Gold(I)/Gold(III) Catalysis that Merges Oxidative Addition and π-Alkene Activation

Article abstract of DOI:10.1002/anie.202006074

Heteroarylation of alkenes with aryl iodides was efficiently achieved with a (MeDalphos)AuCl complex through Au^I/Au^III catalysis. The possibility to combine oxidative addition of aryl iodides and π-activation of alkenes at gold is demonstrated for the first time. The reaction is robust and general (>30 examples including internal alkenes, 5-, 6-, and 7-membered rings). It is regioselective and leads exclusively to trans addition products. The (P,N) gold complex is most efficient with electron-rich aryl substrates, which are troublesome with alternative photoredox/oxidative approaches. In addition, it provides a very unusual switch in regioselectivity from 5-exo to 6-endo cyclization between the Z and E isomers of internal alkenols.

Full text of DOI:10.1002/anie.202006074

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Accepted Article
Title: Gold(I)/Gold(III) Catalysis Merging Oxidative Addition and π-
Alkene Activation
Authors: Mathilde Rigoulet, Olivier Thillaye du Boullay, Abderrahmane
Amgoune, and Didier Bourissou
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10.1002/anie.202006074
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RESEARCH ARTICLE
Gold(I)/Gold(III) Catalysis Merging Oxidative Addition and π-
Alkene Activation
Mathilde Rigoulet,[a] Olivier Thillaye du Boullay,[a] Abderrahmane Amgoune,[a] Didier Bourissou*[a]
Dedication: In memory of K. Muñiz
[a]
M. Rigoulet, O. Thillaye du Boullay, Dr. A. Amgoune, Dr. D. Bourissou
CNRS/Université Toulouse III - Paul Sabatier, Laboratoire Hétérochimie Fondamentale et Appliquée (LHFA, UMR 5069)
118 Route de Narbonne, 31062 Toulouse Cedex 09 (France)
E-mail: dbouriss@chimie.ups-tlse.fr
Homepage: http://lhfa.cnrs.fr/index.php/equipes/lbpb/accueil-lbpb
Supporting information for this article is given via a link at the end of the document
Abstract: The hetero-arylation of alkenes with aryl iodides has been
efficiently achieved with the (MeDalphos)AuCl complex via
Au(I)/Au(III) catalysis. The possibility to combine oxidative addition of
aryl iodides and π-activation of alkenes at gold is demonstrated for
the first time. The reaction is robust and general (>30 examples
including internal alkenes, 5, 6 and 7-membered rings). It is
regioselective and leads exclusively to trans addition products. The
(P,N) gold complex is most efficient with electron-rich aryl substrates,
which are troublesome with alternative photoredox / oxidative
approaches. In addition, it actuates a very unusual switch in
regioselectivity from 5-exo to 6-endo cyclization between the Z and E
isomers of internal alkenols.
Gold complexes are extremely powerful in activating π-bonds
and the associated synthetic developments are numerous.
Aiming at developing further Au(I)/Au(III) catalysis, we wondered
about the possibility to merge oxidative addition of aryl halides
and π-activation of alkenes.[14,15] In this respect, the oxy- and
amino-arylation reactions of alkenes, as pioneered by Wolfe et al
using Pd catalysis,[16] represent very nice examples of gold redox
catalysis under oxidative and photoredox conditions.[17] As
reported hereafter, in the presence of a silver salt and base, the
(MeDalphos)AuCl complex [MeDalPhos = Ad2P(o-C6H4)NMe2]
was found to efficiently catalyse these transformations from aryl
iodides (Figure 1) and it shows unique efficiency towards electron-
rich aryl substrates, which are problematic with alternative
approaches.
Introduction
Homogeneous gold catalysis is developing extremely fast and
is increasingly used in organic synthesis.[1] It offers a unique
balance between activity, functional group compatibility and
accessible molecular complexity. Research efforts were first
focused on reactions involving π-activation of CC bonds and
carbene intermediates,[2] followed by dual gold catalysis in which
substrates are concomitantly σ and π-coordinated to two gold
centers.[3] The field has been recently further expanded with the
advent of Au(I)/Au(III) catalysis. The inherent reluctance of gold
to commute between Au(I) and Au(III) oxidation states has been
overcome using oxidative or photoredox conditions, opening new
avenues in cross-coupling catalysis.[4,5] Indeed, the use of
external oxidants or light activation has been shown to provide
access to aryl Au(III) complexes which can then participate in C–
C and C–X bond-forming reactions. We have recently introduced
another approach in which the faculty of hemilabile (P,N) ligands
to promote oxidative addition of aryl halides to gold is used to
undertake Au(I)/Au(III) catalysis.[6-8] Following the oxidative
addition step, we took advantage of the propensity of Au(III)
species to readily C–H activate electron-rich arenes[9,10] and
thereby achieved for the first time gold-catalyzed C–C cross-
coupling from aryl halides. Accordingly, a mild, efficient and
versatile method for the arylation of indoles with complete C3
regioselectivity was developed (Figure 1).[11] Recently, the
approach was further extended to C–N coupling with anilines,
amides, sulfonamides and carbamates.[12,13]
Figure 1. Au(I)/Au(III) catalysis based on oxidative addition of aryl iodides.
Results and Discussion
Combining oxidative addition of aryl iodides and π-activation
of alkenes at gold raises issues in terms of compatibility between
the involved functional groups and synchronisation of the different
steps. The first stage of our study was thus a robustness screen[18]
of oxidative addition to gold under stoichiometric conditions.
Instantaneous and quantitative oxidative addition occurs when
PhI is added at room temperature to (MeDalPhos)AuCl/AgSbF6.
The ensuing aryl gold(III) complex 2 displays a diagnostic 31P{1H}
NMR signal at δ 74.4 ppm. In the presence of 1 equiv of 1-octene,
1
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RESEARCH ARTICLE
two signals are observed in the 31P{1H} NMR spectrum (in 77:23
ratio after mixing): the major one at δ 74.4 ppm corresponds to
complex 2 while the other at δ 57.9 ppm is associated with the π-
complex (MeDalPhos)Au(1-octene)+.[19] We have recently
reported the ability of the (P,N) ligand to form such tricoordinate
gold(I) π-complexes with a variety of alkenes thanks to the faculty
of the NAu interaction to accommodate the electron demand at
gold.[20] NMR Monitoring reveals slow conversion of the π-
complex into the oxidative addition product (90% of complex 2
after 4 days), indicating that alkenes slow down but do not prevent
the reaction of aryl iodides. It is also noteworthy that no
subsequent reaction was noticed between 2 and 1-octene. Similar
tests have been performed with 1-pentanol and N-tosyl
methylamine.[12b,21] In both cases, small 31P NMR signals are
detected in the typical zone for (MeDalPhos)Au(I) species right
after mixing (at δ 59.8 ppm for 1-pentanol and δ 64.3 ppm for
MeNHTs), but PhI reacts rapidly and oxidative addition is
complete within two hours at RT.
reveals the concomitant formation of the cationic gold(I) complex
3, previously authenticated and thoroughly characterized with
respect to its unprecedented N–H∙∙∙Au hydrogen bonding.[22-24]
This result suggests that catalytic turnover may be achieved
in the presence of a base and indeed, the (P,N)gold(I) complex
proved to efficiently catalyse the oxy-arylation of 4-penten-1-ol
with iodobenzene. The reaction parameters (base, solvent, silver
salt, ratio of substrates, concentration, catalytic loading) were
varied (Tables S1 and S2)[19] to determine the following optimized
conditions: K3PO4 (1 eq.), DCM, 25°C, AgSbF6 (1.05 eq.), 1:1
PhI/4-penten-1-ol, 0.4 M, 5 mol% (P,N)AuCl.
The scope of aryl iodides was then assessed (Table 1). The
oxy-arylation of 4-penten-1-ol works well with a variety of
substrates (with an average yield of 88% over 11 substrates). It
tolerates electron-withdrawing groups (p-COCH3, p-NO2) as well
as ortho-substitutents (o-OCH3, o-Ph). No sign of O-arylation ‒ a
possible side-reaction previously observed with electron-poor aryl
bromides under palladium catalysis[16b] ‒ was detected. The
reaction actually performs best with electron-rich substrates, as
illustrated by the high-yield preparation (>95 %) of the
tetrahydrofurane products Ig-j. Successful incorporation of
protected catechol and trihydroxyphenyl moieties (products Ih,i)
is particularly noteworthy, these two motifs being present in a
number of biologically active compounds.[25] The preference for
electron-rich substrates is a peculiar feature of the (P,N) gold(I)
complex. As shown previously, electron-donating substituents
activate aryl iodides towards oxidative addition to gold, an
electronic bias opposite to that commonly encountered with Pd
catalysts.[6b,11] Thanks to this unique ability to react with electron-
rich iodobenzenes, the (P,N) gold(I) complex displays in the oxy-
arylation of 4-penten-1-ol a reactivity profile complementary to
that observed under photoredox and oxidative conditions, for
which electron-rich substrates were found to be problematic due
to competitive side-reactions.[5d,26]
Scheme 1. Stoichiometric oxy-arylation upon reaction of the gold(III) complex 2
with 4-penten-1-ol.
Then, the ability of the gold(III) complex 2 to activate C=C
double bonds and promote nucleophilic addition was tested. Upon
treatment with 1 equiv of 4-penten-1-ol (Scheme 1), it leads to the
progressive formation of 2-benzyltetrahydrofurane (the oxy-
phenylation product), as deduced from GC-MS and 1H NMR (87%
yield after 2 days at room temperature). 31P NMR spectroscopy
Table 1. Gold-catalyzed oxy-arylation, scope of aryl iodides.
2
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10.1002/anie.202006074
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RESEARCH ARTICLE
.
Table 2. Gold-catalyzed oxy-arylation, scope of alkenols.
The scope of alkenols was then explored (Table 2). Alkyl and
aryl substituents can be introduced on all positions of the tether
between the alkene and the alcohol groups (products IIa-f).
Tetrahydrofuranes fused with cyclohexane and benzene rings
(products IIg,h) can also be readily and efficiently obtained. In all
cases, the cyclization is fully regioselective and proceeds
exclusively in a 5-exo fashion. While modest diastereoselectivities
were observed with gold catalysts operating under photoredox or
oxidative conditions (1:1 dr ratios in most cases, 2.8:1 at
best),[17a,i,k] a good diastereoselectivity was observed with the
(P,N) gold complex for the 3-substituted substrate. The 2,3-
disubstituted tetrahydrofurane IIc was obtained with a dr of 6.1:1.
It is possible that the chelation of the (P,N) ligand to gold induces
higher steric shielding and results in better discrimination between
the formation of the two diastereomers. Remarkably, lengthening
the tether to obtain more challenging >5-membered cycles is also
possible. Cyclizations proceed smoothly at 35°C with 5-hexen-1-
ol as well as 6-hepten-1-ol to give the corresponding pyrane and
oxepane products IIi,j and IIk, respectively, in high yields. Double
oxy-arylation of tetrafunctional substrates is possible too, giving
straightforward access to spirocyclic products such as IIl. Gem-
disubstituted alkenols are suitable substrates, enabling the
formation of quaternary centers (such as in product IIm), although
it requires gentle heating (35°C) and the associated yield is lower.
Substitution in the terminal position (internal alkenes) is also
tolerated. Both the E and Z isomers react and in each case, a
single product resulting from trans addition (IIn and IIo,
respectively) is obtained (see below for mechanistic implications).
Most remarkable is the complete change in regioselectivity
between the two isomers. The more reactive Z-substrate
undergoes the “normal” 5-exo cyclization, whereas the E-
substrate reacts via a 6-endo process to give a pyrane ring.[27] To
3
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10.1002/anie.202006074
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RESEARCH ARTICLE
stereochemical outcomes, respectively syn or anti addition of the
Ar group and O/N-nucleophiles to the C=C double bond.
Palladium-catalyzed transformations have been shown to operate
mainly by the insertion route (into Pd‒O bonds), but anti Wacker-
type additions have also been observed occasionally.[16] With gold,
hetero-arylation reactions were systematically proposed to
proceed via the outer-sphere pathway based on the formation of
trans addition products,[28] but with different variants. Zhang et al
suggested that oxidation and aryl transfer to gold occur first,
before the alkenol / alkenamine substrate is activated and
cyclized.[17a] In contrast, Glorius et al proposed that gold(I) initially
reacts with the alkenol / alkenamine and promotes cyclization,
before the aryl group is added to gold and oxidation to Au(III)
occurs.[17i] In both cases, the hetero-arylation product is released
by reductive elimination. With the (MeDalphos)AuCl complex, the
oxy- and amino-arylation reactions are proposed to proceed via
the Au(I)/Au(III) catalytic cycle depicted in Figure 2. It starts by
oxidative addition of the aryl iodide to gold, based on the faculty
of the (P,N) ligand to promote this step even in the presence of
alkenes, alcohols and amines. It is also noteworthy that exactly
the same catalytic results were obtained in the oxy-arylation of 4-
penten-1-ol using the MeDalphos gold(I) complex or the
corresponding gold(III) complex 2’ deriving from oxidative
addition of 4-iodoanisole.[19] η2-Coordination of the alkene to
gold(III)[29] would then promote cyclization by nucleophilic addition
of the pendant alcohol / amine. The steric crowding induced at
gold by the chelating (P,N) ligand may explain the high
diastereoselectivity achieved upon formation of 2,3-disubstituted
products (tetrahydrofurane IIc and pyrrolidine IIIc) as well as the
switch in regioselectivity from 5-exo to 6-endo cyclization
observed between the Z and E isomers of internal alkenols.
assess the generality of this phenomenon, a Z/E mixture of gem-
dimethyl-substituted substrates was tested. Again, the Z isomer
was found to exclusively undergo 6-endo cyclization while the E
isomer reacted via the classical 5-exo pathway, resulting in a
mixture of pyrane IIp and tetrahydrofurane IIq. The behavior of
the (P,N) gold complex markedly contrasts with that observed by
Glorius et al combining gold and photoredox catalysis. Here, 5-
exo cyclization occurred whatever the stereochemistry of the
internal alkenol used as substrate.[17i] To the best of our
knowledge, a complete switch in regioselectivity as observed with
the (P,N) gold complex is very unusual and has not been
observed either under Pd-catalysis.[16]
The robustness and synthetic practicability of the oxy-
arylation reaction was then assessed using 4-penten-1-ol and p-
methoxy iodobenzene as substrates.[19] The catalytic loading of
(P,N)AuCl was reduced to 2.5 mol% without noticeable decrease
in the yield of the obtained tetrahydrofurane Ib. The reaction does
not require drastic precautions. It proceeds with similar efficiency
operating under air, using reaction-grade solvents and reagents
as received (without specific drying). The reaction could also be
smoothly scaled-up to 5 mmol of substrates (instead of 0.4 mmol).
Gratifyingly, amino-arylation reactions also proceed well via the
oxidative addition / π-activation sequence (Table 3). Alkenes
featuring an N-tosyl amine as well as N-tosyl amide moiety in γ-
position are readily converted into the corresponding arylated-
pyrrolidines IIIa-d and pyrrolidones IIIe,f increasing the catalytic
loading to 10 mol% and slightly raising the temperature (to 35 °C).
Again, the electron-rich p-methoxy iodobenzene performs best,
substituents are tolerated on all the positions of the tether and
strong Thorpe-Ingold effect is not needed for the cyclization to
proceed well. In addition, high diastereoselectivity (dr 10.1:1) was
observed for the formation of the trans-2,3-disubstituted
pyrrolidine IIIc starting from N-tosyl 3-phenyl hex-4-enylamine.
From a mechanistic viewpoint, two general pathways are
conceivable for such hetero-arylation reactions. They involve
either migratory insertion of the alkene or outer-sphere attack of
the O/N-nucleophiles as key steps and result in different
Finally, reductive elimination at gold would induce the Csp2–Csp
3
coupling and regenerate the [(MeDalphos)Au+] active species,
which is in equilibrium with the corresponding π-alkene complex.
This scenario is consistent with trans addition across the C=C
double bond, as apparent from the stereochemistry of the
tetrahydrofurane and tetrahydropyrane products IIn-q. Reactions
from D-labeled N-tosyl pent-4-enyl amines leading to pyrrolidines
Table 3. Gold-catalyzed amino-arylation.
4
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10.1002/anie.202006074
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RESEARCH ARTICLE
IIIg,h also support trans addition as the main route for the amino-
arylation reaction.[19] Of note, small amounts of the cis addition
products were detected in this case, suggesting that the migratory
insertion pathway may compete with the outer-sphere
nucleophilic attack and contribute to a small extent with such
substrates, in line with the feasibility of syn migratory insertion
reactions of alkenes into Au(III)–C bonds recently
substantiated.[30]
acknowledged. M.R. thanks MESRI (Ministère de l’Enseignement
Supérieur, de la Recherche et de l’Innovation) for her PhD
fellowship (Contrat Doctoral Spécifique Normalien). The NMR
service of ICT (S. Massou, P. Lavedan and M. Vedrenne) is
acknowledged for assistance with the TOCSY experiments.
Keywords: Gold • Homogeneous catalysis • Oxidative addition •
π-Activation • (P,N) Ligand
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Figure 2. Proposed catalytic cycle for the oxy-/amino-arylation reactions with
[5]
the (MeDalphos)AuCl complex (counter-anions are omitted).
Conclusion
In summary, the first gold-catalyzed reaction to combine
oxidative addition of aryl iodides and π-activation of alkenes has
been developed. The transformation is efficient and robust. It
works with a broad scope of substrates and gives access to 5, as
well as 6 and 7-membered rings. It is based on a ligand-induced
approach ‒ using the (P,N) ligand MeDalphos ‒ that complements
and significantly extends the synthetic interest of the oxy- and
amino-arylation reactions performed under oxidative / photoredox
conditions. The reaction is compatible and actually best-
performing with electron-rich aryl substrates which otherwise
react sluggishly. The (P,N) ligand brings sterical shielding to gold
and induces synthetically useful levels of diastereoselectivity
upon formation of 2,3-disubstituted products (dr 6-10:1),
surpassing the other gold systems. Also noteworthy and very
unusual is the complete switch in regioselectivity from 5-exo to 6-
endo cyclization between the E and Z isomers of internal alkenols.
Future work will seek to further develop the synthetic potential of
this approach.
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Acknowledgements
Financial support from the Centre National de la Recherche
Scientifique and the Université de Toulouse is gratefully
[13] For the application of oxidative addition of aryl iodides to (P,N)-ligated
gold(I) complexes to cysteine arylation (C–S coupling), see: M. S.
5
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6
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10.1002/anie.202006074
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
Two-in-one: the (MeDalphos)AuCl complex promotes both oxidative addition of
aryl iodides and -activation of alkenols / alkenamines, and displays a unique
profile in catalytic heteroarylation reactions.
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