Lough, A. J. Org. Lett. 2002, 4, 141.