Gold and palladium combined for the Sonogashira coupling of aryl and heteroaryl halides

Article abstract of DOI:10.1055/s-0032-1318119

A highly efficient gold and palladium combined methodology for the Sonogashira coupling of a wide array of electronically and structurally diverse aryl and heteroaryl halides is described. The orthogonal reactivity of the two metals shows high selectivity and extreme functional group tolerance in Sonogashira coupling. A brief mechanistic study reveals that the gold acetylide intermediate enters into the palladium catalytic cycle at the transmetalation step. Georg Thieme Verlag Stuttgart.New York.

Full text of DOI:10.1055/s-0032-1318119

PAPER
▌817
pGapoerld and Palladium Combined for the Sonogashira Coupling of Aryl and
Heteroaryl Halides
Sonogashira Coupling of Aryl and Heteroaryl Halides
Biswajit Panda, Tarun K. Sarkar*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Fax +91(3222)282251; E-mail: tksr@chem.iitkgp.ernet.in
Received: 05.12.2012; Accepted after revision: 07.01.2013
per and silver. Thus it is conceivable that replacement of
the copper(I) co-catalyst by cationic gold(I) would not
only promote the Sonogashira-type cross-coupling reac-
tion of aryl halides with alkynes, but also the extreme re-
Abstract: A highly efficient gold and palladium combined method-
ology for the Sonogashira coupling of a wide array of electronically
and structurally diverse aryl and heteroaryl halides is described. The
orthogonal reactivity of the two metals shows high selectivity and
extreme functional group tolerance in Sonogashira coupling. A sistance of gold compounds to oxidation would mean that
brief mechanistic study reveals that the gold acetylide intermediate
enters into the palladium catalytic cycle at the transmetalation step.
these reactions are unlikely to be accompanied by the usu-
al Glaser-type products that are frequently observed in
Key words: gold catalysis, cross-coupling, Sonogashira coupling,
gold–palladium combined
copper co-catalytic processes. As there is an ongoing in-
terest in methods for C–C bond formation taking advan-
tage of the synergy between gold and palladium catalysts,
it occurred to us that the orthogonal reactivity of the two
Among all C–C bond-forming reactions now in use, the metals may show high selectivities in Sonogashira cou-
Sonogashira reaction1 undeniably occupies the number pling. Indeed, the first gold–palladium dual catalytic
one position in terms of its efficiency for accessing aryl- Sonogashira coupling of aryl halides was reported by
alkynes and conjugated enynes, which are prevalent inter- Laguna and co-workers10 The gold compounds AuCl(tht),
mediates for the synthesis of a diverse array of natural AuCl(PPh3), and Na[AuCl4] were used as co-catalysts in
products, pharmaceuticals, and molecular organic materi- Sonogashira-type cross-coupling reactions (tht = tetrahydro-
als.2 The traditional experimental procedure involves thiophene). In these reactions, phenylacetylene was used
PdCl2(PPh3)2 as a palladium(0) precursor and copper(I) as the alkyne source, tetrahydrofuran as the solvent, and
iodide as a co-catalyst in a solution containing an amine diisopropylamine as the base. It was found that Na[AuCl4]
base;3,4 copper(I) iodide is required to activate the alkynes and AuCl(tht) are efficient co-catalysts in palladium-cata-
as a π-acid. The addition of copper salts as co-catalysts in lyzed alkynylation reaction. Laguna et al. observed full
the typical Sonogashira cross-coupling is not without conversion for aryl iodides at room temperature and for
drawbacks. In particular, the in situ generation of copper activated aryl bromides under reflux conditions. On the
acetylides under the reaction conditions often gives rise to other hand, reactions with non-activated aryl bromides
homocoupling products of the terminal alkyne (the so- proceed in poor yields. They also reported that identical
called Glaser coupling),5 along with the main reaction experiments with hexyne in place of phenylacetylene also
product, upon exposure to oxidative agents or air. This gave poor yields (<10%), showing that the gold co-cata-
side reaction is especially undesirable when the terminal lysts used are much more efficient in activating aryl-
acetylene is difficult to obtain or expensive. Thus, over alkynes than alkylalkynes. Furthermore, use of a different
the years various alternatives to the copper(I) co-catalyst gold co-catalyst, AuCl(PPh3), was shown to be practically
have been developed in order to overcome the problems ineffective (<1% conversion) even in the case of an
emanating from competitive homocoupling to the diyne. electron-poor aryl iodide, 4-iodoacetophenone (1a)
These include employing stoichiometric amounts of silver (Scheme 1).
oxide or tetrabutylammonium salts6 as activators or the
As part of a broader program on the unique reactivity of
use of palladium-only procedures.7 Clearly, the develop-
Pd–Au dual catalytic systems,11 we have had cause to
ment of a new co-catalyst other than copper salts, e.g. cop-
reinvestigate12 the Sonogashira-type cross-coupling of 4-
per(I) iodide, that will not allow homocoupling as a side
iodoacetophenone (1a) with phenylacetylene using a
combination of PdCl2(PPh3)2 and AuCl(PPh3) strictly un-
reaction is desirable.
During the last decade, cationic phosphine–gold(I) com- der the conditions of Laguna and co-workers. The result
plexes have found extensive use as versatile and selective was dramatic (Scheme 1): the product alkyne 2a was ob-
catalysts for a growing number of synthetic transforma- tained in excellent yield (92%) (96% conversion)! Equal-
tions.8,9 The alkynophilicity of cationic gold(I) species is ly surprising was the observation that omission of the co-
superior to that of other coinage metals, for example, cop- 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 rea-
son for this difference.
SYNTHESIS 2013, 45, 0817–0829
Advanced online publication: 15.02.2013
0
0
3
9
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7
8
8
1
1
4
3
7
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2
1
0
X
DOI: 10.1055/s-0032-1318119; Art ID: SS-2012-Z0931-OP
© Georg Thieme Verlag Stuttgart · New York

818
B. Panda, T. K. Sarkar
PAPER
PdCl2(PPh3)2 (1 mol%)
AuCl(PPh3) (1 mol%)
O
i-Pr2NH, THF
r.t., 14 h
Me
2a
<1% conversion (Laguna and co-workers)10
O
96% conversion (this work)
54% (isolated yield)
Ph
I
+
+
2
Me
7%
1a
PdCl2(PPh3)2 (1 mol%)
i-Pr2NH, THF
r.t., 14 h
Scheme 1 Reinvestigation of the work of Laguna et al.
In order to probe the synthetic scope of this gold co-cata- sulfoxide, and N,N-dimethylformamide, and changing the
lyzed Sonogashira-type reaction, it was deemed important base from triethylamine to potassium carbonate allowed
to optimize the reaction conditions by using different bas- identification of the efficient catalytic system for the
es and solvents, as well as changing the reaction tempera- Sonogashira-type coupling of bromobenzene (1b) as
ture. We chose the cross-coupling of bromobenzene (1b) PdCl2(PPh3)2/AuCl(PPh3) in N,N-dimethylformamide or
with phenylacetylene as a model reaction and the results N,N-dimethylacetamide (DMA) in the presence of trieth-
are presented in Table 1. Clearly, the catalytic system is ylamine (entries 8 and 10).
not sufficiently powerful to allow reaction in tetrahydro-
Under our optimized reaction conditions, we accom-
furan at ambient temperature; heating to reflux was re-
plished Sonogashira-type cross-coupling of a wide array
quired in this case, although prolonging heating (>4 h) did
of electronically and structurally diverse aryl and hetero-
not increase the yield of the reaction further (entries 1 and
aryl halides. With respect to the aryl bromides13 and io-
2). The reaction also takes place in water or triethylamine,
dides,14 both electron-neutral and electron-poor aryl
but the yields are unsatisfactory (entries 3 and 4). Finally,
halides 1a–c,f react with alkynes to provide the corre-
sponding products 2a,b,e,f in excellent yields (Table 2,
going from tetrahydrofuran through acetonitrile, dimethyl
Table 1 Effect of the Reaction Conditions on the Cross-Coupling of Bromobenzene with Phenylacetylenea
PdCl2(PPh3)2 (2 mol%)
AuCl(PPh3) (2 mol%)
Br
+
base, solvent
1b
2b
Entry
Solvent
Base
Temp (°C)
Time (h)
Yieldb (%)
c
1
THF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
Et3N
r.t.
reflux
80
8
4
12
6
6
4
3
3
3
3
–
2
THF
81
40
67
33
84
89
96
79
96
3
H2O
4
Et3N
80
5
PhMe
MeCN
DMSO
DMF
DMF
DMA
80
6
80
7
80
8
80
9
80
10
80
a Reaction conditions: bromobenzene (1b, 1 mmol), phenylacetylene (1.1 mmol), base (3 mmol), solvent (3 mL).
b Isolated yield.
c No reaction.
Synthesis 2013, 45, 817–829
© Georg Thieme Verlag Stuttgart · New York

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Sonogashira Coupling of Aryl and Heteroaryl Halides
819
entries 1, 2, and 5–7). Electron-rich aryl halides 1d,g (en- erated in our Pd–Au dual catalytic conditions. For
tries 3, 8, and 9) are amenable to this protocol; however, example, 2-bromobenzyl azide (1t) couples with phenyl-
more notable is that even highly electron-rich systems 1h– acetylene to give the desired product 2w in 92% yield un-
l (entries 10–14) couple efficiently with alkynes. This accompanied by any undesired cyclized products (entry
method is also tolerant of ortho-substitution in aryl bro- 25). A bromobenzene containing an imino group 1u nice-
mides 1m–o (entries 15–18). Even the highly sterically ly couples with phenylacetylene thereby furnishing the
hindered aryl halides 1e,p (entries 4 and 19) couple with desired 2-alkynylimine derivative 2x uncontaminated
alkynes without difficulty.
with any trace of undesired isoquinoline derivatives (entry
26). It is well known that thiophenes are poor substrates in
cross-coupling reactions. It is noteworthy that 2,3,4-tri-
bromothiophene (1v) couples nicely under these condi-
tions with excess phenylacetylene to yield the trialkynyl
derivative 2y (entry 27). Similarly, 1,3,5-tribromoben-
zene (1w) also couples satisfactorily with phenylacety-
lene to furnish the star-like trialkyne 2z (entry 28) in
excellent yield.
Interestingly, several examples (Table 2, entries 3, 6, 9,
16, and 18) in which alkylalkynes are found to couple ef-
ficiently with aryl halides are also in conflict with the
findings of Laguna and co-workers that the gold co-cata-
lysts used in their work are much more efficient in activat-
ing arylalkynes than alkylalkynes.10
Notably, amino groups are tolerated under these condi-
tions. 2-Bromoaniline (1q) and 2-bromo-4-methylaniline
(1r) react with phenylacetylene to furnish the correspond-
ing coupled products 2r and 2s, respectively, in good
yields (Table 2, entries 20 and 21) uncontaminated by
traces of cyclized products, e.g. indoles. It is well known
that terminal alkynes bearing electron-withdrawing
groups directly attached to the ethynyl carbon atom under-
go side reactions such as Michael addition or self conden-
sation under the classical Sonogashira reaction
conditions. Thus, the Sonogashira coupling of aryl halides
with highly electron-deficient terminal alkynes is a chal-
lenging case.15 In order to address this problem, Taran et
al. have developed a Pd–Ag protocol16 for the cross-
coupling of (trialkylsilyl)alkynes bearing an electron-
Our next goal was to probe the efficacy of our methodol-
ogy for the alkynylation of unprotected 8-brominated
adenosines and guanosines. It may be noted that Fairlamb
et al. pioneered the alkynylation of unprotected 8-bromi-
nated adenosines and guanosines by a modified
Sonogashira process.17 As can be seen from Table 2 (en-
tries 29 and 30), the Sonogashira coupling of 8-bro-
moadenosine (1x) and 8-bromoguanosine (1y) with
phenylacetylene at 80 °C gives the desired 8-alkynylated
products 2aa and 2ab in good yields. In terms of yields,
our work is comparable to those of Fairlamb et al., but the
advantages of our conditions are lower temperatures
(120 °C vs. 90 °C) and reaction times (18 h vs. 5 h).
withdrawing group, such as (trimethylsilyl)propiolate After successful Sonogashira coupling with aryl iodides
with aryl and heteroaryl iodides in the presence of a fluo- as well as aryl bromides, our next task was to study the
ride source. The disadvantages here are two-fold: high possibility of cross-coupling alkynes with aryl and hetero-
loading of the catalysts [Pd (10%), silver (20%)] and that aryl chlorides. Thus, an electron-poor heteroaryl chloride,
the protocol needs preparation of (trialkylsilyl)propiolates 2-chloro-4,6-dimethylpyridine-3-carbonitrile (3a), was
from propiolates. As can be seen from Table 2, both bro- found to react with phenylacetylene to furnish the coupled
mobenzene (1b) and 4-bromotoluene (1g) couple nicely product 4a in excellent yield (Table 3, entry 1). Also, 2-
with methyl propiolate and furnish good yields of coupled chloropyridine-3-carbaldehydes 3b and 3c (entries 2–5),
products 2t,u (entries 22 and 23). It may be noted that reacted with various terminal alkynes to give the coupled
when propiolates are the alkyne partners, we used potas- products, formyl-substituted alkynes 4b–e in good to ex-
sium or cesium carbonate as the base rather than triethyl- cellent yields; note that these formyl-substituted alkynes
amine as the latter destroys the propiolic ester were used for the synthesis of quinolines via gold-cata-
exothermally. Between potassium and cesium carbonate, lyzed benzannulation reactions.18
the more basic cesium carbonate gives somewhat better
results (70%) compared to potassium carbonate (60%)
Aliphatic terminal acetylenes also couple with 2-chloro-
4,6-dimethylpyridine-3-carbaldehyde (3b) without for-
(entry 23). Note that no trace of the desired products is ob-
mation of any allenic product (Table 3, entry 5). Notably,
tained from the cross-coupling of 4-bromo- or even 4-io-
the mildness of the reaction conditions can be gleaned
dotoluene and methyl propiolate under classical Pd–Cu
from the fact that no further reaction (e.g.,
catalytic conditions. It is probable that the lower carbo-
benzannulation18,19) occurred between the Sonogashira
philic Lewis acidity of copper(I) compared to gold(I) does
product, that is the formyl-substituted alkyne, and the ex-
not allow binding of the former with the electron-deficient
cess alkyne present in the reaction mixture. Not only that,
alkyne, which is the necessary requisite for acetylide for-
no trace of alkynylisochromene formed from the reaction
mation.
of the Sonogashira product (formyl-substituted alkyne)
As can be seen from Table 2, entry 24, 2-bromophenol with the terminal alkyne in the presence of a base. It may
(1s) couples with phenylacetylene to afford the corre- be noted that alkynylisochromenes are frequently formed
sponding 2-alkynylphenol 2v; no cyclized products, for in gold-catalyzed reactions of formyl-substituted alkynes
example benzofuran, form under these conditions. Note with terminal alkynes in the presence of a catalytic
that benzofuran is the sole product under the classical Pd– amount of amine base.20
Cu-coupling conditions. An azide group is also nicely tol-
© Georg Thieme Verlag Stuttgart · New York
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820
B. Panda, T. K. Sarkar
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Table 2 Sonogashira Coupling of Aryl or Heteroaryl Iodides and Bromides with Terminal Alkynesa
PdCl2(PPh3)2 (2 mol%)
AuCl(PPh3) (2 mol%)
+
H
R
Ar
R
Ar
X
Et3N, DMF
1, X = I, Br
2
Entry
ArX
Temp (°C)
60
Time (h)
0.75
Product
Yieldb (%)
O
O
I
1
93
Me
Me
2a
1a
I
2
3
70
70
0.5
98
92
1c
2b
Me
Me
I
OH
0.75
1d
2c
Me
Me
I
4
5
80
70
1
1
98
93
Me
Me
2d
1e
NO2
NO2
Br
2e
2f
1f
Br
Br
91c
96
94
OH
6
7
8
80
80
80
3
3
3
1b
1b
2b
Me
Me
Br
1g
2g
Me
Me
Br
9
80
80
3
7
OH
91
1g
1h
2h
2i
OMe
Br
OMe
10
91 (42)d
Br
11
12
80
80
7
7
93
94
MeO
MeO
1i
2j
MeO
Br
MeO
1j
2k
Synthesis 2013, 45, 817–829
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sonogashira Coupling of Aryl and Heteroaryl Halides
821
Table 2 Sonogashira Coupling of Aryl or Heteroaryl Iodides and Bromides with Terminal Alkynesa (continued)
PdCl2(PPh3)2 (2 mol%)
AuCl(PPh3) (2 mol%)
+
H
R
Ar
R
Ar
X
Et3N, DMF
1, X = I, Br
2
Entry
ArX
Temp (°C)
90
Time (h)
Product
Yieldb (%)
90 (27)d
MeO
Br
OMe
MeO
13
14
9
OMe
1k
MeO
2l
MeO
Br
90
9
93 (29)d
MeO
MeO
1l
2m
F
F
Br
Br
Br
Br
Br
15
16
17
18
80
80
80
80
3
3
4
4
92e,f
2n
1m
1n
1o
1o
Br
Br
91
OH
2o
2p
Ph
Ph
Ph
Ph
91
89
OH
2q
Me
Me
Me
19
20
90
80
6
4
86
Me
2d
2r
1p
1q
NH2
Br
NH2
62 (0)d
NH2
Br
NH2
21
22
80
80
4
5
60 (0)d
Me
Me
2s
1r
Br
CO2Me
72 (0)d,g
1b
2t
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 817–829

822
B. Panda, T. K. Sarkar
PAPER
Table 2 Sonogashira Coupling of Aryl or Heteroaryl Iodides and Bromides with Terminal Alkynesa (continued)
PdCl2(PPh3)2 (2 mol%)
AuCl(PPh3) (2 mol%)
+
H
R
Ar
R
Ar
X
Et3N, DMF
1, X = I, Br
2
Entry
ArX
Temp (°C)
80
Time (h)
5
Product
Yieldb (%)
Br
Me
Me
CO2Me
23
24
70 (0)d,g,h
1g
2u
OH
OH
92 (0)d
Br
80
80
3
3
2v
1s
1t
N3
Br
N3
25
26
92
90
2w
N
N
80
90
3
Br
2x
1u
Ph
Ph
Ph
Br
Br
27
12
84i
Br
S
S
1v
2y
Ph
Br
Br
Ph
28
100
10
94i
Br
1w
Ph
2z
NH2
N
NH2
N
N
N
N
N
N
N
Ph
Br
OH
OH
29
90
5
83j
H
H
O
H
H
O
H
H
H
H
OH OH
OH OH
1x
2aa
Synthesis 2013, 45, 817–829
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sonogashira Coupling of Aryl and Heteroaryl Halides
823
Table 2 Sonogashira Coupling of Aryl or Heteroaryl Iodides and Bromides with Terminal Alkynesa (continued)
PdCl2(PPh3)2 (2 mol%)
AuCl(PPh3) (2 mol%)
+
H
R
Ar
R
Ar
X
Et3N, DMF
1, X = I, Br
2
Entry
ArX
Temp (°C)
Time (h)
Product
Yieldb (%)
O
N
O
N
N
N
N
HN
HN
Ph
Br
H2N
H2N
N
OH
OH
30
90
5
88j
H
H
H
H
O
O
H
H
H
H
OH OH
OH OH
1y
2ab
a Reaction conditions: aryl halide (1 mmol), acetylene (1.1 mmol), Et3N (3 mmol), DMF (3 mL).
b Isolated yield.
c In the absence of a gold catalyst, 2 mol% PdCl2(PPh3)2 gave the product in 18% yield after 3 h.
d Yield in parentheses refers to the product obtained using CuI in place of AuCl(PPh3).
e Replacement of AuCl(PPh3) by (IPr)AuCl gives the product in 94% yield in 1.5 h.
f 1 mol% PdCl2(PPh3)2/1 mol% AuCl(PPh3) and a reaction time of 5 h gave the product in 89% yield.
g Cs2CO3 was used instead of Et3N.
h 60% of the coupled product was isolated when K2CO3 was used as the base.
i Phenylacetylene (3.6 equiv) and Et3N (9 equiv) were used.
j Workup procedure different from others, see the experimental section.
A pyridine nucleus containing more than one chlorine We have also tested our method with highly reactive cou-
atom also coupled nicely under our reaction conditions. pling partners e.g. a vinyl bromide. As can be seen from
Thus, 2,6-dichloropyridine-3-carbaldehyde (3d) gives the Table 4, entry 1, β-bromostyrene (5) couples with homo-
corresponding dialkynylated product 4f on reaction with propargyl alcohol efficiently and furnishes the coupled
2.2 equivalents of phenylacetylene (Table 3, entry 6). Ad- product 6 in excellent yield. An acyl chloride also couples
ditionally, the dichloro aza-phthalide 3e (entry 7) is also satisfactorily with a terminal alkyne (entry 2). Our method
amenable to this methodology giving the desired di- also proves to be effective for the Sonogashira coupling of
alkynylated aza-phthalide 4g in high yield.
aryl triflates with terminal alkynes; aryl triflate 9 bearing
a sensitive acetonide moiety couples with phenylacetyl-
ene to furnish the desired coupled product 10 in 81% iso-
lated yield (entry 3).22
Electron-deficient aryl chloride 1-chloro-4-nitrobenzene
(3f) couples with phenylacetylene and 4-(dimethylami-
no)phenylacetylene to give 71% and 64% of the coupled
products 4h and 4i, respectively (Table 3, entries 8 and 9). As previously noted by Laguna and co-workers.10 no trace
Also, an electroneutral aryl chloride such as chloroben- of Glaser-type homocoupling of alkynes could be ob-
zene (3g) couples with phenylacetylene to give 62% of the served (TLC) in any of the reactions described in Tables
coupled product 2b (entry 10). Furthermore, electron-rich 2–4, which were essentially clean. Furthermore, indepen-
aryl chloride 4-chlorotoluene (3h) reacts with phenylacet- dent experiments were carried out to examine the role of
ylene to afford the desired coupled product 2g in moderate palladium and gold separately in these reactions. While
yield (entry 11). On the other hand, sterically hindered the gold complex AuCl(PPh3) was found to be totally in-
aryl chloride 1-chloro-2,6-dimethylbenzene (3i) couples active in the absence of the palladium complex
with phenylacetylene to give the desired product 2d, albe- PdCl2(PPh3)2, the latter alone led to the formation of the
it in low yield (entry 12). Unfortunately, highly electron- coupled product (Table 2, entry 6) in 18% yield. Pd–Au
rich 4-chloroanisole (3j) does not couple with phenylacet- dual catalytic reactions are also possible with lower cata-
ylene under these catalytic conditions (entry 13). This lytic loadings, although longer reaction times are needed
may be due to inability of palladium(0), generated from for efficient conversions. For example, using 1 mol%
the precatalyst PdCl2(PPh3)2, to undergo oxidative addi- Pd(PPh3)2Cl2/1 mol% AuCl(PPh3) gave the product 2n in
tion to the electron-rich C–Cl bond. Interestingly, addition 89% isolated yield after a reaction time of five hours
of 20 mol% of potassium iodide in the catalytic ensemble (Table 2, entry 15). Incidentally, the assumption made by
in entries 11 and 12 reduces the reaction time and increas- Laguna and co-workers10 to explain the inactivity of
es the yield from 52% to 64% and 41% to 56%, respec- AuCl(PPh3) in terms of the lesser propensity for the disso-
tively (domino HALEX and Sonogashira reaction21).
ciation of the phosphine ligand seems untenable in view
of our observation that replacement of the phosphine li-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 817–829

824
B. Panda, T. K. Sarkar
PAPER
gand by strongly bonded N-heterocyclic carbene ligand with those obtained under classical conditions, that is, in
(IPr NHC) still gives the product 2n (Table 2, entry 15) in the presence of copper(I) iodide and an amine [under
high yield (94%). It should be noted that the strong metal– identical conditions to those in Table 2 but replacing
carbenic bond of the NHC complex favors tight-binding AuCl(PPh3) by CuI]. In these cases in Table 2 (entries 10,
kinetics, therefore lessening ligand dissociation.23 We 13, 14, and 20–24) and Table 3 (entry 6) yields as given in
have also compared the results of the Sonogashira cou- parentheses are woefully low, the predominant byproduct
pling in the presence of the Pd–Au dual catalytic system being the Glaser-type homocoupling product (31–44%).
Table 3 Coupling of Aryl or Heteroaryl Chlorides with Terminal Alkynesa
PdCl2(PPh3)2 (2 mol%)
AuCl(PPh3) (2 mol%)
Ar
R
+
H
R
Ar Cl
Et3N, DMF
3
4
Entry
ArCl
Temp (°C)
Time (h)
Product
Yieldb (%)
Me
CN
Me
CN
Cl
1
80
3
94
N
N
N
N
N
N
N
Me
Me
3a
Me
4a
Me
CHO
Cl
CHO
CHO
CHO
CHO
2
3
4
80
80
80
3
3
3
91
94
86
N
N
N
N
Me
Me
3b
Me
4b
Me
CHO
Cl
Ph
Ph
3c
Me
4c
CHO
Cl
Me
NMe2
Me
Me
3b
Me
4d
CHO
Cl
Me
Ph
O
5
6
80
90
3
6
90
Me
Me
3b
4e
CHO
CHO
81 (56)c,d
N
Cl
Cl
Ph
Ph
3d
4f
Ph
Cl
N
O
O
O
O
7
90
6
86d
Cl
N
3e
Ph
4g
Synthesis 2013, 45, 817–829
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sonogashira Coupling of Aryl and Heteroaryl Halides
825
Table 3 Coupling of Aryl or Heteroaryl Chlorides with Terminal Alkynesa (continued)
PdCl2(PPh3)2 (2 mol%)
AuCl(PPh3) (2 mol%)
Ar
R
+
H
R
Ar Cl
Et3N, DMF
3
4
Entry
ArCl
Temp (°C)
Time (h)
6
Product
Yieldb (%)
71
Cl
O2N
O2N
8
100
3f
4h
Cl
O2N
O2N
NMe2
9
100
100
120
6
64
4i
3f
Cl
10
11
12
62
2b
3g
Cl
Me
Me
12 (8)
52 (64)e
2g
3h
Me
Me
Me
Cl
12
13
120
120
24(16)
41 (56)e
Me
3i
2d
Cl
MeO
MeO
12
–
3j
2k
a Reaction conditions: aryl or heteroaryl chloride (1 mmol), acetylene (1.1 mmol), Et3N (3 mmol), DMF (3 mL).
b Isolated yield.
c Yield in the parenthesis refers to the product obtained using classical PdCl2(PPh3)2/CuI catalytic systems.
d Phenylacetylene (2.2 equiv) and Et3N (6 equiv) were used.
e Yield and time in parentheses refer to those obtained using KI (20 mol%) as an additive.
Table 4 Coupling of Aryl Halide Surrogates with Alkynesa
Entry
ArX
Temp (°C)
Time (h)
1
Product
Yieldb (%)
1
r.t.
96
Br
OH
5
6
Cl
2
3
80
80
3
4
76
81
O
O
7
8
Me
Me
Me
Me
O
O
O
O
O
O
OTf
9
10
a Reaction conditions: vinyl bromide, acyl chloride, or aryl triflate (1 mmol), acetylene (1.1 mmol), Et3N (3 mmol), DMF (3 mL).
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 817–829

826
B. Panda, T. K. Sarkar
PAPER
ArX
A generally accepted mechanism of the classical Pd–Cu-
catalyzed Sonogashira coupling consists of two catalytic
cycles: (a) the classic palladium-based coupling reaction
that involves the oxidative addition of an aryl halide ArX
to a low coordinate palladium(0) complex, then trans-
metalation of a copper acetylide (formed in the second
catalytic cycle) to generate an ArPd(–C≡CR2)L2 species,
which subsequently undergoes cis–trans isomerization
and reductive elimination to give the arylalkyne and the
regenerated catalyst, and (b) the so-called ‘copper cycle’
in which the copper acetylide is generated from the free
alkyne in the presence of a base, which is often an amine.
The latter cycle is poorly understood; for example, the in
situ formation of a copper acetylide is not proven yet, al-
though recently indirect evidence has been found.24 In
fact, most of the amines used are not basic sufficiently to
deprotonate the alkyne to provide an anionic species that
can further react to give the corresponding copper
acetylide. Therefore, a π-alkyne–Cu complex, which
makes the alkyne proton more acidic is often proposed as
an intermediate.3
Pd0L2
Ar
R
L
ArPdX(L)2
Ar
L
Pd
R
LAu
R
LAuCl
R
H
R
BH+
LAuCl
LAuCl
B
Scheme 2 Possible mechanism of Pd–Au dual catalytic Sonogashira
coupling
room temperature (Scheme 3) and it was characterized by
1H, 31P NMR as well as mass spectral analysis.
For a better understanding of these reactions and other
gold-catalyzed reactions, we embarked on mechanistic
studies and attempted to characterize some intermediates.
As already mentioned the gold-only procedure did not fur-
nish any trace of the coupled product (Table 2, entry 6)
thus proving the ineffectiveness of gold(I) for the oxida-
tive addition to aryl halides. In light of the Pd–Ag catalyt-
ic alkynylation reaction reported by Pale et al.,25 we have
also investigated our Pd–Au dual catalytic reaction based
on the similarities between gold and silver. On the basis of
what is known and what we learned12 from gold and al-
kyne interactions, the steps depicted in Scheme 2 may be
proposed.
The use of this gold acetylide 12 did not allow coupling
with 4-iodotoluene (1d) whatever the conditions used;
however, in the presence of a catalytic amount of
PdCl2(PPh3) it underwent a smooth transformation giving
the expected coupled product 13 in good yield (Scheme
4).28
In conclusion, we have demonstrated that the reportedly
inactive dual catalytic system PdCl2(PPh3)2/AuCl(PPh3)
allows efficient Sonogashira coupling of various aryl and
heteroaryl halides. We have also shown the utility of our
Pd–Au dual catalytic alkynylation method for various aryl
halides that are known to be problematic in classical Pd–
Cu Sonogashira coupling. In addition, other coupling
partners, such as triflates, acyl halides, and vinyl halides
are also amenable to this protocol. A key feature of the
Pd–Au dual catalytic process is its extreme functional
group tolerance. We have also worked out a thorough
mechanistic rationale of the alkynylation process with a
preformed gold acetylide. Further work for alkynylation
of aryl chlorides at room temperature and expanding the
scope of gold organometallics in coupling reactions is un-
derway in our laboratory.
Coordination of alkynes to gold is well known; such coor-
dination activates the alkyne toward nucleophilic addition
or deprotonation. In the latter case a zwitterion should be
formed, but it would rapidly rearrange to the more stable
gold acetylide. Once formed, gold acetylides are known to
enter into the palladium catalytic cycle at the transmetala-
tion step26 like other organometallics do. To check this as-
sumption, we prepared the gold acetylide 1227 by
treatment of a mixture of alkyne 11 and AuCl(PPh3) in
methanol with methanolic sodium hydroxide solution at
H
NaOH
Ph3PAu
+
AuCl(PPh3)
OCH2Ph
MeOH, r.t., 3 h
OCH2Ph
11
82%
12
Scheme 3 Preparation of gold acetylide 12
Ph3PAu
PdCl2(PPh3)2 (2 mol%)
Me
I
Me
+
OCH2Ph
DMF, 70 °C, 1 h
79%
OCH2Ph
12
1d
13
Scheme 4 Sonogashira coupling using preformed gold acetylide 12
Synthesis 2013, 45, 817–829
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sonogashira Coupling of Aryl and Heteroaryl Halides
827
Preparation of Gold–Acetylide Complex 12
General details of the experiments are given in the Supporting In-
formation. Petroleum ether = PE. TLC used detection by UV and I2.
A soln of NaOH (15 mg, 0.375 mmol) in MeOH (2 mL) was added
to the mixture of AuCl(PPh3) (77 mg, 0.15 mmol) and 11 (50 mg,
0.31 mmol) in anhyd MeOH (6 mL). Then the flask was covered by
black paper and the mixture was allowed to stir at r.t. under argon
for 3 h. The solvent was removed under reduced pressure. Then the
crude product was diluted by Et2O and filtered through a small
Celite bed (to remove the salts) and the filtrate was dried in vacuo.
The solid material was washed by anhyd hexane (2 × 4 mL) (to re-
move the excess 11) and the solid was dried under vacuum; yield:
0.076 g (82%).
(IPr)AuCl
= 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene-
gold(I) chloride.
1-[4-(Phenylethynyl)phenyl]ethanone (2a); Typical Procedure
under Laguna’s Conditions10
4-Iodoacetophenone (1a, 369 mg, 1.5 mmol), phenylacetylene
(0.25 mL, 2.25 mmol), and i-Pr2NH (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 r.t. for 14 h, then it was diluted with Et2O (5 mL), and fil-
tered through a small Celite bed. The filtrate was poured into H2O
and the aqueous layer was extracted with Et2O (3 × 10 mL). The
combined organic layers were dried (anhyd Na2SO4), and the sol-
vent was evaporated under reduced pressure. The product 2a was
isolated by column chromatography (silica gel); yield: 0.304 g
(92%); also isolated was 4-iodoacetophenone; yield: 0.017 g (4%).
1H NMR (200 MHz, CDCl3): δ = 7.57–7.01 (m, 20 H), 4.54 (s, 2 H),
3.67 (t, J = 7.6 Hz, 2 H), 2.70 (t, J = 7.6 Hz, 2 H).
31P NMR (161 MHz, CDCl3): δ = 46.15.
HRMS (ESI): m/z [M + Na] calcd for C29H26AuNaOP: 641.1284;
found: 641.1306.
4,6-Dimethyl-2-(phenylethynyl)pyridine-3-carbonitrile (4a)
From 3a (0.17 g); light brown solid; yield: 0.22 g (94%); mp 84–86
°C; Rf = 0.34 (10% EtOAc–PE).
1H NMR (400 MHz, CDCl3): δ = 7.72–7.67 (m, 2 H), 7.42–7.38 (m,
3 H), 7.08 (s, 1 H), 2.61 (s, 3 H), 2.54 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.2,151.2, 145.7, 132.5, 129.8,
Pd–Au Dual Catalytic Sonogashira Coupling; General Proce-
dure
A flame-dried two-necked flask, equipped with a reflux condenser,
gas inlet/outlet, and rubber septum, was evacuated and backfilled
with argon (2 ×) and then charged under a positive pressure of argon
with the aryl or heteroaryl halide (1 mmol), DMF (3 mL),
PdCl2(PPh3)2 (14 mg, 0.02 mmol), and base (3 mmol), followed by
AuCl(PPh3) (10 mg, 0.02 mmol) and a terminal acetylene (1.1
mmol). Then the mixture was heated at given temperature and time.
It was diluted by Et2O (3 mL) and filtered through a small Celite
bed. The filtrate was poured into H2O and the aqueous layer was ex-
tracted with Et2O (3 × 10 mL). The combined organic layers were
dried (anhyd Na2SO4) and the solvent was evaporated under re-
duced pressure. The product was isolated by column chromatogra-
phy (silica gel).
128.5, 123.3, 121.3, 115.7, 110.9, 95.0, 86.1, 24.8, 20.3.
HRMS (ESI): m/z [M + H] calcd for C16H13N2: 233.1073; found:
233.1074.
4,6-Dimethyl-2-(phenylethynyl)pyridine-3-carbaldehyde (4b)
From 3b (0.17 g); light brown solid; yield: 0.214 g (91%); mp 79–
81 °C; Rf = 0.26 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 10.79 (s, 1 H), 7.60–7.56 (m, 2 H),
7.35–7.26 (m, 3 H), 6.98 (s, 1 H), 2.57 (s, 3 H), 2.56 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 193.2, 163.1, 149.9, 147.8, 132.3,
Pd–Au Dual Catalytic Sonogashira Coupling with Propiolates;
General Procedure
129.8, 128.7, 128.7, 126.4, 121.8, 95.7, 85.8, 24.9, 21.0.
A flame-dried two-necked flask, equipped with a reflux condenser,
gas inlet/outlet, and rubber septum, was evacuated and backfilled
with argon (2 ×) and then charged under a positive pressure of argon
with the aryl or heteroaryl halide (1 mmol), DMF (3 mL),
PdCl2(PPh3)2 (14 mg, 0.02 mmol), and Cs2CO3 (3 mmol), followed
by AuCl(PPh3) (10 mg, 0.02 mmol) and propiolate (1.1 mmol).
Then the mixture was heated at the given temperature and time. It
was diluted by Et2O (3 mL) and filtered through a small Celite bed.
The filtrate was poured into H2O and the aqueous layer was extract-
ed with Et2O (3 × 10 mL). The combined organic layers were dried
(anhyd Na2SO4) and the solvent was evaporated under reduced
pressure. The product was isolated by column chromatography (sil-
ica gel).
HRMS (ESI): m/z [M + H] calcd for C16H14NO: 236.1070; found:
236.1075.
4-Methyl-6-phenyl-2-(phenylethynyl)pyridine-3-carbaldehyde
(4c)
From 3c (0.23 g); light brown solid; yield: 0.28 g (94%); mp 115–
117 °C; Rf = 0.41 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 10.89 (s, 1 H), 8.12–8.07 (m, 2 H),
7.68–7.63 (m, 2 H), 7.57 (s, 1 H), 7.53–7.48 (m, 3 H), 7.42–7.37 (m,
3 H), 2.71 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 193.3, 160.4, 150.4, 148.2, 137.7,
132.3, 130.5, 129.8, 129.2, 129.0, 128.7, 127.8, 123.2, 121.8, 95.6,
86.1, 21.5.
Pd–Au Dual Catalytic Sonogashira-Type Cross-Coupling of 8-
Bromoguanosine (1x) or 8-Bromoadenosine (1y); General Pro-
cedure
HRMS (ESI): m/z [M + H] calcd for C21H16NO: 298.1232; found:
298.1238.
A flame-dried two-necked flask, equipped with a reflux condenser,
gas inlet/outlet, and rubber septum, was evacuated and backfilled
with argon (2 ×) and then charged under a positive pressure of argon
with 8-bromoguanosine (1x)17 or 8-bromoadenosine (1y)17 (0.28
mmol, 1 equiv), DMF (4 mL), PdCl2(PPh3)2 (4 mg, 0.0056 mmol),
and Et3N (3 equiv), followed by AuCl(PPh3) (3 mg, 0.006 mmol)
and a terminal acetylene (0.34 mmol, 1.2 equiv). Then the mixture
was heated at 90 °C for 5 h. After that it was allowed to cool to r.t.
and diluted with Et2O (30 mL). The solid precipitate was transferred
to a sintered glass filter and was washed with boiling H2O (3 × 10
mL), EtOAc (3 × 15 mL), and Et2O (2 × 15 mL) yielding the cou-
pled products. Spectral data of both the coupled products were
matched with reported17 values.
2-[4-(Dimethylamino)phenylethynyl]-4,6-dimethylpyridine-3-
carbaldehyde (4d)
From 3b (0.17 g); yellow solid; yield: 0.24 g (86%); mp 132–134
°C; Rf = 0.20 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 10.79 (s, 1 H), 7.46 (d, J = 9.0 Hz,
2 H), 6.90 (s, 1 H), 6.60 (d, J = 9.0 Hz, 2 H), 2.96 (s, 6 H), 2.55 (s,
3 H), 2.54 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 193.7, 162.8, 151.0, 149.7, 148.6,
133.6, 127.8, 125.4, 111.7, 107.8, 98.2, 84.6, 40.1, 24.9, 21.0.
HRMS (ESI): m/z [M + H] calcd for C18H19N2O: 279.1497; found:
279.1510.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 817–829

828
B. Panda, T. K. Sarkar
PAPER
2-[5-(Benzyloxy)pent-1-ynyl]-4,6-dimethylpyridine-3-carbalde-
ding us a gift of four important compounds (1x, 1y, 2aa,and 2ab).
We are also thankful to Prof. A. S. K. Hashmi (Heidelberg) for brin-
ging our attention to ref. 31.
hyde (4e)
From 3b (0.17 g); colorless liquid; yield: 0.276 g (90%); Rf = 0.32
(10% EtOAc–PE)
1H NMR (200 MHz, CDCl3): δ = 10.66 (s, 1 H), 7.35–7.26 (m, 5 H),
6.98 (s, 1 H), 4.52 (s, 2 H), 3.61 (t, J = 6.1 Hz, 2 H), 2.65 (t, J = 7.2
Hz, 2 H), 2.58 (s, 3 H), 2.55 (s, 3 H), 1.96 (t, J = 6.5 Hz, 2 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
13C NMR (50 MHz, CDCl3): δ = 193.3, 162.5, 149.4, 147.9, 138.3,
128.3, 127.5, 125.7, 97.1, 77.6, 72.9, 68.8, 28.4, 24.6, 20.9, 20.7,
16.5, 14.1.
References
(1) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
HRMS (ESI): m/z [M + H] calcd for C20H22NO2: 308.1651; found:
308.1645.
(2) (a) Applied Homogeneous Catalysis with Organometallic
Compounds; Cornils, B.; Herrmann, W. A., Eds.; Wiley-
VCH: Weinheim, 1996. (b) Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.; de Meijere,
A., Eds.; Wiley: New York, 2002. (c) Cross-Coupling
Reactions; Miyaura, N., Ed.; Springer: Berlin, 2000.
(d) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.
Diederich, F.; de Meijere, A., Eds.; Wiley-VCH: Weinheim,
2004. (e) Transition Metals for Organic Synthesis; Building
Blocks and Fine Chemicals, 2nd ed. Beller, M.; Bolm, C.,
Eds.; Wiley-VCH: Weinheim, 2004.
2,3,4-Tris(phenylethynyl)thiophene (2y)
From 1v (0.323 g); white solid; yield: 0.323 g (84%); mp 146–148
°C; Rf = 0.62 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 7.67–7.61 (m, 6 H), 7.47–7.44 (m,
9 H), 7.29 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 133.7, 131.8, 131.7, 129.3, 129.0,
128.8, 128.6, 128.4, 128.3, 127.1, 126.8, 123.6, 123.1, 122.7, 122.5,
98.6, 94.7, 93.8, 83.6, 82.1, 81.9.
HRMS (ESI): m/z [M + H] calcd for C28H17S: 385.1051; found:
(3) (a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(b) Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Reactions; Vol. 1; Diederich, F.; de Meijere, A., Eds.;
Wiley-VCH: Weinheim, 2004, 319.
(4) (a) Doucet, H.; Hierso, J. C. Angew. Chem. Int. Ed. 2007, 46,
834. (b) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107,
874. (c) Plenio, H. Angew. Chem. Int. Ed. 2008, 47, 6954.
(5) (a) Kotora, M.; Takahashi, T. In Handbook of
Organopalladium Chemistry for Organic Synthesis;
Negishi, E.; de Meijere, A., Eds.; Wiley: New York, 2002,
973. (b) Siemsen, P.; Livingston, R. C.; Diederich, F.
Angew. Chem. Int. Ed. 2000, 39, 2632.
(6) Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M.;
Hirabayashi, K.; Nishihara, Y. Org. Lett. 2000, 2, 2935.
(7) (a) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.;
Ryu, I. Org. Lett. 2002, 4, 1691. (b) Alonso, D. A.; Najera,
C.; Pachecho, M. C. Tetrahedron Lett. 2002, 43, 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, 5, 4191.
(e) Komaromi, A.; Novak, Z. Chem. Commun. 2008, 4968.
(f) Torborg, C.; Huang, J.; Schulz, T.; Schaffner, B.; Zapf,
A.; Spannenberg, A.; Börner, A.; Beller, M. Chem.–Eur. J.
2009, 15, 1329.
385.1047.
2,6-Bis(phenylethynyl)pyridine-3-carbaldehyde (4f)
From 3d (0.176 g); light brown solid; yield: 0.250 g (81%); mp
117–118 °C; Rf = 0.18 (5% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 10.66 (s, 1 H), 8.20 (d, J = 8.2 Hz,
1 H), 7.67–7.56 (m, 5 H), 7.45–7.38 (m, 6 H).
13C NMR (50 MHz, CDCl3): δ = 190.4, 148.4, 146.6, 135.2, 132.6,
132.5, 130.5, 130.2, 130.0, 128.8, 128.7, 126.7, 121.7, 121.4, 96.6,
94.0, 88.4, 84.6.
HRMS (ESI): m/z [M + H] calcd for C22H14NO: 308.1075; found:
308.1077.
2,4-Bis(phenylethynyl)-7H-furo[3,4-b]pyridin-5-one (4g)
From 3e (0.204 g); brown solid; yield: 0.288 g (86%); mp 152–154
°C; Rf = 0.17 (10% EtOAc–PE).
1H NMR (200 MHz, CDCl3): δ = 7.71–7.62 (m, 5 H), 7.43–7.41 (m,
6 H), 5.29 (s, 2 H).
13C NMR (50 MHz, CDCl3): δ = 167.7, 148.7, 132.9, 132.6, 131.9,
131.5, 130.5, 130.2, 129.6, 129.3, 128.8, 121.6, 121.4, 117.4, 103.9,
94.5, 87.9, 82.9, 69.7.
HRMS (FAB): m/z [M + H] calcd for C23H14NO2: 336.1025; found:
336.1030.
(8) For some reviews, see: (a) Hashmi, A. S. K. Chem. Rev.
2007, 107, 3180. (b) Gorin, D. J.; Toste, F. D. Nature
(London, U. K.) 2007, 446, 395. (c) Li, Z.; Brouwer, C.; He,
C. Chem. Rev. 2008, 108, 3239. (d) Arcadi, A. Chem. Rev.
2008, 108, 3266. (e) Jimenez-Nunez, E.; Echavarren, A. M.
Chem. Rev. 2008, 108, 3326. (f) Patil, N. T.; Yamamoto, Y.
Chem. Rev. 2008, 108, 3395. (g) Gorin, D. J.; Sherry, B. D.;
Toste, F. D. Chem. Rev. 2008, 108, 3351. (h) Krause, N.;
Winter, C. Chem. Rev. 2011, 111, 1994. (i) Corma, A.;
Perez, L. A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657.
(j) Bandini, M. Chem. Soc. Rev. 2011, 40, 1358. (k) Lu, B.
L.; Dai, L.; Shi, M. Chem. Soc. Rev. 2012, 41, 3318.
(9) Salts or nanoparticles 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, 5946.
CAS Registry Numbers of Known Compounds
2a [1942-31-0], 2b [501-65-5], 2c [16017-24-6], 2d [180783-48-
6], 2e [35010-17-4], 2f [10229-11-5], 2g [3287-02-3], 2h [31208-
53-4], 2i [41398-67-8], 2j [37696-01-8], 2k [7380-78-1], 2l [78594-
14-6], 2m [335605-74-8], 2n [29778-27-6], 2o [116509-98-9], 2p
[10271-65-5], 2q [1001920-52-0], 2r [13141-38-3], 2s [13141-44-
1], 2t [4891-38-7], 2u [7515-16-4], 2v [92151-73-0], 2w [947395-
59-7], 2x [241813-23-0], 2z [118688-56-5], 2aa [85110-32-3], 2ab
[85110-38-9], 4h [1942-30-9], 4i [62197-66-4], 6 [122305-60-6], 8
[7338-94-5], 10 [164014-45-3], 13 [1207298-89-2].
Acknowledgment
This work was supported by DST and CSIR, Government of India.
BP is grateful to CSIR, Government of India for a Senior Research
Fellowship. The NMR facility at IITKGP was supported by the
FIST program of the DST. Prof. T. Gallagher (Bristol), Drs. S.
Djuric and S. Cepa (Abbott, Il) are thanked for continued help and
support. We are thankful to Prof. Ian J. S. Fairlamb (York) for sen-
(10) Jones, L. A.; Sanz, S.; Laguna, M. Catal. Today 2007, 122,
403.
Synthesis 2013, 45, 817–829
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sonogashira Coupling of Aryl and Heteroaryl Halides
829
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(27) This work was presented at the NOST conference on May
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(28) Independent of each other, both the Hashmi group29 and our
group12 showed that the transmetalation from organogold(I)
compounds to palladium is a generally applicable
methodology, and in this context the Hashmi group also
showed that gold acetylide (both phosphine and NHC gold
complexes)29 can enter into the palladium catalytic cycle.
Incidentally, Echavarren et al.30 investigated the Pd–Au dual
catalytic Sonogashira coupling thoroughly. They found that
gold(I) cannot perform the Sonogashira coupling in the
absence of a palladium source. This also supports our
reported12 results, as AuCl(PPh3) was found to be totally
inactive in the absence of the palladium complex
PdCl2(PPh3)2. While the investigation by Echavarren et al. is
interesting, they did not conduct the crucial ICP analysis of
their catalyst, which would have shown that in the control
experiments the other metal is not present.31
(29) Hashmi, A. S. K.; Lothschutz, C.; Dopp, R.; Rudolph, M.;
Ramamurthi, T. D.; Rominger, F. Angew. Chem. Int. Ed.
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(31) Hashmi, A. S. K.; Lothschutz, C.; Dopp, R.; Ackermann, M.;
Becker, J. D. B.; Rudolph, M.; Scholz, C.; Rominger, F. Adv.
Synth. Catal. 2012, 354, 133.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 817–829