Oxidant speciation and anionic ligand effects in the gold-catalyzed oxidative coupling of arenes and alkynes

Article abstract of DOI:10.1039/c9sc02372k

The mechanism of the gold-catalyzed oxidative cross-coupling of arenes and alkynes has been studied in detail combining stoichiometric experiments with putative reaction intermediates and DFT calculations. Our data suggest that ligand exchange between the alkyne, the Au(i)-catalyst and the hypervalent iodine reagent is responsible for the formation of both an Au(i)-acetylide complex and a more reactive "non-symmetric" I(iii) oxidant responsible for the crucial Au(i)/Au(iii) turnover. Further, the reactivity of the in situ generated Au(iii)-acetylide complex is governed by the nature of the anionic ligands transferred by the I(iii) oxidant: while halogen ligands remain unreactive, acetato ligands are efficiently displaced by the arene to yield the observed Csp²-Csp cross-coupling products through an irreversible reductive elimination step. Finally, the nature of competitive processes and catalyst deactivation pathways has also been unraveled. This detailed investigation provides insights not only on the specific features of the species involved in oxidative gold-catalyzed cross couplings but also highlights the importance of both ancillary and anionic ligands in the reactivity of the key Au(iii) intermediates.

Full text of DOI:10.1039/c9sc02372k

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Oxidant speciation and anionic ligand effects in the
gold-catalyzed oxidative coupling of arenes and
Cite this: DOI: 10.1039/c9sc02372k
alkynes†
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Manuel Hofer,a Teresa de Haro,a Enrique Gomez-Bengoa,
and Cristina Nevado
Alexandre Genouxa
b
´
a
*
The mechanism of the gold-catalyzed oxidative cross-coupling of arenes and alkynes has been studied in
detail combining stoichiometric experiments with putative reaction intermediates and DFT calculations.
Our data suggest that ligand exchange between the alkyne, the Au(I)-catalyst and the hypervalent iodine
reagent is responsible for the formation of both an Au(I)-acetylide complex and a more reactive “non-
symmetric” I(III) oxidant responsible for the crucial Au(I)/Au(III) turnover. Further, the reactivity of the in
situ generated Au(III)-acetylide complex is governed by the nature of the anionic ligands transferred by
the I(III) oxidant: while halogen ligands remain unreactive, acetato ligands are efficiently displaced by the
arene to yield the observed Csp2–Csp cross-coupling products through an irreversible reductive
elimination step. Finally, the nature of competitive processes and catalyst deactivation pathways has also
been unraveled. This detailed investigation provides insights not only on the specific features of the
species involved in oxidative gold-catalyzed cross couplings but also highlights the importance of both
ancillary and anionic ligands in the reactivity of the key Au(III) intermediates.
Received 15th May 2019
Accepted 9th July 2019
DOI: 10.1039/c9sc02372k
rsc.li/chemical-science
moieties in the presence of catalytic amounts of late transition
metals as demonstrated by Waser et al.6 In this context, our
Introduction
group reported an oxidative alkynylation of arenes via Au-cata-
lyzed C–H functionalization of both Csp- and Csp2–H bonds
(eqn (1) and Scheme 1).7 One of the most remarkable features of
this protocol was the use of “deactivated” electron rich arenes
and electron decient alkynes as coupling partners. A catalytic
amount of Ph3PAuCl in combination with commercially avail-
able PhI(OAc)2 as the stoichiometric oxidant was found to be
effective in producing new Csp2–Csp bonds.8 A stoichiometric
version of this transformation had been already described by
Fuchita and co-workers back in 2001.9
Aryl alkynes have found widespread use as building blocks in
the synthesis of numerous natural products, bioactive mole-
cules and organic materials.1 In recent years, metal-catalyzed
Csp2–H bond functionalizations have been explored as an
alternative strategy to classical Pd-catalyzed cross-coupling
reactions for the efficient construction of Csp2–Csp bonds.2
These approaches are attractive because they avoid the other-
wise necessary pre-functionalization of the aromatic partner.
However, and in contrast to the large body of metal-catalyzed
Csp2–H arylation reactions,3 the direct Csp2–H alkynylation of
arenes has been much less explored. Few examples though have
shown the viability of this strategy.4 In 2010, the Cu-catalyzed
direct alkynylation of electron decient polyuoroarenes with
terminal alkynes using O2 as the oxidant was reported by Su
et al.5 Despite its efficiency, the reaction is barely catalytic and
relies on the acidity of the Csp2–H bond in the arene substrate.
A different approach focused on the stoichiometric use of
alkynyliodonium species as an electrophilic source of acetylenic
In the catalytic version, a hypervalent iodine reagent10 was
selected as the oxidant on the basis of signicant evidence that
these species could promote Pd(II)/Pd(IV) catalytic cycles.11 We
a
¨
¨
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, Zurich,
CH-8057, Switzerland. E-mail: cristina.nevado@chem.uzh.ch
b
´
´
Departamento de Quımica Organica I, Universidad del Pais Vasco, Apdo 1072, CP-
´
20080 Donostia-San Sebastian, Spain
† Electronic supplementary information (ESI) available. CCDC 1008765. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9sc02372k
Scheme 1 Au-catalyzed alkynylation of arenes.
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thus anticipated that a Au(I)/Au(III) catalytic turnover could be
implemented under the reaction conditions. Furthermore, the
ability of Au(III) species to trigger Csp2–H activation in electron
rich arenes is also well established.9,12 Although Au(I)/Au(III)-cata-
lyzed reactions have recently emerged as powerful tools for C–C
cross couplings,13 with few notable exceptions,14 the mechanistic
understanding of these processes is still limited and the charac-
terization of putative intermediates is scarce. We report herein
a detailed investigation aiming to elucidate the factors governing
both reactivity and selectivity in these transformations.
In our previous work,7 the mechanistic rationale involved: (i) an
equilibrium between the free alkyne and the Au catalyst with the
aid of a base to form a Au(I)-acetylide complex (I); (ii) oxidation of I
with PhI(OAc)2 to form Au(III) species II; (iii) arene auration to
produce intermediate III which evolves via reductive elimination
(iv) yielding product IV (Scheme 2, path A.1). Alternatively, in line
with Waser's reports on the stoichiometric use of alkynyliodonium
salts,6 a ligand exchange between PhI(OAc)2 and Au(I)-acetylide (I)
to give an alkynyliodonium intermediate (V) could also be
proposed. Arene addition to give VI followed by b-Au elimination
would then furnish product IV as shown in path B.1 of Scheme 2.
Alternatively, transmetalation between alkynyliodonium salt V and
putative aryl-Au(III) species (VII) produced in situ within the
oxidative reaction media12 could also deliver intermediate III,
which would yield the observed products aer reductive elimina-
tion as shown in Scheme 2, path B.2.
Our preliminary study le open several key questions: rst
and foremost, the role of PhI(OAc)2 needed to be established,
whether it functioned as a stoichiometric oxidant to achieve the
Au(I)/Au(III) turnover or as an electrophilic source to exchange
and then cross-couple the alkyne to an electron rich arene, or
both. In addition, the order of steps needed to be claried as to
whether the transfer of the alkyne to the gold(I) complex (path
A.1) or a direct oxidation (path A.2) was involved in the initial
step of the catalytic cycle. Furthermore, neither detailed infor-
mation about the metal coordination sphere in the proposed
Au(III) intermediates II and III nor about the oxidant environ-
ment was available from these initial investigations.7
Fig. 1 (a–d) Stoichiometric experiments involving alkynyliodonium
species (paths B.1 and B.2 in Scheme 2). (e and f) Stoichiometric
experiments regarding path A.2.
Treatment of methyl 3-(phenyl(tosyloxy)-l3-iodanyl)propiolate
with stoichiometric amounts of 3,5-dimethoxytoluene (4) and
Ph3PAuCl or Ph3PAuOAc at 90 ꢀC did not furnish the desired
Csp2–Csp cross coupling product and only decomposition of the
alkynyliodonium salt was detected (Fig. 1a and b). Identical
experiments in the presence of gold(III) complexes like Ph3PAuCl3
or Au(OAc)3/PPh3 showed a similar outcome (Fig. 1c and d).
Interestingly, in the case of Ph3PAuCl3 formation of 2-chloro-1,5-
dimethoxy-3-methylbenzene as the by-product could be observ-
ed.12a These control experiments (Section 2 in the ESI†) led us to
rule out pathways B.1 and B.2 and the participation of alkyny-
liodonium species V as intermediates in these transformations.
Experiments to investigate pathway A.2 involved the partici-
pation of the alkyne in the presence of gold(III) species. However,
stoichiometric experiments with 3,5-dimethoxytolueneꢀ(4), methyl
propiolate (5) and Ph3PAuCl3 or Au(OAc)3/PPh3 at 90 C showed
the formation of the arylchloride in the case of Ph3PAuCl3 but no
participation of the alkyne (Fig. 1e and f). To explore the direct
oxidation of the initial catalyst, Ph3PAuCl was treated with an
ꢀ
excess of PhI(OAc)2 at 90 C. However, no reaction was observed
even aer prolonged heating and just Ph3PO could be detected in
trace amounts (Fig. S2 and S3 in the ESI†). These experiments
suggest that the neutral Ph3PAuCl complex used as the catalyst is
scarcely oxidized by PhI(OAc)2 under the reaction conditions, in
contrast to previous results obtained for PhICl2 which furnished
Ph3PAuCl3 in 96% yield even at room temperature.16 In situ
oxidation of the Au(I) catalyst also seems to be at the outset of the
Au-catalyzed oxidative oxo- and aminoarylation of alkenes with
boronic acids.14a,b However, the results described herein clearly
indicate that the present alkynylation reaction proceeds, at least at
the outset, through an alternative reaction mechanism.
Results and discussion
Initial experiments15 to investigate the feasibility of pathways
B.1 and B.2 focused on alkynyliodonium salts (V) in order to
reveal their potential role as intermediates in these
transformations.
Formation and reactivity of Au(I)-acetylide (8)
To investigate path A.1, a careful spectroscopic analysis (1H and
31P NMR) of the reaction mixture stemming from the reaction
between 3,5-dimethoxytoluene (4) and methyl propiolate (5) under
the standard conditions (5 mol% Ph3PAuCl, 1.5 equiv. PhI(OAc)2,
1 equiv. NaHCO3) was performed. The reaction showed the
Scheme 2 Plausible mechanisms for Au-catalyzed alkynylation of
arenes.
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presence of three species: the initial catalyst Ph3PAuCl, and unexpected new role of the oxidant in the initial steps of the
[(Ph3P)2Au]Cl (7) and a Ph3PAu(C^C–CO2Me) complex (8) reaction: PhI(OAc)2 favors the formation of the observed
(Fig. 2a, S4 and S5 in the ESI†).
complex 8 (Fig. S10–S13 in the ESI†).
Complex 8 appears already aer the rst minutes of the reac-
The reactivity of the Au(I)-acetylide 8 was studied next.
tion and it disappears towards the end whereas Ph3PAuCl and 7 Gold acetylides have been proposed as productive reaction
are present aer the starting materials have been completely intermediates in different transformations including the
consumed. Ph3PO could not be detected in the reaction mixture. formation of Au vinylidenes17 or the Au-catalyzed homo-18 and
These results indicate that the phosphine ligand remains bound to heterocoupling19 of alkynes. The reaction of 8 with PhI(OAc)2
the metal center and thus does not get oxidized by PhI(OAc)2 in in CD2Cl2 was monitored by 1H and 31P NMR. Indeed, no
appreciable quantities. In situ generated phosphine-free Au(III) conversion was observed up to 60 ꢀC while only very low
species have been proved to be the productive intermediates in the conversion into Ph3PAuOAc and Ph3PAuCl was detected even
ꢀ
recently reported Au-catalyzed cross coupling reaction of aryl aer prolonged heating at 90 C (eqn (2), Fig. S14 and S15 in
silanes with arenes.14c Interestingly, a catalytic reaction in the the ESI†).20 These results indicate that 8 is hardly oxidized
presence of IPrAuCl gave no product conversion, thus highlighting with PhI(OAc)2 and also that the putative oxidation product
the importance of the ancillary ligand in these transformations.
Ph3PAu(C^C–CO2Me)(OAc)2 9 is rather unstable under the
Once the species detected during the reaction had been reaction conditions undergoing rapid reductive elimination
identied, we decided to interrogate in detail both the mecha- to give Ph3PAuOAc and 3-(acetyloxy)-methyl propiolate (which
nism for the formation, as well as the reactivity of the Au(I)- decomposes in situ due to its highly labile nature).
acetylide complex 8. We monitored the formation of 8 from
In sharp contrast, the reaction of 8 in the presence of
1
Ph3PAuCl, methyl propiolate (5) and NaHCO3 by both H and PhICl2 cleanly proceeded at room temperature to give
31P NMR performing the reaction in CD2Cl2. Experimentally, cis-Ph3PAu(C^C–CO2Me)(Cl)2 keep "cis-Ph3PAu(CC–CO2Me)(Cl)2
the formation of complex 8 is not a favorable process, and even (10)" in single line(10), whose structure could be conrmed by
aer prolonged heating, it could only be detected in marginal X-ray diffraction analysis (eqn (3)). These results not only showcase
amounts (Fig. 2b, S6 and S7 in the ESI†). In contrast, the same the different oxidizing abilities of PhI(OAc)2 vs. PhICl2 but also the
reaction in the presence of PhI(OAc)2 revealed the presence of 8 inuence of the ligand transferred by the hypervalent iodine
aer only 5 minutes (Fig. 2c, S8 and S9 in the ESI†), in line with reagent on the stability of the corresponding Au(III) intermediates
the spectroscopic analysis of a catalytic reaction (Fig. 2a). produced in the reaction mixture. When 8 and PhICl2 were stirred
Interestingly, the reaction of Ph3PAuOAc with 5 proceeded at higher temperature, reductive elimination on 10 occurred,
quantitatively at room temperature in the absence of oxidant furnishing Ph3PAuCl, which is oxidized in the presence of the
producing 8 and AcOH in only 10 minutes (Fig. 2d). On the remaining oxidant to Ph3PAuCl3. In this case, the by-product
other hand, the reverse reaction, although not unfeasible, is not stemming from reductive elimination (i.e. 3-chloro-methyl pro-
a favorable process. These observations suggested an additional piolate 1121) could be clearly observed (eqn (4), Fig. S20 and S21 in
the ESI†).
Due to the labile nature of complex 9, we decided to seek an
alternative model system to study the reactivity of the putative
Au(III) intermediates produced during the aryl alkynylation reac-
tion. Ph3PAuC6F5 (12) was selected expecting that the electron
decient nature of the pentauorophenyl ligand could mimic that
of the propiolate unit while offering a more stable platform for the
isolation of gold(III) species. Reaction of Ph3PAuC6F5 (12) with
PhI(OAc)2 in a 1 : 1 mixture of hexauorobenzene/benzene at
80 ꢀC delivered trans-Ph3PAu(C6F5)(OAc)2 (13) in 64% yield
according to our previously reported procedure (eqn (5)).22
Fig. 2 (a) Standard catalytic reaction. (b and c) Experiments towards
the formation of Au(I)-acetylide 8 from Ph3PAuCl and alkyne 5 in the
absence or presence of PhI(OAc)2, respectively. (d and e) Reactivity of
Ph3PAuOAc towards methyl propiolate (5).
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The reactivity pattern observed for cis-dichloro(methoxy-
carbonylethynyl) (triphenylphosphine)-gold(III) (10) turned out
to be completely different as shown on the right column of
Table 1. In contrast to 13, complex 10 did not react with methyl
propiolate (5) (Fig. S26 and S27 in the ESI†) although it
underwent transmetalation with Au(I)-acetylide complex 8 even
at ꢁ25 ꢀC to give alkyne homocoupling product 18 (ref. 24) and
Ph3PAuCl. As in the previous case, only one Cl/alkyne ligand
exchange took place (Fig. S28 and S29 in the ESI†). Also in
contrast to 13, cis-Ph3PAu(C^C–CO2Me)(Cl)2 (10) proved to be
completely unreactive towards electron-rich aromatic nucleo-
philes even aer prolonged heating at 130 ꢀC (Fig. S30 and S31
in the ESI†).16b,25 The experiments summarized in Table 1
showcase the strong differences in reactivity for diacetato-
Au(III) vs. dichloro-Au(III) complexes26 and highlight the
importance of the oxidant of choice, i.e. the ligand that ulti-
mately the oxidant transfers onto the metal center, for
a productive reaction outcome. In line with this hypothesis,
replacement of the chloro ligands in 10 by reaction with 1
equivalent of LiOAc in the presence of 1,3,5-trimethoxybenzene
in excess resulted in the clean formation of Ph3PAuCl and
alkynylation product 19 in 61% yield (eqn (6)).
Reactivity of putative Au(III)-intermediates
We set out to examine the reactivity of complexes 10 and 13
towards the species present in the media during the standard
aryl alkynylation reaction, namely: methyl propiolate (5), Au(I)-
acetylide complex (8) and electron-rich arenes in a stoichio-
metric fashion. The results of this study have been summarized
in Table 1. Interestingly, trans-Ph3PAu(C6F5)(OAc)2 (13) reacted
with methyl propiolate (5) at 25 ꢀC to give methyl 3-(penta-
uorophenyl)-prop-2-ynoate (14) in 68% yield together with
Au(I)-acetylide complex 8 as a result of the double replacement
of both acetato ligands with free alkyne followed by reductive
elimination (see Fig. S22 and S23 in the ESI†). The reaction of 13
with complex 8 was also illustrative, providing 14 in 62% yield
together with Ph3PAuOAc. Since no Au(I)-acetylide complex 8
was detected at the end of the reaction, we have to assume that
upon a rst Au(I)/Au(III) transmetalation (which could also be
described as a Au(I)/Au(III) ligand exchange reaction), Csp2–Csp
reductive elimination occurs fast, preventing a second ligand
transfer between the different gold species (see Fig. S24 and S25
in the ESI†). Finally, the reactions of 13 with 1,3,5-trimethox-
ybenzene, 1,3-dimethoxytoluene 4 and N-methyl indole were
also enlightening as they proceeded efficiently towards the
corresponding cross-coupling products 15, 16 and 17 in 85, 74
and 85% yield, respectively.16b,23
Additional stoichiometric experiments with Au(I)-acetylide
complex 8 were designed. When the reaction of 3,5-dimethox-
ytoluene (4) was run using Au(I)-acetylide 8 as the stoichiometric
alkynylating agent in the presence of PhI(OAc)2 and NaHCO3
only traces of the desired cross-coupling product 6 were detected
(eqn (7), Fig. S32 and S33 in the ESI†). In contrast, when methyl
propiolate (5) was incorporated into the reaction, arylalkyne
product 6 was clearly observed aer only one hour even if in low
conversion (eqn (8), Fig. S34 and S35 in the ESI†). A catalytic
version of this reaction using 5 mol% of 8 or Ph3PAuOAc also
afforded 6 although again, in a much less efficient manner
compared to the standard conditions (eqn (9), Fig. S36 and S37
in the ESI†).
Table 1 Comparison of reactivity between Au(III)-bis-chloro vs. bis-
acetato complexes
a
c
b
Au(I)-acetylide 8 was also detected. Ph3PAuOAc was also detected.
Compound 16 is obtained as a 0.6 : 1 mixture of regioisomers.
Traces of alkyne homocoupling product 18 were detected.
Ph3PAuCl was also detected. f See also ref. 16b.
d
e
These experiments clearly suggest that the presence of free
alkyne in the reaction mixture favors a productive reaction
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outcome and together with eqn (2) highlight that PhI(OAc)2 is not an
efficient oxidant for 8 and the putative Ph3PAu(C^C–CO2Me)(OAc)2
(9) complex is not a highly competent reaction intermediate. Addi-
tionally, the reactions shown in Fig. 2b–d indicated that the
oxidant is involved in the activation of the alkyne. We hypothe-
sized that the formation of 8 could occur by ligand exchange on
Ph3PAuCl in the presence of PhI(OAc)2 to form Ph3PAuOAc which
rapidly activates the alkyne 5 to form 8 and AcOH, which is then
quenched by NaHCO3 present in the reaction media (Fig. 2d). This
proposal is supported by recent experiments of Shi et al., showing
the formation of R3PAuOAc in the presence of R3PAuCl and
PhI(OAc)2 by MALDI-MS analysis.27 Thus, to gain a deeper insight
into the specic nature of the individual steps involved in these
transformations, DFT calculations and additional control experi-
ments were carried out.
DFT studies and characterization of the oxidizing species
In line with the experimental observations summarized in
Fig. 2, calculations conrmed that formation of Au(I)-acetylide 8
from Ph3PAuCl in the absence of oxidant is a highly unfavorable
process even in the presence of base (+19.1 kcal molꢁ1, Fig. 3a).
The lack of reactivity observed for Ph3PAuCl in the presence of
PhI(OAc)2 could also be conrmed. A potential Au(Cl)/I(OAc)
exchange is also disfavored (+12.8 kcal molꢁ1), and thus such an
equilibrium would be strongly shied towards the starting
materials (Fig. 3b). When alkyne is added into the system, the
energies of these two equilibria remain unchanged. However,
the trace amounts of Ph3PAuOAc that could be produced rapidly
react with the free alkyne present in the media to give Au(I)-
acetylide complexes and acetic acid, which will be quenched
with the base present in the reaction (Fig. 3c and 2d). The
energy for this process decreases to +6.3 kcal molꢁ1. Thus, the
second equilibria will drive the rst one towards the right,
inuenced by the presence of free alkyne. Furthermore, the in
situ generated PhI(OAc)(Cl) intermediate presents a much lower
activation energy towards the oxidation of Au(I) acetylide via TS3
Fig. 3 (a–d) Computed Gibbs free energy values (kcal molꢁ1) for the
potential reaction between Ph3PAuCl, alkyne (methyl alkynyl ketone)
and hypervalent iodine reagents calculated with the M06 functional.
(red path) or a transmetalation between the Au(I) and Au(III)-
acetylide species coexisting in the reaction media (blue path)
could explain the formation of homocoupling product 18,
which is produced in a comparable ratio to that in which 20 is
consumed (Fig. 4c). Additional experiments were carried out to
support the proposed structure of compound 21: the reaction of
m-F-C6H4I(Cl)2 with 1 equivalent of AgOAc delivered, aer only 5
min, the same species observed in the 19F NMR spectrum, thus
conrming the proposed composition of the “non-symmetric”
oxidant (Fig. 4d) (for these and additional control experiments,
see Section 3.8 in the ESI†).
To conrm the ability of chloride transfer from Ph3PAuCl to
PhI(OAc)2, the standard cross-coupling reaction was performed
in the presence of 1 equivalent of (n-Bu)4NCl (see Section 3.9 in
the ESI†). As expected, the initial excess of chloride in the
reaction mixture inhibited the formation of the desired cross-
coupling product. In turn, 2-chloro-3,5-dimethoxytoluene could
be detected, pointing towards in situ generated 21, which in this
case is produced in abundant quantities in the reaction media,
as the chlorinating agent. In line with these results, in the
(+20.1 kcal molꢁ1) compared to PhI(OAc)2 via TS3 (+29.2 kcal
0
molꢁ1) (Fig. 3d).
Stoichiometric experiments were subsequently designed to
support the hypothesis of a Au(Cl)/I(OAc) ligand exchange
triggered by the presence of free alkyne and the formation of
a more reactive “non-symmetrical” oxidant. In an attempt to
detect such species by highly sensitive 19F NMR spectroscopy,
a
uorine-containing iodonium diacetate, namely m-F-
C6H4I(OAc)2 (20), was synthesized.28
The in situ kinetic studies of a reaction between 20, methyl
propiolate (5) and Ph3PAuCl revealed the consumption of 20
and the simultaneous formation of a new product with a char-
acteristic 19F signal at 107.5 ppm which was assigned to m-F-
C6H4I(OAc)(Cl) (21) (Fig. 4a and b). The oxidizing potential of 21
is higher than that of 20 as already revealed by the DFT calcu-
lations (Fig. 3d) and thus the Au(I)-acetylide complex 8 which
has been generated in situ can be slowly oxidized even at room
temperature, thus preventing the accumulation of 21 in the
reaction media. In the absence of other species, an OAc-alkyne
ligand exchange reaction on the Au(III)-acetylide intermediate
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The arene reacts then with INT5A and the acetate ligand
abstracts the proton to restore the aromaticity via TS4A in an
overall highly exergonic process to give INT6 (ꢁ29.7 kcal molꢁ1
from INT3), which is followed by a fast reductive elimination
(the energy prole calculated for a dissociative interaction of the
arene with INT3 can be found in Fig. S69 in the ESI†).15 Deute-
rium labelling experiments on the arene carried out in our
seminal study7 showed no primary KIE, in line with the present
DFT results in which arene auration is not turnover limiting.
Ph3PAuCl is formed in the nal stage, re-entering the cycle,
which shows an overall reaction energy of ꢁ81 kcal molꢁ1
.
Thus, the DFT calculations support the hypothesis of the
transformation of gold(I)-chloride into gold(I)-acetate (INT1),
and this into Au(I)-acetylide (INT2) through two up-hill equi-
libria. The activation energies for these processes are compa-
rable to that of the subsequent oxidation step by the in situ
generated PhI(OAc)(Cl) via transition state TS3 and also to that
of the attack of the arene onto the alkynyl-gold(III) intermediate
via TS4A. DFT calculations also conrmed the lability of the aryl-
aurate intermediate (INT6), which rapidly evolves via reductive
elimination towards the cross-coupling product regenerating
the Ph3PAuCl catalyst.23,30
Proposed catalytic cycle
Fig. 4 Formation of “non-symmetric” I(III) species by reaction of
m-F-C6H4I(OAc)2 20 with Ph3PAuCl and methyl propiolate (5): (a)
Evolution of the temporal concentration of reactants, intermediates
and product. (b) 19F NMR traces of the reaction mixture. (c) Ration-
alization of the observed species. (d) Alternative synthesis and char-
acterization of m-F-C6H4I(OAc)(Cl) (21).
The data presented in previous sections enabled a more detailed
mechanism for the Au-catalyzed alkynylation of arenes to be
proposed based on a better understanding of both oxidant and
catalyst speciation for a productive reaction outcome (Scheme 3).
At the outset of the reaction, the formation of an Au(I)-ace-
tylide complex F takes place. However, the reaction of methyl
propiolate (E) and Ph3PAuCl in the presence of a base to give
acetylide complex F is not a favorable process (Fig. 2b). In
contrast, the same reaction in the presence of PhI(OAc)2
revealed the formation of F aer only 5 minutes (Fig. 2c), in line
with the spectroscopic analysis of a catalytic reaction (Fig. 2a).
These results led us to discard a facile equilibrium between the
Au pre-catalyst and the alkyne while suggesting a new role for
the oxidant in the initial steps of this transformation. Studies,
including F-labeling experiments and DFT calculations, support
a mechanistic scenario involving multiple equilibria between
the alkyne, oxidant and gold. Initially, a ligand exchange
between Ph3PAuCl and PhI(OAc)2 delivers Ph3PAuOAc and
a non-symmetric oxidant, PhI(OAc)(Cl). As shown in Fig. 2d, 3a
and b, free alkyne reacts with the trace amounts of Ph3PAuOAc
to give Au(I)-acetylide complex F and acetic acid, which is
quenched in the presence of NaHCO3. Experimentally, the
absence of chloride available for ligand exchange, the perfor-
mance of 8 or Ph3PAuOAc as catalysts (eqn (9)) delivered the
cross-coupling product in lower yield compared to the standard
conditions.
Finally, DFT calculations were carried out to map the entire
energy potential surface (Fig. 5). The mixture of free alkyne,
PhI(OAc)2 and Ph3PAuCl was taken as the ground state of energy
(G ¼ 0 kcal molꢁ1), mimicking the initial experimental condi-
tions. As detailed in Fig. 5, the Cl/OAc anion exchange between
the gold and the iodine center through TS1 (with Au–O1 and I–Cl
˚
bond distances of 2.35 and 2.90 A respectively) leads to a rst
high energy mixture, INT1 (+12.8 kcal molꢁ1), which is readily
transformed into INT2 (+6.3 kcal molꢁ1) by deprotonation of the
alkyne, alkynyl-gold complex formation and HOAc release via
˚
˚
TS2 (with bond distances: Au–C1 ¼ 2.34 A, Au–O1 ¼ 2.46 A and
C1–H ¼ 1.23 A).29 The oxidation of the alkynyl-gold complex by
˚
formation of
a
non-symmetric hypervalent iodine
m-F-PhI(OAc)(Cl) (21) could also be monitored by 19F NMR
(Fig. 4). This new oxidant formed in situ presents a lower acti-
vation energy towards the oxidation of F into Au(III)-acetylide
the active oxidant species PhI(OAc)(Cl) presents an affordable
activation energy (+20.1 kcal molꢁ1 from INT2 to TS3), involving
˚
˚
the rupture of the I–Cl bond (I–Cl ¼ 3.10 A, Au–Cl ¼ 2.67 A, Au–I
complex G compared to PhI(OAc)2 (DDG† ca. 9 kcal molꢁ1
,
˚
˚
¼ 3.32 A and Au–C1 ¼ 2.0 A). The alternative Au(I) to Au(III)
oxidation involving the I–OAc bond of PhI(OAc)(Cl) is dis-
favoured by more than 8 kcal molꢁ1 with respect to TS3 (Fig. 3d).
Aer the oxidation via INT3, iodobenzene is released to form
a highly stable neutral intermediate INT5A (ꢁ17.9 kcal molꢁ1).
Fig. 3d). Experiments summarized in eqn (2) and (7)–(9) clearly
suggest that free alkyne favors a productive reaction outcome
and also that PhI(OAc)2 is not an efficient oxidant for 8 nor is the
putative Ph3PAu(C^C–CO2Me)(OAc)2 (9) complex a highly
competent reaction intermediate. Still, alternative reaction
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Fig. 5 Top: complete energy profile for the reaction between Ph3PAuCl, alkyne (methyl alkynyl ketone), PhI(OAc)2 and arene (1,3,5-trime-
thoxybenzene). Gibbs free energy values in blue calculated with the M06 functional. Bottom: structures of transition states TS1, TS2 and TS3 (left
to right) highlighting the relevant distances.
pathways operating with PhI(OAc)2 as the oxidant cannot be cross coupling reaction rather than the undesired homocou-
completely ruled out (eqn (9)). Putative analogues of Au(III) pling of alkyne, which is sometimes observed as a minor by-
complexes G (10 and 13 in Table 1) were used as mechanistic product in these transformations. Although a Au(I)/Au(III)
probes in stoichiometric experiments which revealed the crucial transmetalation involving the chloride ligands towards the
role of anionic ligands in the reaction outcome. Thus, acetato formation of a bis-alkynyl Au(III) intermediate cannot be
ligands on the Au(III) center can be rapidly exchanged in the completely ruled out,18,31 control experiments indicate that this
presence of arenes whereas the corresponding chlorides remain process might be slow under the present reaction conditions
unreacted.
A competitive OAc/alkyne exchange in G to give G0 can occur
(see Fig. 4c and S51–S57 in the ESI†).
The proposed Au(Cl)–I(OAc) exchange in the rst steps of the
although in a sufficiently slower rate to enable a productive reaction produces a “non-symmetric” ArI(Cl)(OAc) oxidant
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Scheme 3 Mechanistic proposal for the Au-catalyzed alkynylation of arenes. Structures of TS1, TS2, TS3 and TS5 stem from DFT calculations
reported in Fig. 5.
responsible for reaction by-products stemming from the direct needed to form both a Au(I)-acetylide complex and a more
oxidation (i.e. chlorination) of the arene (<5%) (Section 4.2 in reactive “non-symmetric” oxidant PhI(OAc)(Cl) responsible for
the ESI†).32 Finally, the mechanism for catalyst decomposition the crucial Au(I)/Au(III) turnover. Both processes, i.e. the
has also been studied. Slow de-coordination of Ph3P from the formation of Au(I)-acetylide and its oxidation, are connected
neutral starting complex Ph3PAuCl or other phosphine-Au through an equilibrium which evolves along the reaction
species involved in the reaction results in the formation of trace progress. Reaction of the electron rich arenes with the in situ
amounts of (Ph3P)2AuX (7) visible in the 31P NMR of the stan- generated Au(III)-alkynyl intermediate occurs to produce a short-
dard catalytic reaction media (Fig. 2a). Control experiments lived aryl-alkynyl-Au(III) complex, which evolves by reductive
revealed that these species are catalytically inactive and do not elimination to produce the observed cross-coupling products
interfere with a productive reaction outcome (see Section 4.3 in and the Au(I) catalyst. The mechanisms of both catalyst
the ESI†).33
decomposition and competing side reactions have also been
unraveled.
A few of the lessons learned in this study may also be
applicable to other gold-catalyzed oxidative cross-couplings
employing I(III) oxidants. Unexpectedly, a ligand exchange
between the gold(I) pre-catalyst and the initial hypervalent
iodine might be the key to produce the suitable gold(I)-species
to enable activation of the alkyne in the rst place. Furthermore,
the same process provides the appropriate oxidizing species,
Conclusions
A detailed investigation of the gold-catalyzed alkynylation of
arenes including kinetic and stoichiometric experiments
together with DFT calculations has provided an insightful
perspective on the mechanism of this transformation. A ligand
exchange involving the alkyne, Au(I)-catalyst and oxidant is
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capable of producing reactive Au(III)-intermediates. This process is
inuenced by both the nature of the ancillary ligand on gold and
by the presence of other reaction partners which can shi this up-
hill equilibria. Oxidation is also an energetically demanding
process which translates into a Au(III)-intermediate, whose reac-
tivity will be ne-tuned by the nature of the anionic ligands
transferred by the oxidant: while acetato ligands favor activation
of the arene and are easily displaced to give the cross-coupling
products, chlorides are much less reactive and thus stabilize these
species favoring transmetalation processes. We believe that this
mechanistic study supporting Au(I)/Au(III) redox catalytic cycles
provides novel insights, useful not only for the development of
new gold catalyzed oxidative transformations but also for the
improvement and ne tuning of already available ones.
6 (a) J. P. Brand, J. Charpentier and J. Waser, Angew. Chem., Int.
Ed., 2009, 48, 9346–9349; (b) J. P. Brand and J. Waser, Angew.
Chem., Int. Ed., 2010, 49, 7304–7307; (c) J. P. Brand,
C. Chevalley and J. Waser, Beilstein J. Org. Chem., 2011, 7,
565–569; (d) J. P. Brand, C. Chevalley, R. Scopelliti and
J. Waser, Chem.–Eur. J., 2012, 18, 5655–5666; (e) Y. Li,
J. P. Brand and J. Waser, Angew. Chem., Int. Ed., 2013, 52,
6743–6747; (f) Y. Li and J. Waser, Beilstein J. Org. Chem.,
2013, 9, 1763; (g) J. P. Brand, Y. Li and J. Waser, Isr. J.
Chem., 2013, 53, 901–910.
7 T. de Haro and C. Nevado, J. Am. Chem. Soc., 2010, 132, 1512–
1513.
8 For a Au-catalyzed tandem allenoate cyclization/alkynylation
protocol with Selectuor as the oxidant, see:
M. N. Hopkinson, J. E. Ross, G. T. Giuffredi, A. D. Gee and
V. Governeur, Org. Lett., 2010, 12, 4904–4907.
Conflicts of interest
9 Y. Fuchita, Y. Utsonomiya and M. Yasutake, J. Chem. Soc.,
Dalton Trans., 2001, 2330–2334.
There are no conicts to declare.
10 (a) V. V. Zhdankin, ARKIVOC, 2009, 1; (b) R. M. Moriarty, Org.
Chem., 2005, 70, 2893–2903; (c) J. P. Brand, D. Fernandez
Gonzalez, S. Nicolai and J. Waser, Chem. Commun., 2011,
Acknowledgements
We thank the European Research Council (ERC Starting grant
agreement no. 307948) and the Swiss National Science Foun-
dation (SNF 200020_146853) for nancial support and the SGI/
47, 102–115. For a seminal example of Au(I)/Au(III)
involving hypervalent iodine reagents, see: A. Kar,
N. Mangu, H. M. Kaiser, M. Beller and M. K. Tse, Chem.
Commun., 2008, 386–388.
¨
IZO-SGIker UPV/EHU and Schrodinger (UZH) for allocation of
computational resources. We thank Dr A. Linden for the X-ray 11 (a) N. R. Deprez and M. Sanford, Inorg. Chem., 2007, 46,
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Chem. Sci.
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