Unlikeliness of Pd-free gold(I)-catalyzed sonogashira coupling reactions

Article abstract of DOI:10.1021/ol101012n

The Sonogashira coupling reaction is not catalyzed by AuI/dppe in the absence of Pd complexes. However, addition of 0.1 mol % of Pd(0) led to efficient cross-coupling reactions. The most plausible catalytic cycles for the Au-catalyzed cross-coupling reactions have been examined and are unlikely in the absence of Pd contamination.

Full text of DOI:10.1021/ol101012n

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3006-3009
Unlikeliness of Pd-Free Gold(I)-Catalyzed
Sonogashira Coupling Reactions
Thorsten Lauterbach,† Madeleine Livendahl,† Antonio Rosello´n,† Pablo Espinet,‡,*
and Antonio M. Echavarren†,*
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans 16,
43007 Tarragona, Spain, and IU CINQUIMA/Qu´ımica Inorga´nica, Facultad de
Ciencias, UniVersidad de Valladolid, 47071 Valladolid, Spain
espinet@qi.uVa.es; aechaVarren@iciq.es
Received May 3, 2010
ABSTRACT
The Sonogashira coupling reaction is not catalyzed by AuI/dppe in the absence of Pd complexes. However, addition of 0.1 mol % of Pd(0) led
to efficient cross-coupling reactions. The most plausible catalytic cycles for the Au-catalyzed cross-coupling reactions have been examined
and are unlikely in the absence of Pd contamination.
In the past decade gold has been shown to promote a
bewildering variety of metal-catalyzed processes to the
point that it would seem that other transition metals are
being forced to retreat.1 Most Au(I)-catalyzed reactions
of alkynes and allenes do not involve any change in
oxidation state of the gold center, which acts essentially
as a tunable acidic center throughout the reaction.2
There are other processes where gold is reported to do
the job usually carried out with palladium, producing C-C
cross-coupling.3 This is, for instance, the case of gold-
catalyzed Sonogashira4-7 and Suzuki4,8,9 reactions. For the
standard reaction of phenylacetylene and iodobenzene, with
PhI, Au(III) led only to homocoupling of the acetylene in
low yield,4,10 whereas [AuCl(PPh3)] (20 mol %) gave the
coupling product (tolane) in 54% conversion (xylene, 130
°C, 24 h).4
It has been argued that “Au(I) with the same d10 config-
uration as Pd(0) can catalyze reactions typically catalyzed
by palladium”,4,9 but this statement is too simple. For
instance, Pt(0) does not catalyze many reactions typically
catalyzed by Pd(0),11 showing that isoelectronic metal centers
do not necessarily behave similarly.
(5) (a) Gonza´lez-Arellano, C.; Abad, A.; Corma, A.; Garcia, H.; Iglesias,
M.; Sa´nchez, F. Angew. Chem., Int. Ed. 2007, 46, 1536–1538. (b) Corma,
A.; Gonza´lez-Arellano, C.; Iglesias, M.; Pe´rez-Ferreras, S.; Sa´nchez, F.
Synlett 2007, 1771–1774. (c) Gonza´lez-Arellano, C.; Corma, A.; Iglesias,
M.; Sa´nchez, F. Eur. J. Inorg. Chem. 2008, 1107–1115.
† Institute of Chemical Research of Catalonia (ICIQ).
‡ IU CINQUIMA/Qu´ımica Inorga´nica, Universidad de Valladolid.
(1) (a) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. ReV. 2008, 108,
3326–3350. (b) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008,
108, 3351–3378. (c) Michelet, V.; Toullec, P. Y.; Geneˆt, J. P. Angew. Chem.,
Int. Ed. 2008, 47, 4268–4315. (d) Fu¨rstner, A. Chem. Soc. ReV. 2009, 38,
3208–3221.
(6) Li, P.; Wang, L.; Wang, M.; You, F. Eur. J. Org. Chem. 2008, 5946–
5951.
(7) de Souza, O. M. A.; Bittar, M. S.; Mendes, L. V. P.; Michele, C.;
da Silva, F. Synlett 2008, 1777–1780.
(2) For leading references on mechanistic work Au(I)-catalyzed reactions,
see: (a) Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y.; Goddard,
W. A., III.; Toste, F. D. Nature Chem. 2009, 1, 482–486. (b) Nieto-
Oberhuber, C.; Pe´rez-Gala´n, P.; Herrero-Go´mez, E.; Lauterbach, T.;
Rodr´ıguez, C.; Lo´pez, S.; Bour, C.; Rosello´n, A.; Ca´rdenas, D. J.;
Echavarren, A. M. J. Am. Chem. Soc. 2008, 130, 269–279. (c) Soriano, E.;
Marco-Contelles, J. Acc. Chem. Res. 2009, 42, 1026–1036. (d) Marion,
N.; Lemie`re, G.; Correa, A.; Costabile, C.; Ramo´n, R. S.; Moreau, X.; de
Fre´mont, P.; Dahmane, R.; Hours, A.; Lesage, D.; Tabet, J.-C.; Goddard,
J.-P.; Gandon, V.; Cavallo, L.; Fensterbank, L.; Malacria, M.; Nolan, S. P.
Chem.sEur. J. 2009, 15, 3243–3260.
(8) Han, J.; Liu, Y.; Guo, R. J. Am. Chem. Soc. 2009, 131, 2060–2061.
(9) (a) Carrettin, S.; Corma, A.; Iglesias, M.; Sa´nchez, F. Appl. Catal.,
A 2005, 291, 247–252. (b) Gonza´lez-Arellano, C.; Corma, A.; Iglesias, M.;
Sa´nchez, F. J. Catal. 2006, 238, 497–501. (c) Corma, A.; Gutie´rrez-Puebla,
E.; Iglesias, M.; Monge, A.; Pe´rez-Ferreras, S.; Sa´nchez, F. AdV. Synth.
Catal. 2006, 348, 1899–1907. (d) Debono, N.; Iglesias, M.; Sa´nchez, F.
AdV. Synth. Catal. 2007, 349, 2470–2476.
(10) Dimerization of arylboronic acids with heterogeneous Au catalysts:
(a) Tsunoyama, H.; Sakurai, H.; Ichikuni, N.; Negishi, Y.; Tsukuda, T.
Langmuir 2004, 20, 11293–11296. (b) Carrettin, S.; Guzman, J.; Corma,
A. Angew. Chem., Int. Ed. 2005, 44, 2242–2245. (c) Gonza´lez-Arellano,
C.; Corma, A.; Iglesias, M.; Sa´nchez, F. Chem. Commun. 2005, 1990–
(3) Garcia, P.; Malacria, M.; Aubert, C.; Gandon, V.; Fensterbank, L.
ChemCatChem 2010, 2, 493–497.
(4) Review: Plenio, H. Angew. Chem., Int. Ed. 2008, 47, 6954–6956.
1992.
10.1021/ol101012n  2010 American Chemical Society
Published on Web 06/01/2010

Experimental reports claim that Au(I) is selective and very
active, for instance, toward cross coupling of aryl halides
with acetylenes (“Pd-free Sonogashira” for example), in the
presence of mild bases. Surprisingly, this intriguing process
has not been investigated mechanistically. We decided to
set out experiments that would explain mechanistically the
Pd-free cross-coupling catalysis with gold, but in fact what
we are reporting is our failure to find a plausible mechanism.
Furthermore, our experiments suggest that the presence
of adventitious Pd might explain the positive “Pd-free
Sonogashira” catalysis reported. This is in line with recent
findings in Suzuki coupling reactions, which proceed under
very low Pd loadings.12,13
Scheme 1
.
Plausible Cycles for Au-Catalyzed Cross-Coupling
Reactionsa
At first sight it looks reasonable to consider that a similar
d10/d8 interplay might be operative for the two isoelectronic
couples Pd(0)/Pd(II) and Au(I)/Au(III). Both d8 metal centers
not only are isoelectronic, they also form square-planar com-
plexes. For the d8 metal centers, Au(I) is usually linear
coordinated. Although Pd(0) with common ligands (PPh3) is
tetrahedral, it is known to dissociate in solution and it is believed
that the reactive species are dicoordinated PdL2.14 Thus, the
typical oxidative addition/transmetalation/reductive elimina-
tion cycle of Pd, which applies (in a general sense) to any Pd-
catalyzed cross-coupling process, could in principle be taken
as the model for gold cross-coupling catalysis. However, there
is an important difference in the lower oxidation state of the
two systems: whereas for PdL2 only the oxidative addition
reaction is expected, for AuXL both oxidative addition and
transmetalation reactions are plausible.15,16 Therefore, two
cycles should be considered where these two steps are
transposed (Scheme 1, cycles A and B).17,18 The feasibility
of the two cycles and their steps as isolated processes was
experimentally investigated, starting with [AuI(PPh3)].
a Here R1 ) aryl and R2 ) alkynyl.
Both cycles A and B have in common the third step, the
reductive elimination from the Au(III) intermediate [AuAr-
(alkynyl)XL]. No complex of this kind has been reported,
so we decided to check the transmetalation reaction between
an aryl-Au(III) complex 1 and a silver alkynyl derivative 2
for the in situ formation of a complex 3 of this type (Scheme
2). Thus, the stable complex trans-[Au(C6F5)I2(PPh3)] (1a)19
Scheme 2
(11) See, for example: (a) Mateo, C.; Ferna´ndez-Rivas, C.; Ca´rdenas,
D. J.; Echavarren, A. M. Organometallics 1998, 17, 3661–3669. (b) Nilsson,
P.; Puxty, G.; Wendt, O. F. Organometallics 2006, 25, 1285–1292
.
(12) (a) Up to the level of 50 ppb Pd found in commercially available
Na2CO3 catalyzed the Suzuki coupling reaction of phenylboronic acid with
4-bromoacetophenone: Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.;
Williams, V. A.; Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161–
168
.
(13) For the related role of Cu traces in the context of Fe-catalyzed
coupling reactions see: (a) Buchwald, S. L.; Bolm, C. Angew. Chem., Int.
Ed. 2009, 48, 5586–5587. (b) Bedford, R. B.; Nakamura, M.; Gower, N. J.;
Haddow, M. F.; Hall, M. A.; Huwea, M.; Hashimoto, T.; Okopie, R. A.
Tetrahedron Lett. 2009, 50, 6110–6111
.
was treated with Ag(C2C6H4Me) (2a) (1:1) in order to
exchange one iodide by one alkynyl, but the corresponding
complex could not be obtained. Instead, the cross-coupling
product 4 was obtained showing that the coupling step on
Au(III), common to both cycles, not only is feasible but is
also a very fast process.20 In other words, if the two previous
steps in the cycle take place, the cross-coupling product
should be formed immediately.
(14) (a) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am. Chem.
Soc. 2009, 131, 8141–8154. (b) Surry, D. S.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 6338–6361.
(15) Transmetalation of [AuBrPPh3] with boronic acids: Partyka, D. V.;
Zeller, M.; Hunter, A. D.; Gray, T. G. Angew. Chem., Int. Ed. 2006, 45,
8188–8199
.
(16) Transmetalation from RAu(I) to R′Pd(II) complexes: (a) Shi, Y.;
Ramgren, S. D.; Blum, S. A. Organometallics 2009, 28, 1275–1277. (b)
Shi, Y.; Roth, K. E.; Ramgren, S. D.; Blum, S. A. J. Am. Chem. Soc. 2009,
131, 18022–18023. (c) Hashmi, A. S. K.; Lothschu¨tz, C.; Do¨pp, R.; Rudolph,
M.; Ramamurthi, T. D.; Rominger, F. Angew. Chem., Int. Ed. 2009, 48,
8243–8246
.
Cycle A: The first step in this cycle is the oxidative
addition of ArX to [AuX(PPh3)] to give Au(III) complexes
(17) X- stands for an inorganic anionic ligand, often a halide. Note that
(i) the X group coming with the electrophile R1X can be different from the
X ligand coming with the gold complex and (ii) anionic ligands undergo
fast exchange in solution so that, when two or more were present on the
metal, we should represent the different combinations in, for instance, AuX3.
However, these possible changes are not decisive for the discussion.
(18) Aryl-Au(I) complexes catalyze the isomerization of trans-[PdR2L2]
to cis-[PdR2L2] complexes by Au(I)/Pd(II) transmetalation: Casado, A. L.;
(19) Uso´n, R.; Laguna, A.; Pardo, J. Syn. React. Inorg. Met.-Org. Chem.
1974, 4, 499–513.
(20) This result is in keeping with that observed in the reaction between
[AuPhCl2(lut)] or [Au(2,5-Me2C6H3)Cl2(lut)] (lut ) 2,6-dimethylpyridine)
and phenylacetylene: Fuchita, Y.; Utsunomiya, Y.; Yasutake, M. J. Chem.
Soc., Dalton Trans. 2001, 2330–2334.
Espinet, P. Organometallics 1998, 17, 3677–3683
.
Org. Lett., Vol. 12, No. 13, 2010
3007

[AuArX2(PPh3)]. Complexes of this kind are stable with
perhalogenated aryls such as C6F5, but not for conventional
aryl groups.21,22 They are obtained by oxidative addition of
Au(I) complexes with X2 (X ) Cl, Br, I). To the best of our
knowledge, there is no report for a successful oxidative
addition of ArX to [AuXL], which is the requirement of the
first step of cycle A. In fact all attempts to carry out the
oxidative addition of PhI, p-MeOC6H4I, p-MeOCC6H4I, or
p-O2NC6H4I to [AuCl(PPh3)] in a variety of solvents at
40-80 °C led to complete recovery of the starting materials.
Indeed, only methyl gold(I) complexes [AuMePR3] (PR3 )
PMe3, PMe2Ph, PMePh2, PPh3) are known to undergo slow
oxidative addition reaction with alkyl iodides, following the
expected pattern for SN2 reactions: CH3I > EtI > i-PrI.23
This behavior clearly differs from that of [Pd(PPh3)4] or
[Pd2(dba)3] + PPh3 systems, which are easily oxidized by
aryl halides to give complexes [PdRX(PPh3)2].24 It seems
that the oxidation potentials of the isoelectronic d10 com-
plexes of Au(I) and Pd(0) differ significantly, enough as to
prevent the oxidation to Au(III) by ArX. Therefore, the
viability of cycle A is discarded because the initial step
(oxidative addition to [AuI(PPh3)]) does not seem feasible.
Table 1. Oxidative Addition Reactions of 5a,b under Different
Conditions
entry
5
conditions
additive
yield (%)
1
2
3
4
5
6
5a
5a
5a
5a
5b
5b
toluene, 130 °C, 24 h
toluene, 300 °C,a 24 h
PhI solvent, 30 °C, 24 h
toluene, 130 °C, 24 h
toluene, 130 °C, 24 h
toluene, 130 °C, 16 h
<1%
<1%
<1%
<1%
<1%
7b 100%
K2CO3
[Pd]b
a Microwave heating. b [Pd] ) [PdCl2(PPh3)2] (1.4 mol %), i-Pr2NH.
reaction conditions. This is a strong indication that,
similarly to [AuI(PPh3)], also [Au(C2C6H4Me)(PPh3)] is
resistant to oxidative addition by ArI and frustrates the
coupling cycle.
Cycle B: The formation of [Au(alkynyl)(PPh3)] in the
catalytic cycle would require the alkynylation of [AuI-
(PPh3)] with acetylenes in the presence of base. This
reaction is well-known to occur easily and to be fast and
complete.25 It has been used, for instance, to prepare gold
liquid crystals,26 and takes place also with the starting
complexes implicated in the catalysis under examination.
A mild base (e.g., NaOAc) is enough to promote the
reaction, which even proceeds in the absence of base.26
Indeed complex [Au(C2C6H4Me)(PPh3)] (6) was easily
prepared and the oxidative addition reactions with RC6H4I
(R ) Ph (5a), COMe (5b)) under different conditions were
studied. As discussed above, if an oxidative addition
[AuR(C2C6H4Me)I(PPh3)] product was formed it should
give rise immediately to the heterocoupling product. As
shown in Table 1 (entries 1-5), in no case was coupling
product observed regardless of the R group and the
Interestingly, the addition of a catalytic amount of Pd
complex (entry 6) suffices to produce complete conversion,
suggesting again that Pd performs easily the oxidative
addition that Au does not. In these conditions the gold
alkynyl would simply be an intermediate agent transmeta-
lating the nucleophile (alkynyl in this case) to Pd. In other
words, the reaction would be a common Sonogashira reaction
catalyzed by Pd, with Au(I) playing the role classically
played by Cu(I). In coincidence with this interpretation, the
gold(I) complex [AuCl(tht)] (tht ) tetrahydrothiophene) has
been shown to replace Cu(I) as cocatalyst in Sonogashira
reactions catalyzed by [PdCl2(PPh3)2].27 It is important to
note that [AuCl(tht)] was inactive in the absence of a Pd
complex.27a
According to our results, gold should not be able to
catalyze the so-called Pd-free Sonogashira coupling, since
Au(I) is unable to activate the electrophile ArI by undergoing
oxidative addition. This conclusion is in contrast with recent
reports of reactions that give excellent yields.5,6 Consequently
we decided to check their reproducibility in the reaction
between aryl iodide 5b and tolylacetylene (8).28 In our hands,
only traces of the coupling product 7b were produced using
AuI (Table 2).
(21) (a) Vaughan, L. G.; Sheppard, W. A. J. Am. Chem. Soc. 1969, 91,
6151–6156. (b) Schneider, D.; Schier, A.; Schmidbaur, H. Dalton Trans.
2004, 1995–2005
.
(22) (a) Luquin, A.; Cerrada, E.; Laguna, M. In Gold Chemistry; Wiley-
VCH: Weinheim, Germany, 2009; pp 93-181. (b) Schmidbaur, H.; Schier,
A. Product class 6: Organometallic Complexes of Gold. Sci. Synth. 2004,
3, 691–761. (c) Anderson, G. K. AdV. Organomet. Chem. 1982, 20, 38–
114
.
(23) (a) Tamaki, A.; Kochi, J. K. J. Organomet. Chem. 1972, 40, C81–
C84. (b) Tamaki, A.; Kochi, J. K. J. Chem. Soc., Dalton Trans. 1973, 2620–
2626. (c) Johnson, A.; Puddephatt, R. J. Inorg. Nucl. Chem. Lett. 1973, 9,
1175–1177. (d) Tamaki, A.; Kochi, J. K. J. Organomet. Chem. 1974, 64,
411–425. (e) Johnson, A.; Puddephatt, R. J. J. Organomet. Chem. 1975,
85, 115–121. (f) Reaction of [AuMePR3] with CF3I proceeds by a radical
mechanism: Johnson, A.; Puddephatt, R. J. J. Chem. Soc., Dalton Trans.
1976, 1360–1363.
The material reported to be catalytically active in the
Sonogashira and Suzuki coupling reactions5 was mistakenly
assigned as complex 9, formed from monoimine 10 (Figure
1).29 In our hands, treatment of [AuCl(PPh3)] with the
potassium salts of any of the ligands probably present in
(24) See for instance the oxidative addition of ArI to Pd(PPh3)4: Casado,
A. L.; Espinet, P. Organometallics 1998, 17, 954–959.
(25) (a) Liau, R.-Y.; Schier, A.; Schmidbaur, H. Organometallics 2003,
22, 3199–3204. (b) McArdle, C. P.; Van, S.; Jennings, M. C.; Puddephatt,
R. J. J. Am. Chem. Soc. 2002, 124, 3959–3965. (c) MacDonald, M.-A.;
Puddephatt, R. J.; Yap, G. P. A. Organometallics 2000, 19, 2194–2199.
(d) Vicente, J.; Chicote, M.-T.; Abrisqueta, M.-D.; Jones, P. G. Organo-
metallics 1997, 16, 5628–5636.
(27) (a) Jones, L. A.; Sanz, S.; Laguna, M. Catal. Today 2007, 122,
403–406. (b) Panda, B.; Sarkar, T. K. Tetrahedron Lett. 2010, 51, 301–
305. (c) Panda, B.; Sarkar, T. K. Chem. Commun. 2010, 46, 3131-
3133.
(28) As a control, this Sonogashira reaction proceeds with PdCl2(PPh3)2
(1 mol %) and [AuCl(PPh3)] (1 mol %) or AuCl3 (1 mol %) to give 7b in
72% and 63% yield (determined by GC-MS), respectively.
(26) Alaejos, P.; Coco, S.; Espinet, P. New J. Chem. 1995, 19, 799–
805.
3008
Org. Lett., Vol. 12, No. 13, 2010

acetylene with 1-iodo-4-methylbenzene was observed with
12 (10 mol %) (K2CO3, toluene, 130 °C, 16 h) in the presence
or absence of [Pd2(dba)3 · CHCl3].
Table 2. Effect of Palladium on the Sonogashira Coupling with
AuI/dppea
Even high-purity gold often contains traces of palladium,31
which leads us to suspect that the presence of traces of
palladium is responsible for the success of the Au(I)-
catalyzed “Pd-free Sonogashira reaction”. The gold iodide
used in this work contained 3.1 µg/g Pd in AuI and was
practically inactive in the Sonogashira reaction, but adding
small amounts of Pd(0) increased progressively the yield of
the Sonogashira product (Table 2).
entry
[Pd]b (mol %)
conversion (%)
yield (%)
1
2
3
4
5
6
7c
<2%
6
16
<2%
6
16
24
82
78
<2%
Since a metal catalyst M for cross-coupling processes is
required to activate the electrophile RX by undergoing
oxidative addition to form RMX, it is unlikely that these
processes can be catalyzed by metal centers that cannot
undergo such oxidation, as seems to be the case for Au(I)
with aryl halides. The Au-catalyzed Sonogashira reactions
reported might well proceed thanks to Pd contamination of
any of the compounds involved in the reaction, which would
provide the Pd catalyst necessary to carry out the reaction
according to Scheme 3. The catalysis would fail or succeed
1.2 × 10-4
1.2 × 10-3
1.2 × 10-2
0.12
1.2
1.2
24
100
100
<2%
a AuI (2 mol %), dppe (2 mol %), K2CO3, toluene, 130 °C, 16 h. b [Pd]
) [Pd2(dba)3 · CHCl3]. c Room temperature.
those studies (monoimine 10 and bisimine 11) resulted only
in mixtures of Au(I) complexes that did not catalyze the
Sonogashira coupling of iodobenzene with phenylacetylene.
Scheme 3
in different hands depending on the amount of Pd contami-
nation in the reagents used. Pd contamination should be
tested before a Pd-free catalysis is claimed.
Acknowledgment. We thank the MICINN (CTQ2007-
67411/BQU; CTQ2007-60745/BQU; Consolider Ingenio
2010, Grant CSD2006-0003; Juan de la Cierva Contract to
T.L.), AGAUR (2009 SGR 47), JCyL (GR169), and ICIQ
Foundation for support and Prof. Fe´lix Sa´nchez (CSIC,
Madrid) for experimental details and a sample of the ligand
used to prepare reported 9.
Figure 1. Compounds 9-12.
Since Au(I) complexes with Au-O bonds are a rarity, we
also examined the activity of the well-characterized complex
12,30 containing N-Au and O-Au bonds as had been
proposed for 9. No coupling between 8 or p-acetylphenyl-
Supporting Information Available: Experimental details,
characterization data, and additional results. This material
is available free of charge via the Internet at http://pubs.acs.org.
(29) Complex 9 was depicted in refs 5a and 5c with different formulas
([(C32H28N2)O{Au(PPh3)3}]Cl or [(C32H30N2)O{Au(PPh3)3}], respectively).
OL101012N
1
Examination of the H NMR spectrum of the starting ligand used for the
preparation of 9 in those references, kindly provided by the authors, revealed
that it was in fact the bisimine 11.
(30) Kolb, A.; Bissinger, P.; Schmidbauer, H. Inorg. Chem. 1993, 32,
5132–5135.
(31) (a) Kinneberg, D. J.; Williams, S. R.; Agarwal, D. P. Gold Bull.
1998, 31, 58–67. (b) Karadjova, I.; Arpadjan, S.; Jordanova, L.; Fresenius,
J. Anal. Chem. 2000, 367, 146–150.
Org. Lett., Vol. 12, No. 13, 2010
3009