Base-free palladium-catalyzed sonogashira coupling using organogold complexes

Article abstract of DOI:10.1002/asia.201100263

Turn to gold: An effective protocol for base-free Sonogashira coupling reactions using organogold complexes as nucleophilic partners has been developed. The palladium-catalyzed methodology offers a general synthesis of aryl-alkynes under operationally simple conditions in good to excellent yields. Copyright

Full text of DOI:10.1002/asia.201100263

DOI: 10.1002/asia.201100263
Base-Free Palladium-Catalyzed Sonogashira Coupling Using Organogold
Complexes
Sreekumar Pankajakshan and Teck-Peng Loh*[a]
Sonogashira coupling reac-
tions[1] boast to be one of the
most elegant transition metal
catalyzed protocols owing to
the value of their products as
important building blocks for
bioactive natural products,
agrochemicals, functionalized
Scheme 1. Model Sonogashira coupling with organogold complex A.
materials, and so on.[2] The
classical reaction involves
a
palladium(0) catalyst with a copper co-catalyst and an
amine base, which is practically often used as the solvent.
Though the classical version still remains to be the popular
choice, it suffers from drawbacks such as the variable reac-
tivity of electrophilic partners (triflates=iodides>bro-
mides>chlorides), formation of undesirable homocoupled
dialkyne side products; the often need for inert conditions
and higher temperatures. Much effort has been devoted in
recent years to fine tune the reaction conditions and to de-
velop facile monocatalytic systems.[3] However, a copper-
free, base-free, and ligand-free Sonogashira reaction that
runs efficiently under mild aerobic conditions still remains
elusive. The quest for alternatives to aryl halides is also de-
sirable in the realm of green chemistry. To the best of our
knowledge only very few aryl halide/triflate equivalents are
reported to date[4] and they all demand the necessity of a
base,[4a,c] ligand,[4c] and/or higher temperatures.[4a–b] Herein,
we report a general palladium-catalyzed base-free aerobic
Sonogashira procedure using organogold complexes at room
temperature. These easily synthesized and stable complexes
are explored for the first time[5] in the coupling reaction
with terminal alkynes.[6–9]
The model reaction was attempted with para-methoxy
phenylacetylene (1.5 equivalent) and (phenyl)(triphenyl-
phosphanyl)gold[10] (A, 1 equivalent) using 10 mol% of pal-
ladium acetate as the catalyst (Scheme 1). The reaction was
carried out in dry degassed tetrahydrofuran under an inert
atmosphere and was monitored by 31P NMR spectroscopy.
The gold complex was consumed in 22 hours at room tem-
perature. The Sonogashira product 2a was isolated in 86%
yield, as well as a trace amount of the homocoupling prod-
uct. Curiosity over regeneration of the palladium catalyst in
the catalytic cycle prompted us to try the reaction under an
atmosphere of oxygen. Interestingly the presence of the
oxygen accelerated the reaction multifolds (completed in
1.5 h at 258C) and the coupling product was isolated in 88%
yield (Scheme 1). It is to be noted that the presence of
oxygen did not enhance the extent of homocoupling, and
again only a trace of it was isolated from the reaction
(Scheme 1). The reaction is equally feasible under normal
air albeit with a slightly longer reaction time (6 h). Other
palladium sources such as [Pd
(PPh3)2] were also effective in catalyzing the reaction but
Pd(OAc)2 stood out as the catalyst of choice. The palladium
loading can be reduced to 3 mol% without any significant
alteration in yield or reaction time but we persisted with the
standard loading of 10 mol% for accurate weighing. The
methodology was then extended to different alkynes (1)
with either (phenyl)(triphenylphosphanyl)gold (A) or (para-
anisyl)(triphenylphosphanyl)gold[6a] (B) as the aryl source
ACHTNUGTRNEN(UGN PPh3)4], PdCl2, and [PdCl2
AHCTUNGTRENNUNG
[a] Dr. S. Pankajakshan, Prof. Dr. T.-P. Loh
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
AHCTUNGTRENNUNG
Fax : (+65)6791-1961
E-mail: teckpeng@ntu.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100263.
Chem. Asian J. 2011, 6, 2291 – 2295
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2291

COMMUNICATION
(Table 1). It was gratifying to find that a range of substrates
can be accommodated using this coupling protocol and the
reaction times were normally in the range of 1.5–2.5 hours
(Table 1, entries 1–11). 1-Naphthylacetylene coupled with B
hamper the reaction and the corresponding aryl–alkyne was
obtained in 67% yield (Table 1, entry 7). It is noteworthy
that aliphatic alkynes were also potential coupling candi-
dates as both n-hexyne and 1-phenyl prop-2-yne delivered
the coupling products in 69% and 98% yields, re-
spectively (Table 1, entries 8 and 9). A conjugated
enyne such as ethynylcyclohexene also was toler-
ated and afforded the coupling product in a mod-
erate 53% yield (Table 1, entry 10). It is remark-
able that the (2-ethynylphenyl)methanol substrate
having a potentially coordinating free hydroxy
group selectively coupled with a reasonably good
yield of 61% (Table 1, entry 11). It is to be noted
that no self-coupling of aryl moieties from the
gold complexes were observed in these reactions;
this is attributed to the redox stability, which is
typical for gold. A negligible amount of the
alkyne homo-coupling product was observed in
most of the cases. No coupling was observed when
the reaction was run in the absence of the palladi-
um catalyst.
A handful of other gold complexes were also
tested for their efficiency to undergo Sonogashira
coupling with para-methoxy phenylacetylene as
the standard coupling partner (Table 2, entries 1–
9). The complexes (para-tolyl)(triphenylphospha-
nyl)gold[11] (C) and (3,5-dimethyl)(phenyl-triphe-
nylphosphanyl)gold[12] (D) furnished the coupling
product in excellent yields of 92% and 90%, re-
spectively (Table 2, entries 1 and 2). The (1-naph-
thyl)(triphenylphosphanyl)gold[13] compound (E)
underwent the coupling reraction in a moderate
60% yield while the isomeric (2-naphthyl)(triphe-
nylphosphanyl)gold[13] complex (F) afforded the
product in a good yield of 83% (Table 2, entries 3
and 4, respectively). The complex (anthracenyl)-
(triphenylphosphanyl)gold (G) delivered the cou-
pling product in 64% yield (Table 2, entry 5) and
traces of liberated anthracene were found in the
reaction mixture. A similar complex (1-pyrenyl)-
(triphenylphosphanyl)gold[14] (H) reacted with a
moderate yield of 42% (Table 2, entry 6). The
electron-rich complex (ortho-anisyl)(triphenyl-
phosphanyl)gold (I) delivered the coupling prod-
Table 1. Scope of different terminal alkynes for the palladium-catalyzed Sonogashira
coupling with organogold complexes.
Entry Alkyne (1)
T [h] Product (2)
Yield [%]
69
1
2
2
3
1.5
2
85
86
4[a]
1.5
2
78
72
5
6
7
1.5
2
85
67
8
1.5
1.5
2
69
98
53
9[a]
10
11
2
61
1
[a] The yield calculated from H NMR spectra as the coupling product and the homo-
coupled product were inseparable by column chromatography.
in 69% yield (Table 1, entry 1). para-Bromophenylacetylene
with two potential coupling sites selectively underwent the
reaction at the terminal alkyne in 85% yield (Table 1,
entry 2). 6-Methoxy 2-naphthylacetylene reacted smoothly
with B with an isolated yield of 86% (Table 1, entry 3). An
ortho substitution of the methoxy group did not seem to
alter the reactivity as 2-methoxy phenylacetylene furnished
the coupling product in 78% yield (Table 1, entry 4). Analo-
gously, 3,4,6-Trimethyl phenylacetylene afforded the aryl–
alkyne product in 72% (Table 1, entry 5). Pleasingly, the
electron-deficient substrate 4-cyano phenylacetylene also re-
acted efficiently in 85% yield (Table 1, entry 6). The pres-
ence of an electron-withdrawing ortho-formyl group did not
uct in 74% yield (Table 2, entry 7). The sterically demand-
ing (2,4,6-trimethylphenyl)(triphenylphosphanyl)gold[15] (J)
also reacted well with an appreciable yield of 64% (Table 2,
entry 8). The heterocyclic complex (2-furyl)(triphenylphos-
phanyl)gold[16] (K) responded inefficiently to the coupling
and the product was isolated in a mediocre 34% yield
(Table 2, entry 9).
The mechanistic profile for this coupling could be ration-
alized in correlation with Hashmiꢁs proposal for the palladi-
um-catalyzed biaryl synthesis using organogold complexe-
s.[6a] The reaction is initiated by the coordination of the pal-
ladium catalyst to the alkyne to form the palladium(II)-ace-
tylide intermediate II (Scheme 2).
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Chem. Asian J. 2011, 6, 2291 – 2295

Palladium-Catalyzed Sonogashira Coupling Reactions
Table 2. Exploration of different organogold complexes for the Sonogashira coupling.
The mechanistic rational for the formation of
the palladium(II)-acetylide species is somewhat
intriguing. Normally the formation of such a spe-
cies is assisted by an external base, which is absent
here (interestingly stoichiometric triethylamine
did not have any significant influence on the reac-
tion profile when added to the model reaction).
We presume that the acetate ligand of the palladi-
um catalyst would be acting as a base,[4b,17,18] thus
leading to the formation of the alkynyl-palladium
species II (following an equimolar mixture of Pd-
Entry Gold complex
T [h] Product (2)
Yield [%]
92
1
C
1.5
AHCTUNGRTEN(NGUN OAc)2 and phenylacetylene in deuterated tetra-
2
3
4
D
E
F
2
90
60
83
1
hydrofuran by H NMR spectroscopy showed that
the acetylinic proton diminishes in intensity, while
new signals typical for acetic acid increased in in-
tensity, see the Supporting Information for de-
tails). The subsequent transmetalation from the
gold complex furnishes the aryl–alkynyl palladium
intermediate III.[19] Subsequent reductive elimina-
tion and aerobic oxidation of the resulting palladi-
um(0) species regenerates the catalyst. In line
with a recent report from Gagnꢂ and Weber,[20] we
assume that the [PPh3AuOAc] generated after
transmetalation also acts as a co-oxidant for palla-
2
1.5
5[a]
G
1.5
64
dium. The possibility of a [Pd
formed by the previous transmetalation of Pd-
(OAc)2 and the gold complex reacting with the
alkyne to form the intermediate III was ruled out
by a control experiment (Scheme 3), in which the
gold complex A reacted with catalytic amounts of
ACHTUNGTREN(NUGN OAc)Ar’] species
6
H
I
2
2
42
74
AHCTUNGTRENNUNG
7[a]
PdACTHNUTRGEN(UGN OAc)2, thus furnishing the self-coupled biaryl
in quantitative yields. The absence of such biaryl
products in the Sonogashira reactions points to
the assumption that the catalyst reacts preferen-
tially with the alkyne to form the palladium(II)-
acetylide species II.
8
9
J
2
64
34
K
2.5
To support the intermediacy of the alkynyl-pal-
ladium(II) species II, we synthesized a model al-
kynyl-palladium(II) complex[22] 3 and exposed it
to the organogold complex D under identical con-
ditions to the coupling reactions (Scheme 4).
Pleasingly, the reaction was completed in 15 mi-
nutes, and the Sonogashira product 2 was isolated
in 70% yield. The formation of (triphenylphosphi-
[a] The yield calculated from 1H NMR spectra. The gold seemed to agglomerate to
zero-valent clusters eventually, which explained the wine-red[21] coating on the inner
surface of the reaction flask after the reaction. Attempts to recover the gold by the
addition of halogen donors such as LiCl, MgBr2, or N-bromosuccinimide (NBS)
proved futile.
ne)gold(I) chloride was also observed in the 31P NMR spec-
trum, which further supported the transmetalation. The pos-
sibility of any copper impurities in the commercially avail-
able PdACHTUNTGRNE(UNG OAc)2 that could catalyze/co-catalyze the reaction
Scheme 3. Self-coupling of organogold complex A with palladium cata-
Scheme 2. Plausible mechanism for the reaction.
lyst.
Chem. Asian J. 2011, 6, 2291 – 2295
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2293

T.-P Loh and S. Pankajakshan
COMMUNICATION
Acknowledgements
This research was supported finan-
cially by the Nanyang Technological
University and the Singapore Minis-
try of Education Academic Research
Fund Tier 2 (T207B1220RS). We also
thank Prof. S. Chiba (NTU, Singa-
pore) and Prof. Stephen K. Hashmi
(University of Heidelberg, Germany)
for their kind feedback.
Scheme 4. Coupling with palladium-alkynyl complex and organogold complex.[a,b] [a] A small amount CH2Cl2
was used as a co-solvent to dissolve the palladium complex. [b] Yield calculated from 1H NMR spectroscopy.
Keywords: alkynes · catalysis ·
cross-coupling
palladium
·
gold
·
was ruled out by carrying out the model reaction in the
presence of 5 mol% copper(I) iodide (Scheme 4, [Eq. (1)].
The reaction did not show any rate enhancement compared
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Scheme 5. Model reactions to rule out a copper-catalyzed pathway.
In conclusion, an effective procedure for an aerobic aryl–
alkyne coupling under very mild conditions has been devel-
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complexes as pseudo-aryl halides in the Sonogashira cou-
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tions. Experimental support for the proposed mechanism
was also gained. Current efforts are directed towards impro-
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Experimental Section
The alkyne (1.5 mmol, 1.5 equiv) was added to dry THF (2 mL) in a
flame dried round bottom flask. The gold complex (1 mmol, 1 equiv) was
added and oxygen was bubbled through the solution for 2 min. Palladium
acetate (10 mol%) was added and the reaction mixture was stirred at
room temperature. The progress of the reaction was monitored by
31P NMR spectroscopy until the gold complex was completely consumed
(1.5–2.5 h). The solvent was removed under reduced pressure and the res-
idue was purified over silica gel (hexane/ethyl acetate 100:1) to furnish
the pure cross-coupled product.
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Chem. Asian J. 2011, 6, 2291 – 2295

Palladium-Catalyzed Sonogashira Coupling Reactions
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À
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Received: March 14, 2011
Published online: June 30, 2011
Chem. Asian J. 2011, 6, 2291 – 2295
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