Catalytic Au(i)/Au(iii) arylation with the hemilabile MeDalphos ligand: Unusual selectivity for electron-rich iodoarenes and efficient application to indoles

Article abstract of DOI:10.1039/c9sc01954e

The ability of the hemilabile (P,N) MeDalphos ligand to trigger oxidative addition of iodoarenes to gold has been thoroughly studied. Competition experiments and Hammett correlations substantiate a clear preference of gold for electron-enriched substrates both in stoichiometric oxidative addition reactions and in catalytic C-C cross-coupling with 1,3,5-trimethoxybenzene. This feature markedly contrasts with the higher reactivity of electron-deprived substrates typically encountered with palladium. Based on DFT calculations and detailed analysis of the key transition states (using NBO, CDA and ETS-NOCV methods in particular), the different behavior of the two metals is proposed to result from inverse electron flow between the substrate and metal. Indeed, oxidative addition of iodobenzene is associated with a charge transfer from the substrate to the metal at the transition state for gold, but opposite for palladium. The higher electrophilicity of the gold center favors electron-rich substrates while important back-donation from palladium favors electron-poor substrates. Facile oxidative addition of iodoarenes combined with the propensity of gold(iii) complexes to readily react with electron-rich (hetero)arenes prompted us to apply the (MeDalphos)AuCl complex in the catalytic arylation of indoles, a challenging but very important transformation. The gold complex proved to be very efficient, general and robust. It displays complete regioselectivity for C3 arylation, it tolerates a variety of functional groups at both the iodoarene and indole partners (NO₂, CO₂Me, Br, OTf, Bpin, OMe?) and it proceeds under mild conditions (75 °C, 2 h).

Full text of DOI:10.1039/c9sc01954e

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DOI: 10.1039/C9SC01954E.
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DOI: 10.1039/C9SC01954E
ARTICLE
Catalytic Au(I)/Au(III) Arylation with the Hemilabile MeDalphos
Ligand: Unusual Selectivity for Electron-Rich Iodoarenes and
Efficient Application to Indoles
Received 00th January 20xx,
Accepted 00th January 20xx
Jessica Rodriguez,a Abdallah Zeineddine,a E. Daiann Sosa Carrizo,b Karinne Miqueu,b Nathalie
DOI: 10.1039/x0xx00000x
Saffon-Merceron,c Abderrahmane Amgoune*a and Didier Bourissou*a
The ability of the hemilabile (P,N) MeDalphos ligand to trigger oxidative addition of iodoarenes to gold has been
thoroughly studied. Competition experiments and Hammett correlations substantiate a clear preference of gold for
electron-enriched substrates both in stoichiometric oxidative addition reactions and in catalytic C‒C cross-coupling with
1,3,5-trimethoxybenzene. This feature markedly contrasts with the higher reactivity of electron-deprived substrates
typically encountered with palladium. Based on DFT calculations and detailed analysis of the key transition states (using
NBO, CDA and ETS-NOCV methods in particular), the different behavior of the two metals is proposed to result from
inverse electron flow between the substrate and metal. Indeed, oxidative addition of iodobenzene is associated with a
charge transfer from the substrate to the metal at the transition state for gold, but opposite for palladium. The higher
electrophilicity of the gold center favors electron-rich substrates while important back-donation from palladium favors
electron-poor substrates. Facile oxidative addition of iodoarenes combined with the propensity of gold(III) complexes to
readily react with electron-rich (hetero)arenes prompted us to apply the (MeDalphos)AuCl complex in the catalytic
arylation of indoles, a challenging but very important transformation. The gold complex proved to be very efficient,
general and robust. It displays complete regioselectivity for C3 arylation, it tolerates a variety of functional groups at both
the iodoarene and indole partners (NO2, CO2Me, Br, OTf, Bpin, OMe…) and it proceeds under mild conditions (75 °C, 2 h).
using aryl-silanes, aryl-boronic acids or even simple arenes
with external oxidants, typically F+ sources or I(III) compounds
(route a). This methodology has been used successfully in a
number of catalytic oxidative coupling reactions, in particular
for the arylation of (hetero)arenes3 and for the oxy (and
amino) arylation of alkenes.4 Starting from 2013, aryl
diazonium salts (and diaryl iodonium salts) have been
developed as alternative coupling partners (route b). Using this
approach, the key aryl gold(III) species are most commonly
Introduction
The reluctance of gold complexes to cycle between the Au(I)
and Au(III) oxidation states1 has long impeded the
development of Au(I)/Au(III) catalysis for the formation of
carbon-carbon and carbon-element bonds. However,
spectacular progress has been achieved recently so that gold
redox catalysis now appears as a new paradigm in arylation
reactions,2 with particular interest for transformations in
generated under light activation, with or without
a
which
gold
displays
reactivity
and/or
selectivity
photosensitizer (thermal and base-activation are also
possible), which circumvents the use of strong oxidants. The
efficiency and generality of this method have already been
substantiated in a number of catalytic C–C and C–E (E = P, S,
halogen) coupling reactions, in particular thanks to dual
photoredox and gold catalysis.5 Very recently, a third approach
relying on purposely-designed ligands has been introduced
(route c). Chelating and hemilabile ligands were shown to
enable oxidant-free coupling reactions with aryl halide
electrophiles (Figure 1B).6,7,8
complementary to the other transition metals. The main
challenge in this field is certainly to generate aryl gold(III)
species ready to participate in cross-coupling. To do so, several
strategies have progressively emerged, as schematically
illustrated in Figure 1A. The first and main approach consists in
a. CNRS/Université Paul Sabatier, Laboratoire Hétérochimie Fondamentale et
Appliquée (LHFA, UMR 5069). 118 Route de Narbonne, 31062 Toulouse Cedex 09
(France). Email: dbouriss@chimie.ups-tlse.fr
b. CNRS/UNIV PAU & PAYS ADOUR, Institut des Sciences Analytiques et de Physico-
Chimie pour l’Environnement et les Matériaux (IPREM UMR 5254). Hélioparc, 2
Avenue du Président Angot, 64053 Pau Cedex 09 (France).
c. Institut de Chimie de Toulouse (FR 2599). 118 Route de Narbonne, 31062
Toulouse Cedex 09 (France).
†
Electronic Supplementary Information (ESI) available: Experimental and
computational details, analytical data and NMR spectra, optimized structures,
reaction profiles and bonding analysis (PDF). Crystallographic data for 10 and 13
(CIF). xyz files (XYZ). See DOI: 10.1039/x0xx00000x.
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we know very little about oxidative addition to gold and
View Article Online
A)
AuI
H
AuI
Ar
Ar
catalytic applications with aryl halides asDsOubI:s1t0r.a10t3e9s/Ch9aSvCe0t1o95b4eE
developed beyond the proof-of-concept arylation reaction of
TMB. In the present study, we aimed to gain more insight into
the seemingly specific trend of gold towards substituted aryl
halides. We tried in particular to address the following
questions: Does the (P,N) gold complex also display a
preference for electron-rich substrates? Does the substituent
influence observed for the oxidative addition step transpose to
the catalytic cross-coupling? What is the reason for the
difference between gold and the other transition metals,
palladium in particular? In addition, we sought to illustrate the
synthetic interest of the (P,N) gold complex in catalysis and
thoroughly investigated the direct catalytic arylation of
indoles. The results obtained along these two lines are
reported hereafter.
AuIII
N2
+
Ar
Ar
oxidant
light, thermal
or base activation
M
a
Oxidative
Addition
b
c
M = Si, B
L'
L
AuI
X
+
Ar
X = I, Br
B)
R2
P
N
F
F
N
N
P
R2
P
Ad2
= BH
chelating (P,P)
chelating (N,N)
hemilabile (P,N)
 reversible OA of ArI
 activation by e-donating substituents
 cross-coupling with ArZnCl
 OA of ArI and ArBr
 oxidant-free catalytic
CC coupling with TMB
 reversible OA of ArI
 activation by e-donating substituents
ref. 6a
ref. 6b
ref. 6c
 influence of the substrate electronics:
general trend, rational explanation
 catalytic cross-coupling:
application to the regioselective arylation of indoles
Figure 1. A) Schematic representation of the different means to access aryl gold(III)
species to participate in cross-coupling reactions; B) bidentate ligands shown to
promote oxidative addition of aryl halides to gold.
Results and discussion
Relative reactivities of substituted iodoarenes in the
oxidative addition to the (P,N) gold complex
Our group first discovered that o-carboranyl diphosphines
emulate oxidative addition to gold. The bending induced by
the chelating (P,P) ligand activates and preorganizes the metal
fragment so that oxidative addition of iodoarenes6a as well as
strained carbocycles9 proceeds readily. In the course of these
investigations, we noticed an unusual substituent effect.10
Indeed, iodoarenes featuring electron-donating (EDG) para-
substituents were found to react with the (P,P) gold(I) complex
significantly faster than those bearing electron-withdrawing
groups (EWG), in marked contrast with that classically
observed with other transition metals.11 We then extended the
ligand-based approach to MeDalphos, a hemilable ligand.6b,12
With the (P,N) gold complex, oxidative addition proved to be
even more favored. The scope of iodoarenes was further
extended and bromoarenes could be activated as well. In
addition, we showed that the ensuing (P,N) aryl gold(III)
As we pointed out for the (P,P) gold complex,6a the influence
of the iodoarene electronics on the rate of oxidative addition
to gold is unique and intriguing. As mentioned above, a similar
tendency was recently observed by McGrady, Bower, Russell
et al with a 2,2’-bipyridyl, (N,N) chelated gold complex.6c This
raises the question of the generality of this trend and if so, of
the reason for such a specific behavior of gold. We thus
examined the relative reactivities of a series of para-
substituted iodoarenes with the (P,N) gold complex. To start
with, the scope of the reaction was further extended (Scheme
1). Electron-poor substrates featuring a p-CF3 as well as p-CN
and p-COMe substituents – two potentially coordinating
groups – were found to undergo oxidative addition to gold
within the time of mixing. With the electron-rich p-NMe2
complexes
do
engage
in
C–C
coupling
with
substituted iodobenzene,
a complex mixture of gold
1,3,5-trimethoxybenzene (TMB) used as a model electron-rich
arene. The cross-coupling reaction between iodoarenes and
TMB was amenable to catalysis, using 5 mol% of the (P,N) gold
complex. The (P,N) aryl gold(III) species were then reported by
Maynard and Spokoyny to readily undergo stoichiometric
aryl–S coupling with unprotected peptides and proteins,
providing a very efficient and chemoselective mean for
cysteine bioconjugation.13 Last but not least, a bipyridine
ligand was shown very recently by McGrady, Bower and
Russell to also promote oxidative addition to gold.6c With this
chelating (N,N) ligand, iodoarenes are reversibly activated and
again, electron-rich substrates were found to react unusually
faster than electron-poor ones. The resulting (N,N) aryl
gold(III) complex undergoes transmetallation and C–C
reductive elimination upon reaction with an aryl zinc reagent,
providing evidence for all the elementary steps of a gold-
promoted Negishi-type coupling.
complexes was obtained, which might be due to competitive N
coordination to gold and/or redox processes.14 In contrast,
p-Br iodobenzene reacted smoothly with complete selectivity
for C–I oxidative addition.
I
SbF6
N
N
Au Cl
R
P
Au
I
AgSbF6
+
P
CD2Cl2
-80 °C to RT
99%
R
R = H, Me, OMe, NO2, F, CN, CF3, COMe, Br
Scheme 1. Oxidative addition of a series of para-substituted iodoarenes to the (P,N)
gold complex.
The rate of Ar–I oxidative addition to the (P,N) gold complex is
much faster than with the (P,P) ligand, preventing a direct
comparison of the substrates based on their reaction times (all
reactions are complete by the time the medium reaches room
From all these recent reports, it is clear that ligand design
offers new perspectives in gold chemistry, in particular for
Au(I)/Au(III) catalysis, but the field is still in its infancy. Indeed,
2 | J. Name., 2012, 00, 1-3
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temperature). We thus resorted to competition experiments
and first performed a few test reactions to determine whether
the electron-rich/electron-poor character of the substrate
matters or not. Two competition experiments were carried out
between p-(MeO)C6H4I as electron-rich substrate and
p-(MeCO)C6H4I or p-(F3C)C6H4I as electron-poor substrate
(Scheme 2).14 In each case, equimolar amounts of the two
substituted iodoarenes were mixed and added in 10-fold molar
excess to a solution of the (P,N) gold complex to ensure that
the concentration of the two halides remains approximately
constant over the reaction (Scheme 2). The ratio of the
resulting gold(III) complexes was determined by 31P NMR
spectroscopy. In both cases, the major product formed
corresponds to the gold(III) complex P1 ensuing from oxidative
addition of the electron-rich p-OMe iodobenzene (in 64/36
ratio with p-COMe and 87/13 ratio with p-CF3 iodobenzene).
To confirm this trend, another competition reaction was
performed with p-(F3C)C6H4I and p-MeC6H4I. Here also, the
major product corresponds to the oxidative addition of the
iodobenzene bearing the electron-donating group (in 84/16
ratio).
View Article Online
DOI: 10.1039/C9SC01954E
Figure 2. Hammett correlation for the oxidative addition of different para-substituted
iodoarenes to the (P,N) gold complex.
The (P,N) gold complex thus displays the same reverse
electronic trend towards iodoarenes than the (P,P) and (N,N)
chelated complexes, suggesting it is a general feature of gold
complexes to react faster with electron-rich substrates. This
prompted us to further examine the oxidative addition path
computationally to try to decipher possible underlying factors.
DFT analysis of the oxidative addition path to gold, and
comparison with palladium
SbF6
N
EDG =
OMe
64%
OMe
Me
P
Au
I
EDG
I
I
Our previous DFT studies have substantiated the key role of
the chelating (P,N) ligand.6b It lowers the activation barrier of
oxidative addition and stabilizes the ensuing aryl gold(III)
species thanks to coordination of the nitrogen atom to gold.
P1
10 eq.
+
(P,N)AuCl/AgSbF6
1 eq.
EDG
84%
87%
CD2Cl2
EWG
SbF6
I
36%
10 eq.
–
N
13%
CF3
The weakly coordinating SbF6 counter-anion was also shown
16%
CF3
P
Au
EWG =
COMe
to play no major role. Its displacement by iodobenzene
proceeds with a very low activation barrier and the rate-
determining step is the oxidative addition to gold. As a result,
the gold preference for electron-rich iodoarenes is unlikely to
P2
EWG
Scheme 2. Test competition reactions between EDG and EWG para-substituted
iodoarenes in the oxidative addition to the (P,N) gold complex.
–
originate from the initial displacement of SbF6 at gold, but
rather stands in the oxidative addition process itself.
These encouraging results prompted us to run a Hammett type
analysis. To this end, iodobenzene was reacted with the (P,N)
gold complex in competition with several para-substituted
iodoarenes (p-OMe, p-Me, p-Br and p-CF3) following the same
protocol (1:1 mixture of the two iodoarenes, 10-fold molar
excess with respect to Au). Under these pseudo-first-order
conditions, the relative rate constants for the oxidative
addition can be derived from the ratio of the gold(III) products
(P1 vs P2). The Hammett correlation against σP values15 (Figure
2) reveals a good linear correlation (R2 = 0.93). The negative
slope (ρ = –1.09) confirms the preference of the gold complex
to react with electron-rich iodoarenes. This contrasts with the
general trend of group 10 metals to react faster with electron-
poor substrates,11 as reflected in the positive ρ values reported
for palladium. The magnitude of the ρ value for gold is in the
lower range of those reported for palladium (1.5 – 2.3).16 The
negative sign of the ρ value found for the gold complex
indicates a build-up of positive charge on the aromatic ring
upon oxidative addition of the iodoarene and thus suggests an
electrophilic behavior of gold.
The structure of the associated transition state was thus
further analyzed (Figure 3A).14 Charge analysis reveals an
electron transfer from iodobenzene to gold (by 0.16 e
according to Bader charges computed at the transition state,
Atom-In-Molecules calculations), in line with the electrophilic
behavior of the gold complex observed experimentally.
Consistently, NBO (Natural Bond Orbital) and CDA (Charge
Decomposition Analysis) indicate that donor-acceptor
interactions from PhI to Au largely prevail (Tables S5 and S6).14
Most significant is the donation from an iodine lone pair to the
vacant σ*(Au–P) orbital which is associated with a stabilization
energy of ca 40 kcal/mol. The sum of stabilizing energies for
PhIAu interactions amounts to ca 72 kcal/mol whereas
AuPhI back-donations sum to only ~13 kcal/mol. The
donation/back-donation ratio (d/b) as estimated by CDA is
2.67. Thus, despite the electron-donation from the nitrogen
atom, the gold atom remains highly electrodeficient and the
oxidative addition of the Csp2–I bond is associated with a
charge transfer from PhI to Au.17 Note that recent detailed
analyses of gold carbonyl complexes have also pointed out the
high electrophilicity of cationic gold(I) complexes. Here, strong
σ(CO) to gold charge transfer results in an uncommon high-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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energy shift of the CO stretching frequency due to CO
polarization.18
(A)
View Article Online
DOI: 10.1039/C9SC01954E
2.754
2.419
0.0
(0.0)
2.645
2.304
G ( E)


Oxidative addition of iodobenzene to a model chelating
diphosphine Pd complex was also theoretically investigated to
draw comparison between the two metals (Figure 3B). In line
with previous calculations,19 the Csp2–I bond activation at
palladium is very favored thermodynamically and proceeds
with a very low activation barrier (~ 1 kcal/mol). The structure
of the corresponding transition state was analyzed in detail. Of
note, the charge transfer is opposite to that found with gold
(electron transfer of 0.46 e from Pd to PhI according to the
Bader charges). The NBO picture is also quite different from
that encountered with the gold complex. The PhIPd and
PdPhI donor-acceptor interactions are much more balanced.
The sum of stabilizing energies are 71 and 30 kcal/mol,
respectively (NBO) and the d/b ratio is 0.73 (CDA). This reflects
a significantly higher contribution of Pd to PhI back-donation in
the oxidative addition process, in line with the observed
charge transfer from the metal to the substrate. We surmised
that the reverse electron flow in the oxidative addition
transition state is responsible for the different behavior of the
two metals. Important back-donation from palladium favors
electron-deprived substrates whereas the electrophilicity of
the gold center favors electron-rich substrates. This difference
probably stems from the intrinsic properties of the two metals,
as well as from the charge of the reacting metal species
(cationic vs neutral). Chelation and bending of the L2Au+
fragment has been reported to enhance back-donation from
gold20 but the cationic and electro-deficient character of the
metal remains and makes the difference with neutral L2Pd
moieties.
2.511
in kcal/mol
N
Au
P
-3.0
(-16.7)
Eorb() = -22.9
Ad Ad
I
N-Au-P = 78.91º
+
G : 7.7

-10.7
(-23.8)
N
Au
P
I
Ad
Ad
N
P
Au
-23.1
(-38.5)
I
Ad Ad
(B)
G ( E)


in kcal/mol
Ph
Ph
P
2.537
3.721
Pd
P
2.303
2.323
Ph
Ph
2.049
0.0
(0.0)
P-Pd-P = 86.1°
I
Eorb() = -59.4
+
-16.7
(-29.9)
-17.4
(-30.1)
G : 0.7

Ph
Ph
I
P
P
Pd
Ph
Ph
To further analyze the different behavior of gold and
palladium, the NOCV (Natural Orbital for the Chemical
Valence) extension of the EDA (Energy Decomposition
Analysis) approach was used and the charge flow in the
transition state of oxidative addition was analyzed (Table S7,
Figure S30).14,21 For both gold and palladium, the electrostatic
term contributes to 49-52% of the interaction between the
metal fragment and substrate, while the orbital term accounts
for 40-42%. The primary orbital interaction is associated with
substrate to metal donation for gold, but metal to substrate
back-donation for palladium. The associated deformation
Ph
Ph
P
I
Pd
P
Ph
-49.6
(-62.8)
Ph
Ph
Figure 3. Reaction profiles computed for the oxidative addition of iodobenzene to the
real (P,N) gold complex (A) and to a model (P,P) palladium complex (B). Calculations
performed at the B97D(SMD-DCM)/SDD+f(Au,Pd),SDD(I),6-31G**(other atoms) level of
theory. Structure of the transition state of oxidative addition (bond lengths in Å, bond
angles in °). Contour plot of the NOCV deformation density Δρorb and the associated
stabilizing energy (ΔEorb(ρ), in kcal/mol) for the predominant orbital interaction
between PhI and the Au/Pd metal fragments. The charge flow is red → blue (Δρ < 0 in
densities  are represented in Figure 3, substantiating red and Δρ > 0 in blue). Analysis performed at ZORA-BP86-D3/TZ2P level of theory. The
contour value for density is 0.001 a.u.
inverse charge flows of the electron density (redblue). The
overall charge flow estimated by Hirshfeld partitioning
confirms the electron-accepting behavior of gold (0.08 e
transfer from PhI) but electron-donating behavior of palladium
Relative reactivities of iodoarenes in the gold-catalyzed
cross-coupling with TMB
(0.38 e transfer to PhI).
We were then keen to examine if the reverse electronic trend
observed with gold in the oxidative addition step may be
extrapolated to the catalytic cross-coupling of iodoarenes. For
this purpose, competition experiments analogous to those
described above have been performed to compare the relative
reactivities of para-substituted iodoarenes in the
cross-coupling with TMB catalyzed by the (P,N) gold complex.
The reactions were carried out under the previously reported
conditions (5 mol% Au complex, 1.05 eq. AgSbF6, 1 eq. K3PO4,
75 °C, 2 h), except that we used a 10-fold excess of the para-
4 | J. Name., 2012, 00, 1-3
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substituted iodoarene and iodobenzene with respect to TMB. main challenge of the transformation is the control of
View Article Online
The ratios of the resulting biaryl products [P1]/[P2] were regioselectivity in the absence of dirDeOctIi:n1g0.10g3r9o/uCp9SsC. 0M195o4sEt
determined by GC at complete consumption of TMB and used transition metals tend to intrinsically favour C2 arylation,25,27
to build the Hammett correlation shown in Figure 4.
while direct arylations of indoles at the C3 position remain
scant.28,29
MeO
C3 arylation
rarely observed with other TM
C2 arylation
well-developed
OMe
I
OMe
X
X
[(P,N)AuCl] (5 mol%)
AgSbF6 (1.05 eq.)
MeO
P1
(10 eq.)
R
FG
+
I
+
PG
R1
R1
MeO
OMe
K3PO4 (1 eq.)
DCB/MeOH (50:1)
75 °C, 2 h
N
R
X = SiR3, B(OR)2, H
X = I, Si(OMe)3, B(OH)2
N
N
MeO
MeO
(1 eq.)
C2
Oxidative Au(I)/Au(III)
catalysis
cat: Pd, Rh, Ru
R
R
OMe
C3
R
P2
(10 eq.)
- Stoichiometric oxidant required
- Works well with electron-deprived substrates
- Functional group compatibility issues
this work
I
(MeDalphos)AuCl (5 mol%)
AgOTf (1.05 eq.)
R1
R1
N
N
K3PO4 (1 eq.)
R3
+
R2
R2
DCB/MeOH (50:1)
75 °C, 2 h
(2 eq.)
(1 eq.)
R3
* 27 examples, up to 99% yield
* Mild conditions
* Complete C3 regioselectivity
* Electron-rich and -poor iodoarenes
* High functional group compatibility
* No protecting group needed at N
* Lack of air and moisture sensitivity
* Gram-scale
Scheme 3. Transition metal catalyzed methodologies for the regioselective arylation of
indoles.
Figure 4. Competition cross-coupling reaction of para-substituted iodoarenes with TMB
and associated Hammett correlation.
Over the last few years, gold-catalyzed methodologies have
started to be developed for the arylation of indoles. These
transformations are based on the oxidative coupling of
N-substituted indoles with aryl silanes,30 aryl boronates3f or
perfluoro arenes3d (see Supporting Information and Scheme S1
for a detailed state-of-the-art). An appealing feature of these
gold-catalyzed reactions lies in the mild conditions in which
they operate, typically between room temperature and 110 °C,
while Pd, Rh and Ru-catalyzed reactions generally require
prolonged heating at 120 °C or above. Moreover, gold
selectively promotes C3 arylation in the absence of directing
groups and is thus very complementary to the other transition
metals (Scheme 3). However, the gold-catalyzed arylation of
indoles remains relatively limited in scope. Due to
compatibility issues associated with the use of a strong oxidant
in stoichiometric amount, the indole is generally protected
with an electron-withdrawing group at N (such as Ts, SiiPr3 or
Piv). Electron-deprived arylating reagents are also usually
preferred, the presence of strong electron-donating
substituents commonly leading to greater extents of side-
reactions. Note that merging gold and photoredox catalysis2
offers another way to achieve Au(I)/Au(III) cross-couplings, but
attempts to apply this methodology to the arylation of indoles
have been unsuccessful so far due to competing azo
coupling.5e
As observed for the oxidative addition step, the reactivity of
iodoarenes towards cross-coupling with TMB increases with
increasing the electron donating ability of the para-substituent
(Table S2).14 The slope of the Hammett correlation is negative
and similar in magnitude to that found for the oxidative
addition step (ρ value = –1.09 vs –0.92).22,23 Thus, the unusual
electronic trend observed in the oxidative addition under
stoichiometric conditions is transposed to the cross-coupling
reaction under catalytic conditions. The favoured activation
and coupling of iodoarenes featuring electron-donating
substituents as observed with the (P,N) gold complex is quite
unique. It markedly contrasts with the behavior of group 10
metals and provides an efficient alternative to the
gold-catalyzed coupling reactions under oxidative and/or
photoredox conditions, for which electron-rich aryl
electrophiles are challenging substrates.3,4,5
Synthetic application of gold-catalyzed cross-coupling to the
arylation of indoles
We were then interested in applying our gold-catalyzed
arylation methodology to an important and challenging
transformation with the aim to assess how gold compare with
the other transition metals and eventually complement their
performance. In this perspective, we targeted the preparation
of aryl-substituted indoles, which are important structural
motifs found in many natural products and pharmaceuticals.24
The arylation of indoles with transition metal catalysts has
garnered tremendous efforts over the last two decades and Pd
clearly occupies the forefront position (Scheme 3).25,26 The
The promising preliminary result we obtained upon
arylation of N-phenyl pyrrole (61% yield of coupling with 9/1
selectivity in favor of the  isomer)6b prompted us to
investigate the (P,N) gold catalyst for the coupling of indoles
and iodoarenes. As reported hereafter, it proved to be very
efficient, general and robust, giving access to a variety of
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Journal Name
R1
N
C3-arylated indoles with complete regioselectivity within 2
hours at 75 °C.
View Article Online
I
R1
N
(MeDalphos)AuCl (5 mol%)
AgOTf (1.05 eq.), K3PO4 (1 eq.)
DOI: 10.1039/C9SC01954E
To start with, the coupling of N-methyl indole with
iodobenzene was tested under the catalytic conditions used
for the arylation of TMB and N-phenyl pyrrole (1 eq. of each
substrate, 5 mol% of (P,N)AuCl complex, 1.05 eq. of AgSbF6,
1 eq. of K3PO4, o-DCB/MeOH 50:1, 75 °C, 2 h).6b GC-MS
analysis of the crude mixture revealed the formation of a
single regioisomer of phenyl-substituted N-methyl indole but
only in trace amount. Fast screening of the reaction conditions
enabled significant improvement. Using two equivalents of
N-methyl indole and replacing AgSbF6 by AgOTf, the coupling
product was obtained in 99% yield (Scheme 4).31 The TfO–
+
DCB/MeOH (50:1)
75 °C, 2 h
(1 eq.)
(2 eq.)
H
N
N
N
N
1 99%
2
95%
3
82%
4
51%
O
Ts
N
SiiPr3
N
–
counter-anion is more coordinating than SbF6 and may
N
stabilize the gold(III) intermediate by the time the indole
reacts. 1H NMR spectroscopy indicated the exclusive formation
of the C3-arylated product 1.32 This regioselectivity is
consistent with the C–H activation of the indole at gold
proceeding via electrophilic aromatic substitution.33
5
0%
6
0%
7
0%
Scheme 4. Scope of N-substituted indoles. Cross-coupling of iodobenzene and indoles
catalyzed by the (P,N) gold complex. Yields determined using calibrated GC-MS with
n-dodecane as internal standard.
Next, we examined the applicability of these catalytic
conditions to the reaction of iodobenzene with different
N-substituted indoles (Scheme 4). The reaction works well with
N-phenyl and N-benzyl indoles to afford the corresponding aryl
products 2 and 3 in high yields (95 and 82%, respectively) and
with complete C3 regioselectivity. Noticeably, the N-tosyl and
N-triisopropylsilyl protected substrates used standardly in
gold-catalyzed oxidative arylations of indoles3d,30 did not work
in our conditions (the N-Ts indole is inert while the N-SiiPr3
undergoes desilylation). No coupling product was detected
either with N-acetyl indole. Indoles not depleted in electron
density are needed for the reaction to take place,
underpinning the electrophilic mechanism of the indole
auration.28c Selective arylation of unprotected indoles is
challenging. It often requires harsh conditions and gives
mixtures of regioisomers. It was thus of interest to test our
methodology with N-H indole. The coupling proceeded with
moderate yield (51%), but gratifyingly the C3-arylated product
4 was obtained without by-products stemming from N or C2
arylation. This regioselectivity is complementary to those
usually observed upon Pd- and Cu-catalyzed arylation of N-H
indoles.34,35 The operating conditions for the Au(I)/Au(III)
arylation of indoles are remarkably mild for such reactions (2 h
at 75 °C, while Pd catalysts typically require heating at
120-150 °C for ~ 24 h).27b
The scope of iodoarenes was then examined with N-methyl
indole as partner (Scheme 5). Pleasingly, the arylation
proceeds with good yields and complete C3 selectivity with
both electron-rich (8-9) and electron-deficient (10-12)
para-substituted iodobenzenes. More sterically hindered
substrates such as 1- and 2-iodonaphthalenes as well as ortho-
methoxy iodobenzene also react smoothly and regioselectively
(16-18). Notably, bifunctional iodoarenes featuring C–Br or
C–OTf bonds display complete chemoselectivity. In contrast to
Pd-catalysts that usually react with C–I, C–Br and C–OTf bonds
with limited selectivity, only the C–I bond is activated at gold
under these conditions. The corresponding C3-arylated indoles
13 and 14 are obtained in good to excellent yields and offer
the possibility for subsequent cross-coupling transformations.
Boronate moieties are also compatible with the gold-catalyzed
arylation, as shown by the preparation of compound 15.36 The
scope of iodoarenes was further studied with N-H indole. With
both electron-rich (19) and electron-deficient (20) substrates,
the arylation proceeds with moderate yield but complete C3
selectivity. Preliminary tests with 2-iodopyridine and
3-iodothiophene show that the reaction is also feasible with
heteroaryl iodides (21 and 22), although the corresponding
C3-arylated indoles were obtained in moderate yields. Note
that in some cases, the use of 2,6-di-tert-butylpyridine (DTBP)
instead of K3PO4 as the base afforded better results (for
example indole 9 was obtained in 86% yield with DTBP but
only 37% with K3PO4). X-ray diffraction analyses of compounds
10 and 13 unambiguously confirmed the regiochemical
outcome of the indole arylation.13
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ARTICLE
common functional groups are well tolerated on the indole
View Article Online
DOI: 10.1039/C9SC01954E
partner, as illustrated by the preparation of the CO2Me, Br,
OMe and Bpin-substituted products 28-31.
I
N
(MeDalphos)AuCl (5 mol%)
AgOTf (1.05 eq.), K3PO4 (1 eq.)
7
R
N
N
6
5
2
+
R
DCB/MeOH (50:1)
75 °C, 2 h
3
4
(1 eq.)
N
(2 eq.)
N
N
N
23
24 80%
25
2
6
%
27
72
%
0%
77%
66
MeO2C
N
N
N
N
Br
MeO
pinB
78%
58%
60%a
50%a
28
29
30
31
Yields determined by 1H NMR with n-dodecane as internal standard. aDTBP (1 eq.)
Scheme 6. Scope of substituted N-methylindoles. Cross-coupling of
iodobenzene and indoles catalyzed by the (P,N) gold complex.
A robustness screen was also conducted to further assess the
tolerance of the catalytic reaction towards various functional
groups. The arylation of N-methyl indole with iodobenzene was
undertaken in the presence of one molar equivalent of additives.
The yield of 1 was determined by GC-MS analysis, as well as the
amount of additive and starting material (SM) remaining (see Table
S3 in the Supporting Information).37 The results show that alkenes
(1-octene), alcohols (phenol, methanol), amides (acetanilide) and
nitriles (benzonitrile) are well tolerated: the coupling product 1 is
obtained in >87% yield, the recovery yields of excess substrate (N-
methyl indole) and additive are >94% and >74%, respectively. In
contrast, the presence of acids (benzoic acid) or amines
(p-toluidine) completely quenched the reactivity, while the addition
Scheme 5. Scope of iodoarenes. Cross-coupling of iodoarenes and N-methyl indole
catalyzed by the (P,N) gold complex. Unless otherwise stated, yields determined using
calibrated GC-MS with n-dodecane as internal standard. Crystallographic structures of
indoles 10 and 13 as inserts.
The robustness and scalability of the reaction was assessed using
4-iodobenzotrifluoride as substrate. The corresponding C3-arylated
indole 12 was obtained in excellent yield using only 1 eq. of
N-methyl indole. The reaction displays low air and moisture
sensitivity. It allows the use of commercial chemicals without
further purification and does not require inert atmosphere. The
synthetic applicability of the process was further substantiated by
carrying out gram scale experiments using lower catalytic loadings.
The C3-arylated indole 12 was for example obtained in 85% yield
of
aldehydes
(cyclohexanecarboxaldehyde)
or
ketones
(cyclohexanone) gives rise to side-reactions with consumption of
both the N-methyl indole and the additive. Compatibility of
heterocycles was also studied. While imidazole inhibited the
reaction, the presence of thiophene and benzofurane did not alter
the catalytic arylation of the indole.
when performing the reaction overnight with
(MeDalphos)AuCl.
1 mol% of
Conclusions
Then the influence of the substitution pattern at the indole
moiety was investigated. The coupling of iodobenzene with a
variety of N-methyl indoles was tested (Scheme 6). No
coupling product was obtained from 2-methyl indole,
indicating that the reaction is very sensitive to steric hindrance
at this position. Conversely, indoles methylated at either C4,
C5, C6 or C7 position readily couple with iodobenzene to give
the corresponding C3-arylated products 24-27 in good yields.
Particularly noteworthy is the 4-methyl substrate in which the
proximity of the methyl substituent at C4 does not hamper the
arylation in the C3 position. It is also worth noting that
Judicious choice of ligand has been recently demonstrated to
emulate oxidative addition of iodo- and bromoarenes to gold,
a basic elementary step long considered inadequate to access
aryl gold(III) complexes. Among the three sets of suitable
ligands, only the hemilabile (P,N) MeDalphos ligand has been
shown to date to pave the way for Au(I)/Au(III) catalysis from
aryl halides. The present study advances our knowledge of the
factors controlling this new gold reactivity and its synthetic
interest is illustrated in an important catalytic transformation,
namely the C3 arylation of indoles.
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In the presence of AgSbF6, the (MeDalphos)AuCl complex
Journal Name
Acknowledgements
View Article Online
DOI: 10.1039/C9SC01954E
reacts instantaneously and quantitatively with a variety of
iodoarenes at room temperature. To assess the influence of
electronics on the oxidative addition, competition experiments
have been performed with para-substituted substrates,
revealing a clear preference for electron-rich iodoarenes. Thus,
whatever the ligand, (P,P), (N,N) or (P,N), gold displays in
oxidative addition a reactivity trend opposite to that typically
encountered with palladium. Of note, similar competition
experiments could be carried out with the (P,N) ligand under
Financial support from the Centre National de la Recherche
Scientifique and the Université de Toulouse is gratefully
acknowledged. J. R. thanks the Fundación Ramón Areces for a
post-doctoral fellowship and the European Commission for a
MCIF (Gold3Cat-799606). The "Direction du Numérique" of the
Université de Pau et des Pays de l'Adour, MCIA (Mésocentre
de Calcul Intensif Aquitain) and CINES under allocation
A005080045 made by Grand Equipement National de Calcul
Intensif (GENCI) are acknowledged for computational facilities.
E. D. Sosa Carrizo thanks CDAPP for funding part of his post-
doctoral contract.
catalytic
conditions.
The
cross-coupling
of
1,3,5-trimethoxybenzene with para-substituted iodoarenes
was found to follow the same trend, showing that the unique
preference of gold for electron-rich substrates can be
transposed from the elementary step to
transformation.
a catalytic
Notes and references
Analysis of the oxidative addition process by DFT
calculations has provided a plausible rationale for the different
behavior of gold and palladium. Indeed, the respective
transition states display opposite electron flows according to
NBO, CDA and ETS-NOCV analyses. Despite the donor
bidentate ligand, the cationic (L,L’)Au+ complexes are highly
electrophilic and significant PhIAu charge transfer is
observed at the oxidative addition transition state. Conversely,
metal to PhI back-donation is prevalent for neutral L2Pd(0)
complexes, which explains why electron-deprived substrates
are more reactive.
Taking advantage of the facile oxidative addition of
iodoarenes and of the propensity of the ensuing aryl gold(III)
complexes to react with electron-rich (hetero)arenes via
electrophilic C‒H activation, we have applied the
(MeDalphos)AuCl complex to the catalytic arylation of indoles.
The transformation proved to be very efficient, general and
robust. As the recently developed gold-catalyzed oxidative
arylation of indoles, it displays complete regioselectivity for C3
arylation and thus nicely complements the Pd-catalyzed
transformations that tend to favor C2 arylation. The
(MeDalphos)AuCl complex operates under mild conditions
(75 °C, 2 h) without any external oxidant. As a result, it does
not require protection of the N atom of the indole and
tolerates a variety of functional groups at both the iodoarene
and indole partners (NO2, CO2Me, Br, OTf, Bpin, OMe…).
This study underscores the unique properties of (P,N) gold
complexes towards oxidative addition and highlights their
potential in Au(I)/Au(III) catalysis with aryl halide electrophiles.
Future studies will aim to further develop this chemistry by
taking advantage of the easy access and rich reactivity of aryl
gold(III) complexes.
1
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Conflicts of interest
There are no conflicts to declare.
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8
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10 Little is known yet about the effects of aryl electronics in Au(III)
and Au(I)/Au(III) reactivity. See: (a) ref. 3b; (b) K. Kang, S. Liu, T. 26 For transition-metal-free processes using highly electrophilic
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17 Same calculations have been performed on the (N,N) and (P,P)
chelated gold complexes6a,c which displayed preference for
electron-rich aryl iodides. Similar results were obtained with
electron transfer from iodobenzene to the (L,L)Au+ fragment at
the transition state of oxidative addition, and prevalent
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DOI: 10.1039/C9SC01954E
2018, 9, 4203−4216; (c) X. Qiu, H. Deng, Y. Zhao and Z. Shi, Sci.
Adv. 2018, 4, eaau6468; (d) X. Qiu, P. Wang, D. Wang, M. Wang,
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and references cited therein.
30 (a) K. Hata, H. Ito, Y. Segawa and K. Itami, Beilstein J. Org. Chem.
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31 The catalytic reaction did not proceed when the K3PO4 / AgOTf
combination was replaced by Ag3PO4.
32 Y. Zou, G. Yue, J. Xu and J. Zhou, Eur. J. Org. Chem. 2014,
5901−5905.
33 Electrophilic substitutions are known to proceed selectively at
the C3 position of indoles: A. H. Jackson and P. P. Lynch, J. Chem.
Soc., Perkin Trans. 2, 1987, 1215−1219.
34 Pd catalysts generally show high C2 selectivity (see ref. 25). For
a rare example of C3 arylation of N-H indoles, using sterically
demanding magnesium salts, see ref. 28a.
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36 For the selective coupling of B,Si-difunctional arenes with aryl
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37 For recent discussions of such robustness screening, see: (a) K.
D. Collins and F. Glorius, Nat. Chem. 2013, 5, 597–601; (b) K. D.
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PleaseCdhoemnoictaal dScjuiesntcme argins
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Chemical Science
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Graphical TOC:
0.2
0
H
0
Me
OMe
-0.2
-0.4
-0.6
-0.8
CF3
Br
ρ = -0.92
-0.4
-0.2
0.2
0.6
0.4 σp
Oxidative addition to gold & Au(I)/Au(III) catalysis
Unusual selectivity for electron-rich iodoarenes (Au vs Pd)
Mild, selective & general C3 arylation of indoles
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