Metal-ligand-Lewis acid multi-cooperative catalysis: A step forward in the Conia-ene reaction

Article abstract of DOI:10.1039/d0sc05036a

An original multi-cooperative catalytic approach was developed by combining metal-ligand cooperation and Lewis acid activation. The [(SCS)Pd]2 complex featuring a non-innocent indenediide-based ligand was found to be a very efficient and versatile catalys

Full text of DOI:10.1039/d0sc05036a

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Clerc, E.
Marelli, N. Adet, J. Monot, B. Martin-Vaca and D. Bourissou, Chem. Sci., 2020, DOI:
10.1039/D0SC05036A.
Volume
Number
9
1
This is an Accepted Manuscript, which has been through the
7
January 2018
Pages 1-268
Royal Society of Chemistry peer review process and has been
accepted for publication.
Chemical
Science
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
rsc.li/chemical-science
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 2041-6539
EDGE ARTICLE
Xinjing Tang et al.
Caged circular siRNAs for photomodulation of gene
expression in cells and mice
rsc.li/chemical-science

Please do not adjust margins
Page 1 of 8
Chemical Science
View Article Online
DOI: 10.1039/D0SC05036A
ARTICLE
Metal-Ligand-Lewis Acid Multi-Cooperative Catalysis: A Step
Forward in the Conia-Ene Reaction
Arnaud Clerc,‡ Enrico Marelli,‡ Nicolas Adet, Julien Monot, Blanca Martín-Vaca,* and Didier
Bourissou*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An original multi-cooperative catalytic approach was developed by combining metal-ligand cooperation and Lewis acid
activation. The [(SCS)Pd]2 complex featuring a non-innocent indenediide-based ligand was found to be a very efficient and
versatile catalyst for the Conia-Ene reaction, when associated with Mg(OTf)2. The reaction operates at low catalytic loadings
under mild conditions with HFIP as co-solvent. It works with a variety of substrates, including those bearing internal alkynes.
t
It displays complete 5-exo vs 6-endo regio-selectivity. In addition, except for the highly congested Bu-substituent, the
reaction occurs with high Z vs E stereo-selectivity, making it synthetically useful and complementary to known catalysts.
promote the cycloisomerization of alkynoic acids and N-tosyl
alkynylamides, giving access in high yield and selectivity to a
wide variety of alkylidene lactones and lactams, including
Introduction
Major breakthroughs have been made in homogeneous
catalysis thanks to cooperative approaches.1 Concomitant and
synergistic participation of several active sites, as in enzymes, is
very attractive to achieve chemical transformations under
milder conditions and reduce wastes. Thanks to cooperativity,
not only the efficiency and selectivity of catalysts can be
improved, but the diversity and complexity of the obtainable
chemical compounds can also be expanded. In this context,
metal-ligand cooperativity (MLC) is clearly prominent.2 Here, a
ligand participates directly in the substrate activation, in
addition to modulate the stereoelectronic properties of the
metal center. Complexes of the group 7-9 metals featuring non-
innocent pincer ligands, in particular amido and pyridine-based
scaffolds, occupy a forefront position in this area.3 Tremendous
achievements in hydrogenation and dehydrogenation reactions
have been reported with these catalysts.4 Extending the scope
of transformations5 and developing further the MLC catalytic
approach is currently a major endeavor, along with the
diversification of complexes displaying MLC.
Our group introduced a few years ago a SCS pincer framework
featuring an electron-rich indenediide back-bone.6 The paucity
of MLC behavior reported for Pd and Pt complexes,7 despite the
prominent role of these metals in homogeneous catalysis, led
us to study complexes of type I (Figure 1). The electron-rich
indenediide motif was shown to be non-innocent and to open a
MLC pathway for Pd and Pt-catalyzed C–O and C–N bond
formation. The (SCS) Pd,Pt complexes proved to very efficiently
seven-membered rings.8 Of note, indepth mechanistic studies
substantiated the participation of proton shuttling in addition
to MLC.9 This drove us to use catechols as hydrogen bond donor
(HBD) additives. The activity and selectivity of the (SCS) Pd,Pt
complexes were thereby spectacularly improved.9 The synergy
between MLC and proton shuttling is a very appealing way to
boost catalytic performance. It has been proposed for many
hydrogenation/dehydrogenation reactions involving MLC10 and
recently unequivocally demonstrated by Hazari et al.11 Its
impact in intermolecular hydroamination reactions has also
been substantiated.7g
Metal-Ligand Cooperation
HB-Donor
e-rich backbone
X-H activation
electrophilic M
π-activation
Catechols
Lewis Acid
Mg(OTf)2
O
H
R2P
S
R
previous
work
this
work
M
O
H
S
R2P
I
proton
shuttling
M = Pd, Pt
O
O
Conia-ene
reaction
O
O
O
O
XH
X
n
n
R
C-C bond formation
19 examples, 52-92% yield
5-7 membered rings
R
Y
Y
n = 1-3
X = O, NTs
R
n
n
n = 1-3
Y = C, N, O
C-O & C-N bond formation
5-exo cyclization, Z selectivity
R
Figure 1. Multi-cooperative catalysis combining metal-ligand cooperation (MLC,
indenediide-based (SCS)M pincer complexes) with hydrogen-bond donors (HBD,
previous work) or Lewis acid activation (LA, this work) to promote cycloisomerization
reactions (C–O, C–N and C–C bond formation).
Encouraged by these results, we wondered about the possibility
to develop new multi-cooperative catalytic approaches based
on MLC. Another aim was to expand the scope of the SCS Pd,Pt
catalysts to more challenging transformations. In this work, we
focused on Conia-Ene cyclizations, i.e. the formation of carbo-
Laboratoire Hétérochimie Fondamentale et Appliquée (UMR 5069), Université de
Toulouse (UPS), CNRS, 118 route de Narbonne, F-31062 Toulouse, France
‡These authors contributed equally.
Electronic Supplementary Information (ESI) available: Full experimental procedures,
1
characterization data of all new compounds (including H, 13C-NMR spectra, and
ADEQUATE,
NOESY
and
dsel-HSQMC-IPAP
experiments).
See
DOI: 10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 2 of 8
ARTICLE
Journal Name
and heterocycles by C–C coupling between an enolizable group, 4/1 chloroform/HFIP solvent mixture, high conversions of the
View Article Online
typically a β–dicarbonyl moiety, and an alkyne. As pointed out β–diketone 1a and β–dinitrile 4a were aDchOiIe: v10e.d10i3n9/tDh0isSCc0a5s0e36aAt
by Enders et al in their recent review,12 this is a very powerful 60°C with only 1 mol% of Pd (entry 6). The fact that 4a was
transformation and much progress has been achieved recently readily cyclized is particularly noteworthy since β–dinitriles are
from both methodological and synthetic viewpoints, but several usually significantly less reactive than β–dicarbonyl substrates
limitations still need to be addressed. While investigating the in the Conia-Ene reaction.12 It is because the linear geometry of
ability of the MLC Pd indenediide complex to catalyze Conia-Ene the cyano group is not suited for intramolecular hydrogen-
cyclizations, we discovered it is extremely efficient and versatile bonding and thus tautomerization is more demanding. Under
when associated with a Lewis acid (LA). The combined use of these milder conditions, the β–keto,ester 2a could also be
TM catalysts and Lewis acids (often referred as dual activation) efficiently cyclized and 2b was formed in high yield without side
has attracted increasing interest and led to impressive product. In turn, the β–diester 3a was unreactive. Due to their
developments over the last decade,13 including in the Conia-Ene weaker acidity, β–diester substrates are notoriously less
reaction.12,14 Yet, synergistic effects between MLC and LA reactive and more challenging in the Conia-Ene reaction.12 The
activation have not been realized so far. As reported hereafter, contribution of proton shuttling to the carbocyclization of 1a,
the association of [(SCS)Pd]2 and Mg(OTf)2 provides a first 2a and 4a in the presence of HFIP is supported by a strong
example of such a dual and multi-cooperative catalytic system. solvent dependence. While toluene and dichloromethane gave
It is a very efficient and useful catalyst for Conia-Ene results close to those obtained in chloroform, hydrogen-bond
cyclizations, displaying broad substrate scope and high regio as accepting solvents such as THF or DMSO completely inhibited
well as stereo-selectivity.
the reaction.
Thus, the indenediide pincer Pd complex [(SCS)Pd]2 is a
competent catalyst for the Conia-Ene reaction of β–diketo, β–
keto,ester and β–dinitrile substrates, when combined with HFIP
as co-solvent. However, it fails to cyclize the corresponding β–
diester under the same conditions. Although the [(SCS)Pt]2
complex proved superior for the cyclization of challenging
alkynoic acids and amides,8c no improvement was observed in
the Conia-Ene reaction upon changing Pd for Pt. The Pt complex
proved in fact less active, with only 40% (vs 90%) conversion of
2a after 16 h (Table S2).15 Looking for another way to boost the
catalytic activity, we envisioned to use di or trivalent Lewis
acids, which are known to activate β–dicarbonyl compounds
and facilitate the formation of the corresponding enols.
Combinations of hard and soft Lewis acids have been
occasionally used in Conia-Ene reactions. Such dual activation
proved in particular successful to promote enantioselective
cyclization of β–diketo and β–keto,ester derivatives.14a,b,c,f
Given these precedents, we wondered about the possibility to
implement a new type of multi-cooperative catalytic approach
by merging metal-ligand cooperation, as achieved by the (SCS)
Pd complex, with the activation of the β–dicarbonyl moiety by
a LA.18 Multi-cooperative catalytic systems are very attractive
but challenging to achieve. They inherently raise compatibility
issues and the different components must be carefully adjusted
to act synergistically. In the case of the (SCS) Pd complex, the
Lewis acid additive may interact with the electron-rich
indenediide motif as well as the sulfur atoms and thereby
interfere with the Pd-ligand cooperativity.19 A series of triflate
salts were evaluated as LA additives to [(SCS)Pd]2 in the
cyclization of the β–keto,ester 2a in 4/1 chloroform/HFIP as
solvent. Initial screenings were performed at 60 °C with 1 mol%
Pd and 20 mol% LA (Figure 2, Table S3).15 While Cu(OTf)2 and
Sc(OTf)3 had no or negative impact on catalysis, significant
improvement of activity was observed with Ca(II), Mg(II), Zn(II)
and Yb(III) salts.20 High conversions were achieved in only one
hour (>82% vs only 25% without LA), demonstrating the
compatibility and synergy between MLC with the [(SCS)Pd]2
complex and electrophilic activation of the β–dicarbonyl moiety
RESULTS AND DISCUSSION
To start with, the carbo-cyclization of the β–dicarbonyl
compounds 1a-3a and β–dinitrile 4a bearing an alkyne moiety
was studied applying the reaction conditions previously
optimized for the cycloisomerization of alkynoic acids (Scheme
1).9 A series of hydrogen-bond donors (catechols…, 30 mol%,
Table S1)15 were probed as proton shuttling additives to the
indenediide-derived Pd complex [(SCS)Pd]2 (5 mol% Pd). The
best results were obtained with 4-nitrocatechol. Heating at
120°C for 16 h, full conversion could be achieved in all cases but
3a (only 30% in this case). The expected cyclized products 1b
and 4b were selectively obtained from the β–diketone and β–
dinitrile substrates 1a and 4a, whereas 2a led to the formation
of a secondary product 2c (30% yield) resulting from double
addition of the catechol to the C≡C triple bond,16 besides the
targeted carbocycle 2b (47% yield). As for the β–diester 3a, no
cyclized product 3b was formed, only the secondary product 3c
was obtained.
O
O
E1
E2
O
O
NO2
E1
Me
2a
OMe
E2
Me
Me
Reaction conditions
O
1a
+
O
5 mol% Pd
1b
2b
3b
4b
85%
E1 = E2 = COMe
1c
2c
0%
30%
3c 30%
[(SCS)Pd]2
O
O
l
47% E1 = COMe, E2 = CO2Me
NO2-catechol 30 mo %
NC
CN
chloroform
0%
>95%
E1 = E2 = CO2Me
E1 = E2 = CN
MeO
OMe
120 °C
4c
, 16 h, 0.5 M
0%
3a
4a
iPr2
P
S
1b 90%
2b 90%
3b
4b >95%
1 mol% Pd
[(SCS)Pd]2
chloroform/
HFIP
4/1
0%
Pd
S
60 °C,
16 h, 0.5 M
iPr2
P
2
[(SCS)Pd]2
Scheme 1. Conia-Ene cyclization of the β–dicarbonyl and β–dinitrile substrates 1a-
4a catalyzed by the [(SCS)Pd]2 complex in the presence of 4-nitrocatechol or HFIP.
Throughout the paper, the a/b letters in the com-pound numbers refer to the
substrate/cyclized Conia-Ene product, respectively.
The known ability of hexafluoroisopropanol (HFIP) to form
hydrogen-bond networks and participate in proton shuttling17
prompted us to screen a series of fluorinated alcohols as
additives. This resulted in noticeable improvement of activity
and selectivity (Scheme 1 and Table S2, entries 1-4).15 Using a
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 8
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
Table 1. Impact of the different components of the catalytic system (Pd complex, Lewis
acid, proton shuttle additive) on the carbocyclization of the keto,ester 2a.
DOI: 10.1039/D0SC05036A
with a LA. Taking advantage of the catalytic boost triggered by
the LA additive, the reaction conditions were then softened.
The temperature was decreased to 25 °C and the LA loading was
reduced to 5 mol%. Under these mild conditions, Mg(OTf)2 and
Yb(OTf)3 led to the best results (~90% conversion to 2b within
only 30 min, and >95% after 1.5 h). The β–diketo substrate 1a
was also readily cyclized under these conditions (>95% after 8
h). In contrast, similar results were obtained with and without
Lewis acid in the case of the β–dinitrile 4a (85 % conv. is
achieved in 16 h at 25°C). Chelating coordination of the two
cyano groups is not possible geometrically, and thus the LA
cannot facilitate deprotonation, as in the case of the β–
dicarbonyl substrates. Most remarkably, the combination of
[(SCS)Pd]2 with the LA allowed for the cyclization of the
challenging β–diester 3a as well. Here, Mg(OTf)2 significantly
outperformed Yb(OTf)3 (83 vs 13% conversion of 3a within 30
min). Given the superior efficiency, abundance and biological
tolerance of Mg over Yb, the catalytic studies were continued
with Mg(OTf)2 as LA.21
View Article Online
Reaction conditions, deviations from the optimal
conv. / reaction time
Optimal: [(SCS)Pd]2 1 mol% Pd, 5 mol% Mg(OTf)2
>95% / 1.5 h
46% / 60 h
chloroform/HFIP 4/1, 25°C
[(SCS)Pd]2 5 mol% Pd, 20 mol% Mg(OTf)2
chloroform, 25°C, No HFIP
No Mg salt, 60°C
>95% / 22 h
traces / 16 h
0% / 2 h
No Pd complex, No Mg salt, 60°C
No Pd complex, 20 mol% Mg(OTf)2
Indenyl [(SCS-Me)Pd] complex
>95% / 8.5 h
Indenyl [(SCS-Me)Pd] complex, 5 mol% Pd
No Mg salt, 60°C
90% / 15 days
[PdCl(allyl)]2 1 mol% Pd
[PdCl2(PhCN)2] 1 mol% Pd
6% / 24 h
7% / 24 h
35% / 24 h
O
O
O
O
[Pd(SCS)] 1 mol% Pd
[PdCl2(PhCN)2] 1 mol% Pd, dppe 1 mol%
Me
LA
X
additive mol%
OMe
Me
OMe
HFIP
chloroform/
4/1
[PdCl2(PhCN)2] 1 mol% Pd, dppe 1 mol%,
iPr2EtN 1 mol%
2a
2b
78% / 24 h
[(SCS)PhPd]3 5 mol% Pd, 20 mol% Mg(OTf)2
>95% / 20 min
iPr2P
Ph2P
S
S
Me
Pd
Pd
Cl
S
iPr2P
S
Ph2P
3
Indenyl [(SCS-Me)Pd]
[(SCS)PhPd]3
Seeking to evidence the non-innocent character of the ligand
via the formation of indenyl [(SCS-H)PdX] species, several
catalytic reactions were in situ analyzed by 31P NMR
spectroscopy (see SI for a detailed description, Figures S1-S4).
These monitorings were complicated by the fact that HFIP has
an impact on the structure/association degree of the catalyst,
and only broad signals could be observed (the dimer [(SCS)Pd]2
was recovered intact after evaporation of the solvent at the end
of the catalytic reaction). When the reaction was carried out in
the absence of HFIP, only the dimer [(SCS)Pd]2 was observed
along the reaction, indicating it is the resting state. This
behaviour is reminiscent of that observed in the
cycloisomerization of alkynoic acids,9 and is consistent with the
tight association of the two (SCS)Pd fragments. We decided
then to evaluate the behaviour of a pre-catalyst bearing Ph
instead of iPr groups on the P atoms. The less electron-donating
Ph2P=S sidearms lead to weaker association of the (SCS)PhPd
fragments.8a Only broad signals were again observed in the
presence of HFIP, but when the reaction was carried out in the
absence of HFIP, minor signals corresponding to indenyl species
were clearly detected by 31P NMR spectroscopy. Although
[(SCS)PhPd]3 remains the major species, the observation of
indenyl species during the catalytic transformation is consistent
with the indenediide ligand backbone acting as a base.
Figure 2. Evaluation of the catalytic activity of the Pd complex [(SCS)Pd]2 in the presence
of LA additives.
To ascertain the need and synergy of all the catalytic
components, a series of control reactions were carried out for
the cyclization of the β–keto,ester substrate 2a. Results
obtained in conditions deviating from the optimal ones [1 mol%
Pd, 5 mol% Mg(OTf)2, chloroform/HFIP 4:1, 25°C] are disclosed
in Table 1. As previously pointed out, the presence of HFIP and
Mg(OTf)2 is crucial to boost the catalytic activity and makes the
Conia-Ene reaction to work at 25°C with low Pd loadings.
Conversely, in the absence of Pd complex, no cyclized product
(or only a very small amount) was formed with HFIP alone or
with a mixture of Mg(OTf)2 and HFIP. The electron-rich
indenediide moiety of the SCS ligand also plays a major role, as
substantiated by the noticeable decrease in activity observed
when shifting to the corresponding 1-Me-2-indenyl Pd complex.
In addition, much lower conversions were observed with
[PdCl(allyl)]2 and [PdCl2(PhCN)2] (6-7 % after 24 h), as well as
[PdCl2(dppe)] (35%). Even the combination of [PdCl2(dppe)]
with a base (iPr2EtN, 1 mol%) performed poorly (78% conversion
after 24 h) compared to the [(SCS) Pd] system (> 95% in 1.5 h).
A simplified 3-step mechanism for the Conia-Ene reaction
catalyzed by the association of [(SCS)Pd]2 and Mg(OTf)2 is
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 4 of 8
ARTICLE
Journal Name
depicted in Scheme 2: (i) double activation of the substrate: the The length of the linker between the β–dicarbonyl moiety and
View Article Online
DOI: 10.1039/D0SC05036A
LA chelates the β–dicarbonyl moiety, the acidic proton is the terminal alkyne was then modified with the aim to access
transferred to the electron-rich indenediide backbone of the larger rings (8a-12a). 6-Exo cyclization of β–keto,esters such as
SCS ligand while the alkyne coordinates to palladium 8a featuring a flexible butylene tether is tricky. It has only been
(intermediate A); (ii) cyclization: the ensuing enolate adds to the scarcely achieved, using a Au(I) complex featuring a tris-alkynyl
π-activated C≡C triple bond to give the alkenyl Pd complex B; phosphine with bulky end caps (1 mol%, 25 °C, 1.5 h) or In(NTf2)3
(iii) product release: back-transfer of the proton from the ligand (1 mol%, 80 °C, 4 h).22,23 Pleasingly, the methylene-cyclohexane
backbone to the C(sp2) atom bonded to Pd results in proto- product 8b could also be obtained efficiently using the
depalladation and regenerates the indenediide Pd catalyst. HFIP [(SCS)Pd]2 complex (5 mol% Pd) and Mg(OTf)2 (20 mol%) within
is presumed to help dissociating the dimeric pre-catalyst,17c and 20 h at 75°C (90%). The dual catalytic system proved particularly
to promote proton shuttling from the substrate to the efficient when the enol position bears an oxygen or nitrogen
indenediide moiety in step (i) and from the ligand backbone to atom. Such substrates have been shown by Hatakeyama et al to
the C(sp2) carbon at Pd in step (iii).
provide straightforward entry to valuable heterocycles and very
good results in terms of activity and selectivity were obtained
using In(OTf)3 with DBU (5 mol% each) in refluxing toluene.24 In
our hands, the β–diester substrates 9a-11a reacted smoothly
and high yields (>85 %) were achieved with low catalytic
loadings (1 mol% Pd, 5 mol% Mg). Particularly noteworthy is the
formation of the δ-valerolactame 10b which was accomplished
in only 2.5 h at 25°C. Even 7-exo cyclization was possible and
high-yielding. Using the same conditions as for 8a, the ε-
caprolactame 12b was obtained in 90% yield within 40 h, and
the reaction time could be reduced to 7 h using microwave
irradiation.25 The preparation of such seven-membered rings
was previously described using In(OTf)3/DBU as catalyst, but in
modest yield (41%) and with high catalytic loading (15 mol%).24
To assess the robustness of the Pd-Mg dual catalytic system, the
cyclization of the amide-tethered substrate 10a was carried out
under the optimized conditions (25 °C, 1 mol% Pd, 5 mol% Mg,
chloroform/HFIP 4/1) but in open-flask conditions and with
technical grade solvents. The δ-valerolactame 10b was
obtained in similar yield than under inert conditions,
demonstrating that the reaction does not require stringent
precautions. Furthermore, when the catalytic loading was
reduced by a factor of ten (0.1 mol% Pd and 0.5 mol% Mg), the
product was still obtained in very high yield (>95% in 18 h at 50
°C). These reaction conditions were successfully applied to
larger scale: 920 mg of pure product 10b were prepared using
only 1.4 mg of [(SCS)Pd]2 and 4.5 mg of Mg(OTf)2. Merging
metal-ligand cooperation and Lewis acid activation, as realized
with the [(SCS)Pd]2 complex and Mg(OTf)2, thus appears
general, practical and of synthetic value. It promotes 5, 6 and 7-
exo cyclization of β–dicarbonyl substrates featuring terminal
alkynes under mild conditions, and gives access to a variety of
carbo- and hetero-cycles.
H
O
O
P
P
S
H
Mg(OTf)2
OTf
Pd
S
O
O
Mg(OTf)
R
R
(i)
A
P
P
S
Pd
S
(ii)
(iii)
P
S
H
O
O
R
O
Pd
S
+ Mg(OTf)2
O
R
Mg(OTf)2
H
P
B
Z-isomer
Scheme 2. Catalytic cycle proposed to account for the Conia-Ene reaction catalyzed by
the (SCS)Pd complex and Mg(OTf)2 (the iPr groups at P are omitted for clarity)
The scope and functional group tolerance of the reaction was
then explored (Figure 3). Our aim was not only to probe the
generality of the new MLC-LA dual catalytic approach, but also
to improve the efficiency of the Conia-Ene transformation and
expand its synthetic interest. Substrates with a terminal alkyne
and prone to 5-exo cyclization were investigated first. The
(SCS)Pd-Mg association proved particularly efficient to cyclize
β–diesters 5a-7a featuring an adjacent heteroatom (N or O).
The amide-tethered substrate 5a was quantitatively cyclized in
only 5 min at 25°C. Shifting the amide moiety in the exo position
(6a) slowed down the transformation somewhat, but it still
proceeded rapidly and efficiently at 25°C (>95% in 50 min).
Cyclization of the ether-tethered substrate 7a was more
challenging, but heating to 75°C enabled to achieve high
conversion (90%) in only 4.25 h.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 5 of 8
Chemical Science
View Article Online
DOI: 10.1039/D0SC05036A
ARTICLE
Terminal alkynes
5-exo cyclizations
O
O
O
O
O
O
CN
CO2Et
CO2Et
CO2Me
OMe
OMe
NC
EtO2C
BnN
5b
EtO2C
BzN
6b
MeO2C
MeO
3b
O
1b
2b
4b
7b
O
1 mol% Pd
5 mol% Mg
1 mol% Pd
5 mol% Mg
1 mol% Pd
5 mol% Mg
1 mol% Pd
-
1 mol% Pd
5 mol% Mg
1 mol% Pd
5 mol% Mg
1 mol% Pd
5 mol% Mg
rt, 8 h, >95% (85%) rt, 1.5 h, >95% (90%) rt, 1.5 h, >95% (91%) rt, 16 h, >95% (83%) rt, 5 min, >95% (95%) rt, 50 min, >95% (85%) 75°C, 4.25 h, 90% (81%)
6-exo cyclizations
7-exo cyclization
MeO2C
O
CO2Me
O
CO2Et
EtO2C
EtO2C
CO2Et
EtO2C
BnN
CO2Et
CO2Me
BzN
BnN
8b
9b
10b
11b
12b
O
O
5 mol% Pd
1 mol% Pd
1 mol% Pd
5 mol% Mg
rt, 2.5 h, 85%
1 mol% Pd
5 mol% Pd
20 mol% Mg
5 mol% Mg
5 mol% Mg
20 mol% Mg
75°C, 20 h, 90% (84%)
75 °C, 22 h, >95% (85%)*
75 °C, 6 h, 90% (72%)*
75°C, 40 h, 90% (78%)*
75°C MW, 7 h, 90%
open-flask
conditions
lower cat. loading
and gram scale
0.1 mol% Pd
0.5 mol% Mg
50°C 18 h, >95% (92%)*
1 mol% Pd
5 mol% Mg
rt, 2.5 h, 90%
Figure 3. Substrate scope for the Conia-Ene reaction catalyzed by the (SCS)Pd complex and Mg(OTf)2: β–dicarbonyl substrates bearing a terminal alkyne (isolated yields are indicated
in parentheses, * stands for 0.1 M substrate concentration instead of 0.5 M).
The good performance of the dual Pd-Mg catalytic sys-tem primary alkyl substituents, while examples with secondary alkyl
prompted us to explore then the cyclization of substrates groups are much rarer and tertiary ones are
bearing internal alkynes, which are significantly more unprecedented.12,24,27,29 Due to the lower reactivity of these
challenging than terminal alkynes (Figure 4). Being way less substrates, the catalytic loadings were fixed to 5 mol% Pd and
reactive, these substrates require harsher conditions, which 20 mol% Mg. For the less hindered substrates, with Me (15a)
often results in regio-selectivity issues with formation of and Et (16a) substituents, cyclization occurred at 25°C within 3
mixtures of exo and endo cyclization products.26 Given the and 24 h, respectively, while those bearing Cy (17a), Ph (18a)
t
preference of 5-endo against 4-exo-dig cyclization, the β– and Bu (19a) groups required heating at 75-120 °C to achieve
keto,ester 13a and β–diester 14a were tested first. Longer high conversions. For all substrates, including the tBu-
reaction time was needed for 13a than for 14a (25 vs 1.5 h) but substituted 19a, the reaction was highly selective. The
in both cases, the reaction proceeded readily at 25°C and structures of the obtained products were unambiguously
1
afforded high yield (95%) of the 5-endo product. No trace of the determined thanks to thorough H and 13C NMR spectroscopic
less favored 4-exo product was detected by 1H NMR analyses including ADEQUATE, NOESY and dsel-HSQMC-IPAP
spectroscopy. Our dual catalytic system does not compete with experiments.15 Complete selectivity in favor of 5-exo vs 6-endo
(Ph3P)AuOTf for the formation of cyclopentene 13b (83% yield cyclization was observed, whatever the substituent at the
was achieved in only 5 min at room temperature using 1 mol% alkyne (alkyl or phenyl). For 15a and 16a, a single 5-exo product
Au),27 but on the other hand, the gold catalyst works only with was obtained, authenticated as the Z isomer. For the substrates
β–keto,esters and failed to cyclize β–diesters.23 As far as the 17a and 18a bearing bulkier groups, which required higher
cyclization of 14a is concerned, it had only been efficiently reaction temperature, two 5-exo products were formed. In all
accomplished with Zn halides (10 mol%) but required high cases, the Z isomer was very major (Z/E ratio from 7 to 10). In
t
temperature and long reaction time (100 °C, 15 h).28 We then the case of the Bu group, opposite stereo-selectivity was
investigated 5-exo Conia-Ene cyclization with internal alkynes observed. Steric congestion favored here the E product (E/Z of
(β–diester substrates 15a-19a). The terminal substituent was 11.5). Reaction monitoring indicated that it is not due to
t
varied (R = Me, Et, Cy, Ph, Bu) to assess the impact of sterics isomerization of 19b over prolonged heating, the same E/Z ratio
and electronics. It should be noted that precedents of Conia- being observed from the beginning of the cyclization. From a
Ene cyclization with internal alkynes mostly involve aryl and mechanistic viewpoint, the Z-selectivity observed with 15a-18a
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 6 of 8
ARTICLE
Journal Name
is consistent with the outer-sphere approach outlined in mol% Mg). Most remarkably, it is also active and selective with
View Article Online
Scheme 2. The enolate adds to the π-activated alkyne trans to substrates featuring internal alkynes. WhDaOteI:v1e0r.1t0h3e9/sDu0bSsCt0it5u0e36nAt
Pd, resulting in the Z product after proto-depalladation.30 This in terminal position (1°/2°/3° alkyl, aryl), 5-exo fully prevails
Z-selectivity markedly contrasts with the E-selectivity induced over 6-endo cyclization. Moreover, except for the highly
n
by the In(OTf)3/DBU catalyst (with R = Me, Bu).24 In the latter congested tBu product, the reaction occurs with high Z-
case, the reaction was proposed to proceed by syn selectivity. This behavior contrasts with the E-selectivity
carbometalation, with the In(III) center simultaneously observed with In-based catalysts, the other known catalysts for
activating the β-dicarbonyl and alkyne moieties.31 Formation of internal alkynes. This is due to the way the C–C bond formation
the E product 19b most likely results from isomerization of the and cyclization proceeds with the dual Pd/Mg catalyst, the Mg-
vinyl-Pd intermediate B prior to proto-depalladation, due to chelated enolate attacks the π-coordinated C≡C triple bond
steric congestion.32
trans to Pd.
These results expand the scope of MLC catalysis in terms of
metal (the potential of Pd complexes in MLC catalysis is clearly
under-exploited) and catalytic transformations (while
hydrogenation/dehydrogenation processes have been
extensively developed, examples of C–C bond forming reactions
are very rare). Moreover, this work introduces a new multi-
cooperative catalytic approach combining MLC and Lewis Acid
activation. The MLC/LA synergy parallels and complements that
involving MLC and proton shuttling. It also represents a new
type of dual activation, in which the TM catalyst displays MLC
behavior (towards the enolizable C–H bond in this case) while
the LA activates another reactive site of the substrate (the β–
dicarbonyl motif). Future studies will seek to explore the
generality of such MLC/LA synergy and to exploit it in other
catalytic transformations.
Internal alkynes
5-endo cyclizations
O
O
O
O
OMe
Et
[Pd]2 1 mol%/ Mg(OTf)2 5 mol%
OMe
OEt
chloroform/HFIP 4/1
rt, 25 h
13a
Et
95%
13b
O
O
EtO2C
BnN
CO2Et
[Pd]2 1 mol%/ Mg(OTf)2 5 mol%
EtO
BnN
chloroform/HFIP 4/1
O
14b
rt, 1.5 h
14a
O
>95%
5-exo cyclizations
R
O
O
EtO2C
EtO2C
[Pd]2 5 mol%/ Mg(OTf)2 20 mol%
EtO
OEt
Z
BnN
BnN
O
chloroformHFIP 4/1
Conflicts of interest
“There are no conflicts to declare”.
rt-120 °C, 3-32 h
O
15a-18a
15b-18b
R
O
O
EtO2C
EtO2C
Acknowledgements
tBu
[Pd]2 5 mol%/ Mg(OTf)2 20 mol%
EtO
OEt
O
BnN
E
Financial support from the Centre National de la Recherche Sci-
entifique and the Université de Toulouse is gratefully acknowl-
edged. E. M. thanks the European Commission for a MCIF (Au-
MLC 841877). A.C. thanks the French government (MESRI,
Ministère de l’Enseignement Supérieur, de la Recherche et de
l’Innovation) for his PhD funding. The NMR service of ICT is
acknowledged for the ADEQUATE and NOESY NMR experi-
ments (M. Vedrenne, P. Lavedan) and for the dsel-HSQMBC-
IPAP experiments (Dr. S. Massou).
BnN
chloroformHFIP 4/1
19a
O
120 °C, 64 h
19b
81%
tBu
R
T (°C)
Time (h)
Yield
85%
Me (15b)
Et (16b)
Cy (17b)
Ph (18b)
tBu (19b)
25
25
3
Z/E > 50
Z/E > 50
Z/E = 7
24
32
16
64
85%
120
75
76% (52% Z)
79% (65% Z)
81% (60% E)
Z/E = 10
Notes and references
120
E/Z = 11.5
1
(a) Y. J. Park, J. W. Park and C. H. Jun, Chem. Res., 2008, 41,
222-234; (b) A. E. Allen and D. W. C. MacMillan, Chem. Sci.,
2012, 3, 633–658; (c) Z. Du and Z. Shao, Chem. Soc. Rev., 2013,
42, 1337–1378; (d) Cooperative Catalysis, (Ed.: R. Peters),
Wiley–VCH Weinheim 2015; (e) S. Afewerki and A. Córdova,
Chem. Rev., 2016, 116, 13512–13570; (f) D. S. Kim, W. J. Park
and C. H. Jun, Chem. Rev., 2017, 117, 8977–9015.
Figure 4. Conia-Ene reaction catalyzed by the (SCS)Pd complex and Mg(OTf)2: β-
dicarbonyl substrates bearing an internal alkyne (isolated yields in Z isomer are indicated
in parentheses).
Conclusions
2
(a) J. R. Khusnutdinova and D. Milstein, Angew. Chem. Int. Ed.
2015, 54, 12236–12273; (b) T. Higashi, S. Kusumoto and K.
Nozaki, Chem. Rev., 2019, 119, 10393–10402.
When combined with Mg(OTf)2 and HFIP, the indenediide-
based SCS Pd pincer complex was found to be a very powerful
catalyst for Conia-Ene cyclizations. It works with a variety of
substrates, β–keto,esters as well as β–dinitriles and β–diesters,
and gives access with complete regio-selectivity to 5, 6 and 7-
membered carbo- as well as hetero-cycles. It is robust and
operates at low catalytic loading (down to 0.1 mol% Pd and 0.5
3
4
Pincer compounds, Chemistry and Applications, 1st edition
(Ed.: D. Morales–Morales), Elsevier, 2018.
(a) C. Gunanathan and D. Milstein, Science, 2013, 341,
1229712; (b) C. Gunanathan and D. Milstein, Chem. Rev.,
2014, 114, 12024–12087; (c) R. H. Crabtree, Chem. Rev., 2017,
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 8
Chemical Science
Please do not adjust margins
Journal Name
ARTICLE
117, 9228–9246; (d) L. Alig, M. Fritz and S. Schneider, Chem. 16 For related transformations, see: (a) M. Li and R. Hua, J. Org.
View Article Online
Rev. 2019, 119, 2681–2751.
Selected examples: (a) S. Kuwata and T. Ikariya, Chem. Eur. J.,
2011, 17, 3542–3556; (b) S. Tobisch, Chem. Eur. J., 2012, 18,
Chem., 2008, 73, 8658–8660; (b) Y. Oonishi, A. Gómez–Suárez,
A. R. Martin and S. P. Nolan, Angew. CDheOmI: 1.0In.1t0.3E9d/D.,02S0C10350, 3562A,
9767–9771.
5
7248–7262; (c) A. Nerush, M. Vogt, U. Gellrich, G. Leitus, Y. 17 (a) I. Colomer, A. E. R. Chamberlain, M. B. Haughey and T. J.
Ben–David and D. Milstein, J. Am. Chem. Soc., 2016, 138,
6985–6997; (d) U. K. Das, S. Chakraborty, Y. Diskin–Posner and
D. Milstein, Angew. Chem. Int. Ed. 2018, 57, 13444–13448; (e)
S. Chakraborty, P. Daw, Y. Ben David and D. Milstein, ACS
Catal., 2018, 8, 10300–10305; (f) J. Bruffaerts, N. von Wolff, Y.
Donohoe, Nat. Rev. Chem., 2017, 1, 0088; (b) C. Yu, J. Sanjosé–
Orduna, F. W. Patureau and M. H. Pérez–Temprano, Chem.
Soc. Rev., 2020, 49, 1643–1652; (c) V. Pozhydaiev, M. Power,
V. Gandon, J. Moran, D. Leboeuf, Chem. Commun., 2020, 56,
11548–11564.
Diskin-Posner, Y. Ben-David and D. Milstein, J. Am. Chem. Soc., 18 Milstein reported very recently a tandem catalytic approach
2019, 141, 16486-16493.
for the oxidation of alkenes by water. In(OTf)3 promotes the
hydration of the alkene and a PNP Ru pincer complex then
promotes dehydrogenation: S. Tang, Y. Ben–David and D.
Milstein, J. Am. Chem. Soc., 2020, 142, 5980–5984.
6
7
P. Oulié, N. Nebra, N. Saffon, L. Maron, B. Martin–Vaca and D.
Bourissou, J. Am. Chem. Soc., 2009, 131, 3493–3498.
(a) A. Scharf, I. Goldberg and A. Vigalok, J. Am. Chem. Soc.,
2013, 135, 967–970; (b) A. Scharf, I. Goldberg and A. Vigalok, 19 For reactions of organic and metal–based electrophiles on the
Inorg. Chem., 2013, 53, 12–14; (c) J. Takaya, N. Iwasawa,
Chem. Eur. J., 2014, 20, 11812–11819; (d) A. Scharf, I.
Goldberg, A. Vigalok and A. Vedernikov, Eur. J. Inorg. Chem.,
2015, 28, 4761–4768; (e) V. Salamanca, A. Toledo and A. C.
Albéniz, J. Am. Chem. Soc., 2018, 140, 17851–17856; (f) H.
Kameo, J. Yamamoto, A. Asada, H. Nakazawa, H. Matsuzaka
indenediide ligand backbone, see: (a) P. Oulié, N. Nebra, S.
Ladeira, B. Martin–Vaca and Bourissou, Organometallics,
2011, 30, 6416–6422; (b) N. Nebra, N. Saffon, L. Maron, B.
Martin–Vaca and D. Bourissou, Inorg. Chem., 2011, 50, 6378–
6383; (c) N. Nebra, S. Ladeira, L. Maron, B. Martin–Vaca and
D. Bourissou, Chem. Eur. J., 2012, 18, 8474–8481.
and D. Bourissou, Angew. Chem. Int. Ed., 2019, 58, 18783– 20 31P NMR monitoring showed rapid reaction between
18787; (g) M. Virant, M. Mihelač, M. Gazvoda, A. E. Cotman,
A. Frantar, B. Pinter, J. Košmrlj, Org. Lett. 2020, 22,
2157−2161.
[(SCS)Pd]2 and Cu(OTf)2, while no change was observed for the
other salts.
21 Enabling direct reaction monitoring by NMR spectroscopy,
Mg(OTf)2 has also a practical advantage over Yb(OTf)3.
8
9
(a) N. Nebra, J. Monot, R. Shaw, B. Martin–Vaca and D.
Bourissou, ACS Catal., 2013, 3, 2930–2934; (b) N. Á. Espinosa– 22 A. Ochida, H. Ito and M. Sawamura, J. Am. Chem. Soc., 2006,
Jalapa, D. Ke, N. Nebra, L. Le Goanvic, S. Mallet–Ladeira, J.
128, 16486–16487.
Monot, B. Martin–Vaca and D. Bourissou, ACS Catal., 2014, 4, 23 6–Exo cyclization of
a
β–keto,ester derived from
3605–3611; (c) D. Ke, N. Á. Espinosa, S. Mallet–Ladeira, J.
Monot, B. Martin–Vaca and D. Bourissou, Adv. Synth. Catal.,
2016, 358, 2324–2331.
cyclopentanone was also reported via gold catalysis: J. J.
Kennedy–Smith, S. T. Staben and F. D. Toste, J. Am. Chem.
Soc., 2004, 126, 4526–4527.
J. Monot, P. Brunel, C. E. Kefalidis, N. Á. Espinosa–Jalapa, L. 24 K. Takahashi, M. Midori, K. Kawano, J. Ishihara and S.
Maron, B. Martin–Vaca and D. Bourissou, Chem. Sci., 2016, 7,
2179–2187.
Hatakeyama, Angew. Chem. Int. Ed., 2008, 47, 6244–6246.
25 The formation of medium to large–sized carbocycles from ω–
alkynyl–β–keto,esters has been reported using In(NTf2)3 as
catalyst: (a) H. Tsuji, K. I. Yamagata, Y. Itoh, K. Endo, M.
Nakamura and E. Nakamura, Angew. Chem. Int. Ed., 2007, 46,
8060–8062; (b) Y. Itoh, H. Tsuji, K. I. Yamagata, K. Endo, I.
Tanaka, M. Nakamura and E. Nakamura, J. Am. Chem. Soc.,
2008, 130, 17161–17167.
10 (a) J. Li, Y. Shiota and K. Yoshizawa, J. Am. Chem. Soc., 2009,
131, 13584–13585; (b) S. Qu, Y. Dang, C. Song, M. Wen, K. W.
Huang and Z. X. Wang, J. Am. Chem. Soc., 2014, 136, 4974–
4991; (c) X. Yang, ACS Catal., 2014, 4, 1129–1133; (d) S.
Chakraborty, P.O. Lagaditis, M. Forster, E. A. Bielinski, N.
Hazari, M. C. Holthausen, W. D. Jones and S. Schneider, ACS
Catal., 2014, 4, 3994–4003; (e) U. Gellrich, J. R. 26 (a) H. Ito, Y. Makida, A. Ochida, H. Ohmiya and M. Sawamura,
Khusnutdinova, G. M. Leitus, and D. Milstein, J. Am. Chem.
Soc., 2015, 137, 4851–4859.
11 N. E. Smith, W. H. Bernskoetter and N. Hazari, J. Am. Chem.
Soc., 2019, 141, 17350–17360.
12 D. Hack, M. Blumel, P. Chauhan, A. R. Philipps and D. Enders,
Chem. Soc. Rev., 2015, 44, 6059–6093.
13 See recent reviews: (a) G. Bouhadir and D. Bourissou, Chem.
Org. Lett., 2008, 10, 5051–5054; (b) W. Chaladaj, A.
Kolodziejczyk and S. Domanski, ChemCatChem, 2017, 9,
4334–4339.
27 S. T. Staben, J. J. Kennedy–Smith and F. D. Toste, Angew.
Chem. Int. Ed., 2004, 43, 5350–5352.
28 W. Hess and J.W. Burton, Adv. Synth. Catal., 2011, 353, 2966–
2970.
Soc. Rev., 2016, 45, 1065–1079; (b) W. Guan, G. Zeng, H. 29 Upon Conia-Ene cyclization of β–ketoesters featuring internal
i
Kameo, Y. Nakao and S. Sakaki, Chem. Rec., 2016, 16, 2405–
2425; (c) D. You and F. P. Gabbaï, Trends in Chemistry, 2019,
1, 485–496; (d) J. Becica and G. E. Dobereiner, Org. Biomol.
Chem., 2019, 17, 2055–2069.
alkynes (R = Me, nBu, Pr, Ph) with a Au(I) complex, anti
addition and Z–selectivity was also observed, but the regio-
selectivity was poor (mixtures of 5–exo/6–endo were
formed). See reference 26a.
14 (a) B. K. Corkey and F. D. Toste, J. Am. Chem. Soc., 2005, 127, 30 For a review in proto-depalladation, see: M. L. O'Duill and K.
17168–17169; (b) A. Matsuzawa, T. Mashiko, N. Kumagai and M. Engle, Synthesis, 2018, 50, 4699–4714.
M. Shibasaki, Angew. Chem. Int. Ed., 2011, 50, 7616–7619; (c) 31 Carbometalation–type mechanisms have also been proposed
S. Suzuki, E. Tokunaga, D. S. Reddy, T. Matsumoto, M. Shiro
and N. Shibata, Angew. Chem. Int. Ed., 2012, 51, 4131–4135;
(d) P. Barrio, M. Kumar, Z. Lu, J. Han, B. Xu and G. B.
to account for the syn addition observed with Zn (see
reference 28) and Cu catalysts: S. Montel, D. Bouyssi and G.
Balme, Adv. Synth. Catal., 2010, 352, 2315–2320.
Hammond, Chem. Eur. J., 2016, 22, 16410–16414; (e) M. Cao, 32 For examples of vinyl-Pd Z/E isomerization, see: (a) C.
A. Yesilcimen and M. Wasa, J. Am. Chem. Soc., 2019, 141,
4199–4203; (f) T. Horibe, M. Sakakibara, R. Hiramatsu, K.
Takeda and K. Ishihara, Angew. Chem. Int. Ed., 2020, 38,
16470-16474.
Amatore, S. Bensalem, S. Ghalem and A. Jutand, J.
Organomet. Chem., 2004, 689, 4642–4646; (b) N. Panda and
R. Mothkuri, J. Org. Chem., 2012, 77, 9407–9412; (c) J. Aziz, G.
Frison, P. Le Menez, J. D. Brion, A. Hamze and M. Alami, Adv.
Synth. Catal., 2013, 355, 3425–3436.
15 See Supplementary Information.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 8 of 8
View Article Online
DOI: 10.1039/D0SC05036A
Chemical Science
ARTICLE
Graphical TOC:
MLC-LA
multi-catalysis
H
X
R
+ Mg(OTf)2
O
O
H
P
S
P
S
Pd
Pd
O
S
P
P
S
O
Mg
OTf
R
X
O
H
5-exo cyclization
Z-isomer
19 examples
X = CH2, O, NR
5-7 membered cycles
R
O
This journal is © The Royal Society of Chemistry 20xx
Chem. Sci., 2013, 00, 1-3 | 1
Please do not adjust margins