Combinatorial approach to chiral tris-ligated carbophilic platinum complexes: Application to asymmetric catalysis

Article abstract of DOI:10.1002/chem.201304794

A straightforward methodology for the synthesis of libraries of chiral tris-ligated cationic platinum complexes and their in situ evaluation as asymmetric carbophilic catalysts in a model domino hydroarylation/cyclization reaction of a 1,6-enyne was developed. A catalyst-generation process based on a combination of a monodentate and a bidentate phosphorus ligand allowed the formation of 108 chiral complexes. One-pot screening of the stereoinduction obtained with this library in a test domino addition/cyclization reaction validated this approach and stressed the key role played by the monodentate ligand partner in obtaining high enantioselectivities. In the case of two challenging substrate/nucleophile combinations, the combinatorial approach resulted in a significant gain in enantioselectivity.

Full text of DOI:10.1002/chem.201304794

DOI: 10.1002/chem.201304794
Full Paper
&
Combinatorial Chemistry
Combinatorial Approach to Chiral Tris-ligated Carbophilic
Platinum Complexes: Application to Asymmetric Catalysis
Alexandre Pradal,[a] Serafino Gladiali,[b] Veronique Michelet,*[a] and Patrick Y. Toullec*[a]
Abstract: A straightforward methodology for the synthesis
of libraries of chiral tris-ligated cationic platinum complexes
and their in situ evaluation as asymmetric carbophilic cata-
lysts in a model domino hydroarylation/cyclization reaction
of a 1,6-enyne was developed. A catalyst-generation process
based on a combination of a monodentate and a bidentate
phosphorus ligand allowed the formation of 108 chiral com-
plexes. One-pot screening of the stereoinduction obtained
with this library in a test domino addition/cyclization reac-
tion validated this approach and stressed the key role
played by the monodentate ligand partner in obtaining high
enantioselectivities. In the case of two challenging sub-
strate/nucleophile combinations, the combinatorial ap-
proach resulted in a significant gain in enantioselectivity.
Introduction
The development of synthetic methodologies involving the
use of p Lewis acid catalysts has received considerable atten-
tion in the last decade. The late heavy transition metals, espe-
cially the triad constituted by platinum, gold, and mercury,
indeed have excellent affinity towards carbon–carbon multiple
bonds.[1] On coordination to these carbophilic metal centers,
the multiple bond is activated towards anti attack of a wide
array of nucleophiles, which proceeds by an outer-sphere
mechanism (intermediate I, Scheme 1). On nucleophilic attack,
slippage of the metal fragment along the multiple-bond axis
generates a s-bound metal complex (intermediate II). Since
the protodemetalation step mandatory for completing the cat-
alytic cycle is considerably more difficult for metal–Csp3 than for
metal–Csp2 intermediates, processes involving nucleophilic ad-
ditions to alkynes (or alternatively allenes) have been consider-
ably more successful than additions to alkenes. The late transi-
tion metals exhibiting this reactivity have been therefore
termed “alkynophilic”. Although gold catalysts, especially cat-
ionic gold(I) complexes, display the highest activity in many
transformations, allowing these processes to occur under very
mild reaction conditions, a parallel in reactivity has often been
observed with platinum(II) species, and a wide range of syn-
Scheme 1. General catalytic cycle of cycloisomerization reactions of alkyne-
containing substrates in the presence of carbophilic Lewis acids.
thetic applications exploiting the carbophilic character of plati-
num complexes has also appeared.[2]
Reports of enantioselective variants of reactions involving p
Lewis acid catalysis have so far been scarce. Limiting our dis-
cussion to transformations in which the initial step involves
the carbophilic activation of an alkyne and the stereodetermin-
ing event is the consecutive nucleophilic attack, this situation
is a direct consequence of the respective mode of coordination
associated with AuI and PtII complexes (Scheme 2). Cationic AuI
complexes have a linear structure in which the coordinated CÀ
C p system occupies the position trans to the neutral two-elec-
tron donor ligand stabilizing the metal center. Furthermore,
[a] Dr. A. Pradal, Dr. V. Michelet, Dr. P. Y. Toullec
Institut de Recherche de Chimie Paris, UMR 8247
Chimie ParisTech, ENSCP
11, rue Pierre et Marie Curie
75231 Paris CEDEX 05 (France)
Fax: (+33)144071062
E-mail: veronique.michelet@chimie-paristech.fr
patrick.toullec@chimie-paristech.fr
[b] Prof. S. Gladiali
Dipartimento di Chimica e Farmacia, Universita di Sassari
Via Vienna 2, 07100 Sassari (Italy)
Scheme 2. Schematic representations of the geometries of linear AuI alkyne
and square-planar PtII alkyne complexes.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304794.
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theoretical investigations and spectroscopic data indicate
a low barrier of rotation of the alkyne around the metal-to-
ligand centroid axis. Thus, efficient transfer of chiral informa-
tion between the coordinated ligand L1 and the unsaturated
substrate in the opposite position relative to the metal center
is extremely difficult to achieve. Indeed, the few highly enan-
tioselective gold-catalyzed transformations[3] proceeding via
alkyne activation that appeared in the literature since 2005 are
based on a combination of a monocationic metal fragment
and an extremely bulky chiral ligand, which can be derived
from a bidentate atropisomeric phosphane,[4] a phosphorami-
dite or phosphite,[5] or an N-heterocyclic carbene.[6] Further-
more, in many instances, chiral induction is also extremely de-
pendent on the steric hindrance of the substrate engaged in
the transformation and thus has a limited scope.
Platinum(II) d8 complexes are characterized by a coordination
number of four and a square-planar geometry. As only one co-
ordination site is required for p activation of the substrate and
the subsequent steps of the general catalytic cycle presented
in Scheme 1, the chiral environment around the metal center
can be designed by careful choice of the ligands occupying
the three remaining sites. This structural arrangement places
two ligands, potentially chiral, on coordination sites cis to the
activated carbon–carbon multiple bond and thus induces
a much more pronounced steric interaction between the coor-
dinated substrate and the chiral pocket surrounding the metal
center and, expectedly, stronger chiral induction in the chemi-
cal transformation. Such a strategy has already received much
attention and resulted in the development of a range of plati-
num-catalyzed asymmetric transformations involving carbo-
philic activation of carbon–carbon multiple bonds.[7] In a first
approach, combinations of three neutral monodentate ligands
(L1) or a mono- and a bidentate ligand (L2) on a dicationic plat-
inum center were investigated. A system consisting of three
chiral monodentate phosphines ligated to a dicationic plati-
num center generated in situ was used as catalyst for the
asymmetric hydroxy- and alkoxycyclization of 1,6-enynes[8]
(Scheme 3, complex A). The participation of complexes formed
from combinations of chiral bidentate phosphine ligands and
achiral monodentate ligands (a phosphine or an N-heterocyclic
carbene) in the enantioselective Pt-catalyzed cycloisomeriza-
tion of 1,5-dienes,[9] 1,5-enynes,[10] and 1,6-enynes[11] has also
been reported (Scheme 3, complex B). A second class of plati-
num catalysts resulting from the association of an achiral me-
tallacyclic N-heterocyclic carbene ligand and a chiral mono-
phosphine ligand has been applied in the cycloisomerization
of 1,6-enynes[12] and 1,5-enynes.[13] (Scheme 3, complex C). A
third option consisting of the combination of a chiral neutral
bidentate ligand and an anionic monodentate ligand leads to
the formation of monocationic platinum complexes that have
found application in the cycloaddition of alkynones with al-
kenes[14] (Scheme 3, complex D).
Scheme 3. Representative tris-ligated chiral platinum complexes having
a single coordination site, complexes used as alkynophilic Lewis acid
catalysts.
tion in catalytic reactions of a large number of soluble catalysts
under a variety of conditions including temperature, solvent,
pressure, and additives, has become a tool of increasing inter-
est for catalyst optimization. The automated formation of the
catalysts and performance of the catalytic tests, which were
made possible by the development of robotics,[17] coupled
with high-throughput analytical techniques,[18] allow the
screening of a previously inaccessible number of catalyst sys-
tems.[19] As mechanistic knowledge is often insufficient to
design the optimum catalyst combination, asymmetric homo-
geneous catalysis remains a field of research driven by empiri-
cism, leaving room for intuition and serendipity. The develop-
ment of libraries of new chiral transition-metal complexes from
combinations of known chiral and achiral ligands is expected
to introduce a large diversity of catalytic properties for tackling
issues of activity and selectivity raised by modern homoge-
neous catalysis. Considering the prominent role played by bi-
dentate chiral phosphine ligands in late transition-metal asym-
metric catalysis, most combinatorial approaches to the design
of ligating architectures have dealt with associations of two
monodentate ligands (a phosphine or an N-heterocyclic car-
bene), the spatial arrangement of which around the metal
center is dictated by steric repulsion[20] or supramolecular inter-
actions,[21] including metal coordination,[22] hydrogen bond-
ing,[23] and charge-transfer complexation.[24]
During the last decades, combinatorial methods have
become popular and are routinely used in a number of areas
of chemistry, including therapeutic-drug discovery, peptide
synthesis, and materials science.[15] More recently, combinatori-
al homogeneous catalysis,[16] that is, the synthesis and applica-
Following our ongoing study on domino nucleophilic addi-
tion/enyne cyclization reactions catalyzed by carbophilic Lewis
acids[4d,f,h,25] and our report on Pt-catalyzed enantioselective hy-
droarylation/cyclization of 1,6-enynes,[26] we envisioned the
synthesis of libraries of complexes with a chiral tris-ligated en-
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vironment around a square-planar late transition-metal center,
that is, platinum, by using combination of a mono- and a bi-
dentate ligand, at least one of which is chiral. Herein, we
report on the synthesis of libraries of chiral tris-ligated plati-
num complexes by synergetic use of libraries of mono- and bi-
dentate phosphorus ligands and their in situ evaluation as car-
bophilic Lewis acid catalysts for the asymmetric domino hydro-
arylation/cyclization reaction of 1,6-enynes. Three routes to the
introduction of the chiral information in the library of com-
plexes were sequentially investigated: 1) the use of a library of
chiral bidentate ligands L2; 2) the use of a library of a chiral
monodentate ligands L1; and 3) the use of libraries of both
chiral bidentate ligands L2 and chiral monodentate ligands L1.
Results and Discussion
Preliminary experiments showed that in the presence of an
catalytically active species [L3Pt2+] of type A (L=(R)-BINE-
PINE[27]) formed in situ, good yields and high enantioselectivi-
ties were obtained for the domino 5-exo cyclization/nucleophil-
ic addition of 1,6-enyne 1 with a variety of electron-rich aro-
matic and heteroaromatic nucleophiles such as 2 (Scheme 4,
system A). Control experiments ruled out the hypothesized in-
volvement of the [L2Pt2+] com-
Scheme 4. Asymmetric Pt-catalyzed domino cyclization/hydroarylation of
1,6-enynes.
plex (Scheme 4, system B) and
demonstrated the possibility to
mimic the optimal chiral envi-
ronment around the Pt center
by association between a chiral
monodentate phosphane and an
achiral bidentate bis-phosphine
(Scheme 4, system C).
To obtain the simplest and
most reliable protocol for access-
ing libraries of chiral environ-
ments featuring
a tris-ligated
platinum center, we focused on
a two-step methodology. In the
first step, PtCl2 was mixed with
a set of bidentate chelating bis-
phosphines L2 to form the corre-
sponding library of square-
planar complexes of general for-
Scheme 5. Library of tris-ligated [(L2)(L1)Pt]2+ complexes.
1
mula [(L2)PtCl2], which can be purified and characterized by H
and 31P NMR spectroscopy. In the second step, addition of 2.5
equivalents of a silver salt followed by addition of one equiva-
lent of a monodentate phosphine ligand L1 led to in situ for-
mation of a library of tris-ligated complexes [(L2)(L1)Pt]2+
having a single empty coordination site (Scheme 5). Consider-
ing the low stability of these intermediates, neither purification
nor characterization was performed at this stage. Consequent-
ly, the asymmetric induction of these libraries was evaluated in
situ by adding substrate and nucleophile (1,6-enyne and elec-
tron-rich aromatic or heteroaromatic compounds, respectively;
see Scheme 4) and analyzing the enantioselectivity by chiral
HPLC techniques after filtration of the crude reaction mixture
through a pad of silica gel.
In a first test, we focused on the combination of enyne 1 as
substrate and N-methylindole (2) as nucleophile to validate the
combinatorial approach proposed in this study. In accordance
with the optimized conditions obtained with catalyst A for the
domino hydroarylation/cyclization reaction,[26] the catalytic
tests were performed in 1,4-dioxane for 18 h at 608C.[28]
Library of chiral Pt complexes with chiral ligands L2
A first library formed from the combination of an achiral
monodentate phosphorus ligand (4a–f) and a chiral chelating
bis-phosphine (5a–j) was synthesized and evaluated in asym-
metric catalysis (Scheme 6). These ligands sets were chosen to
screen a large scope of stereoelectronic parameters for phos-
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Scheme 6. Combinatorial screening in a domino cyclization/hydroarylation reaction of Pt complexes combining an achiral monodentate ligand 4 and a chiral
bidentate ligand 5.
phine ligands. The set of chiral bidentate ligands included
1) atropisomeric phosphanes including BINAP[29] ((R)-5a) and
MeO-BIPHEP derivatives[30] with either electron-donating and
hindered ((R)-5b) or electron-withdrawing ((R)-5c) aryl substitu-
ents; 2) C2-symmetric spiroindanyldiphosphane Tol-SDP[31] ((S)-
5d); 3) C-stereogenic cyclic dialkyl- and trialkylphosphanes Me-
DUPHOS[32] ((R,R)-5e) and TANGPHOS[33] ((S,S,R,R)-5g); 4) C1-
and C2-symmetric planar chiral diphosphanes tetrakis-cyclohex-
yl-Josiphos derivative[34] (R,S)-5 f and [2.2]PHANEPHOS[35] ((S)-
5i); 5) P-stereogenic bidentate phosphanes BIPNOR[36] ((R,R)-
5h) and DIPAMP[37] ((R,R)-5j). Enantioselectivities were low for
all ligand combinations tested (<30% ee, see Scheme 6), that
is, introduction of chiral information on the bidentate ligand
has little or no effect on the stereoinduction in comparison
with the corresponding chiral tris-coordinated Pt complexes.
Library of chiral Pt complexes with chiral ligands L1
Alternatively, a second approach based on the combination of
chiral monodentate phosphine ligands 4g–n and achiral bi-
dentate phosphine ligands 5k–o was studied. The chiral
monodentate ligand set was designed to include 1) the atropi-
someric triarylphosphane MOP[38] ((R)-4g); 2) the C2-symmetric
electron-rich dialkylphosphine (R)-BINEPINE ((R)-4h)[27] and spi-
rophospholane (R)-SITCP ((R)-4n);[39] 3) the C-stereogenic phos-
phines (1R,2S,5R)-4i[40] and (R,R)-4j;[41] 4) the sterically congest-
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Scheme 7. Combinatorial screening in a domino cyclization/hydroarylation reaction of Pt complexes combining a chiral monodentate ligand 4 and an achiral
bidentate ligand 5.
ed triaryl phosphite (R)-4k[42] and the C2-symmetric electron-
poor binaphthol-based phosphoramidites (R)-4l and (R)-4m[43]
(Scheme 7).
Only marginal enantioselectivities were observed for the
combinations of ligands involving the monodentate phosphite
(R)-4k or the phosphoramidite ligands (R)-4l and (R)-4m as
well as for the phosphane ligands (R)-4g and (1R,2S,5R)-4i
(Scheme 7). In contrast, moderate to excellent enantioselectivi-
ties were obtained with combinations involving the aryldialkyl-
phosphanes (R)-4h, (R,R)-4j and (R)-4n. The optimal combina-
tion was reached in all cases with a different bidentate partner,
5l, 5k, and 5o to give 95, 60, and 82% ee, respectively. In the
case of (R)-4h, a clear relationship could be established be-
tween the bite angle[44] of the achiral bidentate ligand and the
enantioselectivity (Figure 1), with the optimum enantiomeric
excess observed for 5l (bite angle of 858). In the case of mono-
dentate ligand (R)-4n, a relationship between the bite angle of
5 and the enantioselectivity also seems to exist but with a dif-
ferent optimum: the complex formed from ligand 5o (bite
angle of 998) led to the highest enantiomeric excess, whereas
that involving ligand 5l afforded only a very moderate enan-
tioselectivity (20% ee for a bite angle of 858). For the chiral
monodentate ligands (R)-4h and (R)-4n, the active species
[(L1)3Pt2+] furnished a highly enantioselective catalyst for the
1,6-enyne 1/heteroaromatic nucleophile 2 test combination
(Scheme 4, system A), with enantioselectivities of 95 and 88%
respectively. Overall, these results reveal the key factors influ-
Figure 1. Effect of the bite angle of the achiral L2 ligand on the enantioselec-
tivity of the domino hydroarylation/cyclization reaction of 1 with 2 involving
monodentate ligands 4h and 4n.
encing the enantioselectivity of this asymmetric transforma-
tion: 1) The need for a chiral electron-rich ligand of moderate
steric hindrance as the monodentate partner L1; 2) The need
for a complementary achiral bidentate partner of carefully opti-
mized bite angle L2.
Library of chiral Pt complexes with a combination of chiral
L1 and L2 ligands
To further highlight the relative roles played by the bidentate
and monodentate ligands in the stereoinduction observed in
the presence of the complex formed by their association, com-
binations of both chiral monodentate and bidentate ligands
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Table 1. Combinatorial screening in a domino cyclization/hydroarylation
reaction of Pt complexes combining a chiral monodentate ligand 4 and
a chiral bidentate ligand 5.
Entry
L1
L2
Enantiomeric ratio [%][a]
1
2
3
4
5
6
7
8
(R)-4h
(R)-4h
(S)-4h
(S)-4h
(S)-4h
(S)-4h
(R)-4h
(S)-4h
(R)-5p
(S)-5p
(R)-5p
(S)-5p
(R)-5a
(S)-5a
(R,S)-5 f
(R,S)-5 f
92.5/7.5 (À)
90.5/9.5 (À)
7/94 (+)
8/92 (+)
7/94 (+)
8/92 (+)
75/25 (À)
8.5/91.5 (+)
Scheme 8. Combinatorial evaluation in domino cyclization/hydroarylation re-
actions of 6/2 and 1/7 of Pt complexes involving chiral monodentate ligands
(R)-4h, (R)-4n and achiral bidentate ligands 5k–o.
[a] Determined by chiral HPLC.
to an ee of 79%. These results compared favorably to those
obtained in the presence of the original catalyst system A with
ligand (R)-4h, which furnished 80 and 70% ee, respectively, for
the corresponding substrate/nucleophile combinations.[26]
were also been investigated. All tests were done with the mono-
dentate ligand (R)- or (S)-4h. In combination with the C2-sym-
metric chiral bidentate ligand MeOBIPHEP (5p), catalytic ex-
periments gave enantiomeric excesses between 81 and 86%,
and no match/mismatch effect was observed (Table 1, en-
tries 1, 4 versus 2, 3). The sense of the stereoinduction is only
governed by the stereochemistry of the chiral monodentate
partner. A similar situation was also monitored for a second
atropisomeric ligand, namely, BINAP (5a), which led to enantio-
selectivities in the same range (Table 1, entries 5, 6). In contrast,
with the C1-symmetric bidentate ligand (R,S)-5 f, a significant
match/mismatch effect was observed, whereas the sense of
stereoinduction remained dictated by the stereochemistry of
the monodentate partner 4h, which led to enantiomeric ratios
of 8.5/91.5 and 75/25, respectively (Table 1, entries 7 and 8).
To validate the combinatorial approach to catalyst design
through mixing of mono- and bidentate ligands developed
here, this strategy was tested for two challenging combina-
tions of substrates and nucleophiles. The domino hydroaryla-
tion/cyclization reactions of 1) sterically congested tert-butyl
malonate-derived enyne 6 with N-methylindole (2) and 2) 1,6-
enyne 1 with pyrrole (7) were investigated. Catalyst combina-
tions involving the s-donating chiral monodentate ligands (R)-
4h and (R)-4n and the achiral bidentate ligand set 5k–o,
which showed the most promising stereoinductions in the
case of our test combination (see Scheme 7), were evaluated
(Scheme 8).
Conclusion
We have reported a new combinatorial approach to the syn-
thesis of square-planar platinum complexes with tris-ligated
chiral environments and their in situ evaluation in the asym-
metric homogeneous catalysis of hydroarylation/cyclization re-
actions of 1,6-enynes. The combinatorial strategy relies on
a simple, reproducible procedure and involves the combina-
tion of commercially available mono- and bidentate phospho-
rus ligands. Nonbonded interactions between the two com-
plexing entities allow the formation of a chiral environment
around the metal center that can mimic either tridentate li-
gands or the association of three monodentate ligands. In this
study, a library of more than 100 tris-ligated cationic platinum
complexes [Pt(L1)(L2)]2+ having a single active coordination site
was prepared and evaluated in a catalytic test reaction of
domino hydroarylation/cyclization of a 1,6-enyne involving ac-
tivation by a carbophilic Lewis acid. Our investigations re-
vealed negligible influence of the chirality present on the bi-
dentate ligand L2, and high enantioselectivities were observed
exclusively in the case of ligand combinations in which mono-
dentate ligand L1 was chiral. The best results were obtained
with monodentate ligands 4h and 4n, which have similar ste-
reoelectronic properties: C2-symmetric dialkyl aryl phosphanes
with medium cone angle (e.g., 1518 estimated for 4h)[27] and
strong s-donating character. No clear trend could be estab-
lished with respect to the bite angle of the bidentate partner
L2, so that combinatorial assays are needed in the search for
the optimum ligand combination for a substrate-sensitive or
For the reaction involving substrate 6 and nucleophile 2, the
best ligand combination (R)-4n/5m afforded an enantiomeric
excess of 92%. For the reaction involving substrate 1 and nu-
cleophile 7, two combinations, (R)-4h/5m and (R)-4n/5m, led
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[3] For reviews dealing with enantioselective Au catalysis, see: a) N. Bong-
ers, N. Krause, Angew. Chem. 2008, 120, 2208; Angew. Chem. Int. Ed.
2008, 47, 2178; b) R. A. Widenhoefer, Chem. Eur. J. 2008, 14, 5382; c) S.
Sengupta, X. Shi, ChemCatChem 2010, 2, 609; d) A. Pradal, P. Y. Toullec,
V. Michelet, Synthesis 2011, 1501.
reagent-sensitive transformation. A significant improvement
was indeed found in the case of two challenging hydroaryla-
tion/cyclization reactions. Our investigations therefore high-
lighted the potential of such a strategy for the optimization of
the selectivity of transformations catalyzed by transition-metal
complexes having three sites of coordination occupied by li-
gands throughout the catalytic cycle.[45,46] This concept for op-
timization of the activity and/or the selectivity of a variety of
existing catalyst systems thus has promising applications in
asymmetric homogeneous catalysis.
[4] For selected reports on the use of atropisomeric diphosphine ligands in
asymmetric AuI catalysis involving alkyne activation, see: a) M. P.
MuÇoz, J. Adrio, J. C. Carretero, A. M. Echavarren, Organometallics 2005,
24, 1293–1300; b) M. J. Johansson, D. J. Gorin, S. T. Staben, F. D. Toste, J.
Am. Chem. Soc. 2005, 127, 18002; c) M. Uemura, I. D. G. Watson, M. Kat-
sukawa, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 3464; d) C.-M. Chao,
M. R. Vitale, P. Y. Toullec, J.-P. GenÞt, V. Michelet, Chem. Eur. J. 2009, 15,
1319; e) A. S. K. Hashmi, M. Hamziꢂ, F. Rominger, F. W. Bats, Chem. Eur. J.
2009, 15, 13318; f) C.-M. Chao, D. Beltrami, P. Y. Toullec, V. Michelet,
Chem. Commun. 2009, 6988; g) A. Martꢄnez, P. Garcꢄa-Garcꢄa, M. A.
Fernꢅndez-Rodrꢄguez, F. Rodrꢄguez, R. Sanz, Angew. Chem. 2010, 122,
4737; Angew. Chem. Int. Ed. 2010, 49, 4633; h) A. Pradal, C.-M. Chao, P. Y.
Toullec, V. Michelet, Beilstein J. Org. Chem. 2011, 7, 1021; i) J.-F. Brazeau,
S. Zhang, I. Colomer, B. K. Corkey, F. D. Toste, J. Am. Chem. Soc. 2012,
134, 2742; j) J. F. Briones, H. M. L. Davies, J. Am. Chem. Soc. 2012, 134,
11916.
Experimental Section
Typical procedure for the synthesis of chiral tris-ligated
platinum complexes and their in situ evaluation in an
asymmetric hydroarylation/cyclization reaction
Degassed dioxane (0.2 mL) was added to a 3 mL vial containing
[(5)PtCl2] (0.00875 mmol, 0.05 equiv) and AgSbF6 (0.0219 mmol,
0.125 equiv) under argon, and the solution was stirred at room
[5] For selected reports on the use of chiral monodentate phosphite and
phosphoramidite ligands in asymmetric AuI catalysis involving alkyne
activation, see: a) H. Teller, S. Flꢃgge, R. Goddard, A. Fꢃrstner, Angew.
Chem. 2010, 122, 1993; Angew. Chem. Int. Ed. 2010, 49, 1949; b) H.
Teller, A. Fꢃrstner, Chem. Eur. J. 2011, 17, 7764; c) H. Teller, S. Corbet, L.
Mantilli, G. Gopakumar, S. Flꢃgge, R. Goddard, W. Thiel, A. Fꢃrstner, J.
Am. Chem. Soc. 2012, 134, 15331.
[6] For selected reports on the use of chiral N-heterocyclic ligands in asym-
metric AuI catalysis involving alkyne activation, see: a) Y. Matsumoto,
K. B. Selim, H. Nakanishi, K. Yamada, Y. Yamamoto, K. Tomioka, Tetrahe-
dron Lett. 2010, 51, 404; b) W. Wang, J. Yang, F. Wang, M. Shi, Organo-
metallics 2011, 30, 3859; c) Y. M. Wang, C. N. Kuzniewski, V. Rauniyar, C.
Hoong, F. D. Toste, J. Am. Chem. Soc. 2011, 133, 12972; d) S. Handa,
L. M. Slaughter, Angew. Chem. 2012, 124, 2966; Angew. Chem. Int. Ed.
2012, 51, 2912; e) J. Francos, F. Grande-Carmona, H. Faustino, J. Iglesias-
Sigꢃenza, E. Dꢄez, I. Alonso, R. Fernꢅndez, J. M. Lassaletta, F. Lꢆpez, J. L.
MascareÇas, J. Am. Chem. Soc. 2012, 134, 14322; f) D. Banerjee, A. K.
Buzas, C. Besnard, E. P. Kꢃndig, Organometallics 2012, 31, 8348.
[7] P. Y. Toullec, V. Michelet, Curr. Org. Chem. 2010, 14, 1245.
[8] a) L. Charruault, V. Michelet, R. Taras, S. Gladiali, J.-P. GenÞt, Chem.
Commun. 2004, 850; b) V. Michelet, L. Charruault, S. Gladiali, J.-P. GenÞt,
Pure Appl. Chem. 2006, 78, 397.
[9] J. A. Feducia, A. N. Campbell, M. Q. Doherty, M. R. Gagnꢂ, J. Am. Chem.
Soc. 2006, 128, 13290.
[10] Y. Zhang, H. Jullien, D. Brissy, P. Retailleau, A. Voituriez, A. Marinetti,
ChemCatChem 2013, 5, 2051.
[11] D. Brissy, M. Skander, P. Retailleau, G. Frison, A. Marinetti, Organometal-
lics 2009, 28, 140.
[12] D. Brissy, M. Skander, H. Jullien, P. Retailleau, A. Marinetti, Org. Lett.
2009, 11, 2137.
[13] H. Jullien, D. Brissy, P. Retailleau, A. Marinetti, Eur. J. Org. Chem. 2011,
5083.
[14] K. Ishida, H. Kusama, N. Iwasawa, J. Am. Chem. Soc. 2010, 132, 8842.
[15] For an introduction to combinatorial chemistry, see: K. C. Nicolaou, R.
Hanko, W. Hartwig in Handbook of Combinatorial Chemistry, Vol. 1,
Wiley-VCH, Weinheim, 2002, 3.
[16] a) B. Jandeleit, D. Schaefer, T. S. Powers, H. W. Turner, W. H. Weinberg,
Angew. Chem. 1999, 111, 2648; Angew. Chem. Int. Ed. 1999, 38, 2494;
b) M. T. Reetz, Angew. Chem. 2008, 120, 2592; Angew. Chem. Int. Ed.
2008, 47, 2556; c) P. Dydio, P.-A. R. Breuil, J. N. H. Reek, Isr. J. Chem.
2013, 53, 61.
temperature for 15 min. The chiral monodentate ligand
4
(0.01 mmol, 0.055 equiv) was then added and the solution heated
to 608C for 30 min. After cooling to room temperature, the nucleo-
phile (0.525 mmol, 3 equiv) and 100 mL of a solution of the 1,6-
enyne (1.75m in dioxane, 0.175 mmol, 1 equiv) were sequentially
added and the reaction mixture was heated to 608C for 18 h. Pu-
rification was accomplished by filtration through a Grace Extract-
Clean 8 mL filter filled with a pad of silica. Elution with spectro-
scopic grade n-hexane/iPrOH (90/10) gave first a fraction contain-
ing the excess of the aromatic nucleophile then a second fraction
containing the product, which can be injected into a high-pressure
liquid chromatograph without further manipulation.
Acknowledgements
This work was supported by the Agence Nationale de la Re-
cherche, the Centre National de la Recherche Scientifique
(CNRS) and the Ministꢁre de l’Education et de la Recherche.
A.P. is grateful to the Agence Nationale de la Recherche (ANR-
09-JCJC-0078) for a doctoral grant (2009–2012). Dr. M. Scalone
(Hoffmann-La Roche, Switzerland), Prof. Q.-L. Zhou (Nankai Uni-
versity, China), and Dr. N. Mꢂzailles (Ecole Polytechnique,
France) are acknowledged for a generous gift of MeOBIPHEP li-
gands (5b, 5p), spiroligands (5d, 4n), and phosphole 4c, re-
spectively. Dr. F. Le Boucher d’Herouville (Chimie ParisTech,
France) is acknowledged for providing a sample of the com-
plex [(R)-5c)PtCl2]. Johnson-Matthey is acknowledged for a gen-
erous loan of PtCl2.
Keywords: asymmetric catalysis · combinatorial chemistry ·
cyclization · platinum · P ligands
[17] a) L. Lefort, J. A. F. Boogers, A. H. M. de Vries, J. G. de Vries, Org. Lett.
2004, 6, 1733; b) A. Duursma, L. Lefort, J. A. F. Boogers, A. H. M. de Vries,
J. G. de Vries, A. J. Minnaard, B. L. Feringa, Org. Biomol. Chem. 2004, 2,
1682; c) R. B. C. Jagt, P. Y. Toullec, E. P. Schudde, J. G. de Vries, B. L. Ferin-
ga, A. J. Minnaard, J. Comb. Chem. 2007, 9, 407.
[18] a) M. T. Reetz, Angew. Chem. 2002, 114, 1391; Angew. Chem. Int. Ed.
2002, 41, 1335; b) M. Tsukamoto, H. B. Kagan, Adv. Synth. Catal. 2002,
344, 453.
[1] a) D. J. Gorin, F. D. Toste, Nature 2007, 446, 395; b) H. Schmidbaur, A.
Schier, Organometallics 2010, 29, 2; c) A. Leyva-Pꢂrez, A. Corma, Angew.
Chem. 2012, 124, 636; Angew. Chem. Int. Ed. 2012, 51, 614.
[2] a) A. Fꢃrstner, P. W. Davies, Angew. Chem. 2007, 119, 3478; Angew.
Chem. Int. Ed. 2007, 46, 3410; b) A. R. Chianese, S. J. Lee, M. R. Gagnꢂ,
Angew. Chem. 2007, 119, 4118; Angew. Chem. Int. Ed. 2007, 46, 4042;
c) A. Fꢃrstner, Chem. Soc. Rev. 2009, 38, 3208.
Chem. Eur. J. 2014, 20, 7128 – 7135
www.chemeurj.org
7134
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[19] a) M. T. Reetz, Angew. Chem. 2001, 113, 292; Angew. Chem. Int. Ed. 2001,
40, 284; b) J. G. de Vries, A. H. M. de Vries, Eur. J. Org. Chem. 2003, 799;
c) C. Gennari, U. Piarulli, Chem. Rev. 2003, 103, 3071; d) K. Ding, H. Du, Y.
Yuan, J. Long, Chem. Eur. J. 2004, 10, 2872; e) C. Jꢇkel, R. Paciello, Chem.
Rev. 2006, 106, 2912; f) J. G. de Vries, L. Lefort, Chem. Eur. J. 2006, 12,
4722–4734.
Michelet, Electronic Encyclopedia of Reagents for Organic Synthesis (Eds.:
L. Paquette, P. Fuchs, D. Crich, P. Wipf), John Wiley & Sons, 2011.
[28] A control experiment showed no reactivity of enyne 1 with methylin-
dole 2 in the presence of 12.5 mol% AgSbF6 at 608C for 18 h.
[29] A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T. Souchi, R. Noyori,
J. Am. Chem. Soc. 1980, 102, 7932.
[20] a) M. T. Reetz, T. Sell, A. Meiswinkel, G. Mehler, Angew. Chem. 2003, 115,
814; Angew. Chem. Int. Ed. 2003, 42, 790; b) D. PeÇa, A. J. Minnaard,
J. A. F. Boogers, A. H. M. de Vries, J. G. de Vries, B. L. Feringa, Org. Biomol.
Chem. 2003, 1, 1087–1089; c) J. A. F. Boogers, U. Felfer, M. Kotthaus, L.
Lefort, G. Steinbauer, A. H. M. de Vries, J. G. de Vries, Org. Process Res.
Dev. 2007, 11, 585; d) N. Toselli, D. Martin, G. Buono, Org. Lett. 2008, 10,
1453.
[30] a) R. Schmid, A. E. Broger, M. Cereghetti, J. Foricher, M. Lalonde, R. K.
Mꢃller, M. Scalone, G. Schoettel, U. Zutter, Pure Appl. Chem. 1996, 68,
131; b) L. Leseurre, F. Le Boucher d’Herouville, K. Puntener, M. Scalone,
J.-P. GenÞt, V. Michelet, Org. Lett. 2011, 13, 3250.
[31] J.-H. Xie, L.-X. Wang, Y. Fu, S.-F. Zhu, B.-M. Fan, H.-F. Duan, Q.-L. Zhou, J.
Am. Chem. Soc. 2003, 125, 4404.
[32] M. J. Burk, J. Am. Chem. Soc. 1991, 113, 8518.
[21] S. Carboni, C. Gennari, L. Pignataro, U. Piarulli, Dalton Trans. 2011, 40,
4355.
[33] W. Tang, X. Zhang, Angew. Chem. 2002, 114, 1682; Angew. Chem. Int. Ed.
2002, 41, 1612.
[22] a) V. F. Slagt, P. W. N. M. van Leeuwen, J. N. H. Reek, Angew. Chem. 2003,
115, 5777; Angew. Chem. Int. Ed. 2003, 42, 5619; b) X.-B. Jiang, L. Lefort,
P. E. Goudriaan, A. H. M. de Vries, P. W. N. M. van Leeuwen, J. G. de Vries,
J. N. H. Reek, Angew. Chem. 2006, 118, 1245; Angew. Chem. Int. Ed. 2006,
45, 1223; c) P. W. N. M. van Leeuwen, D. Rivillo, M. Raynal, Z. Freixa, J.
Am. Chem. Soc. 2011, 133, 18562; d) N. C. Thacker, S. A. Moteki, J. M.
Takacs, ACS Catal. 2012, 2, 2743.
[23] a) J. Wieland, B. Breit, Nat. Chem. 2010, 2, 832; b) P. A. Duckmanton,
A. J. Blake, J. B. Love, Inorg. Chem. 2005, 44, 7708; c) Y. Liu, C. A. Sandov-
al, Y. Yamaguchi, X. Zhang, Z. Wang, K. Kato, K. Ding, J. Am. Chem. Soc.
2006, 128, 14212; d) P.-A. R. Breuil, F. W. Patureau, J. N. H. Reek, Angew.
Chem. 2009, 121, 2196; Angew. Chem. Int. Ed. 2009, 48, 2162; e) L.
Pignataro, S. Carboni, M. Civera, R. Colombo, U. Piarulli, C. Gennari,
Angew. Chem. 2010, 122, 6783; Angew. Chem. Int. Ed. 2010, 49, 6633.
[24] O. Chuzel, C. Magnier-Bouvier, E. Schulz, Tetrahedron: Asymmetry 2008,
19, 1010.
[25] a) P. Y. Toullec, E. Genin, L. Leseurre, J.-P. GenÞt, V. Michelet, Angew.
Chem. 2006, 118, 7587; Angew. Chem. Int. Ed. 2006, 45, 7427; b) E.
Genin, L. Leseurre, P. Y. Toullec, J.-P. GenÞt, V. Michelet, Synlett 2007,
1780–1784; c) L. Leseurre, P. Y. Toullec, J.-P. GenÞt, V. Michelet, Org. Lett.
2007, 9, 4049; d) C.-M. Chao, E. Genin, P. Y. Toullec, J.-P. GenÞt, V. Michel-
et, J. Organomet. Chem. 2009, 694, 538; e) L. Leseurre, C.-M. Chao, T.
Seki, E. Genin, P. Y. Toullec, J.-P. GenÞt, V. Michelet, Tetrahedron 2009, 65,
1911; f) C.-M. Chao, P. Y. Toullec, V. Michelet, Tetrahedron Lett. 2009, 50,
3719; g) P. Y. Toullec, T. Blarre, V. Michelet, Org. Lett. 2009, 11, 2888;
h) E. S. Andreiadis, M. R. Vitale, N. Mezailles, X. Le Goff, P. Le Floch, P. Y.
Toullec, V. Michelet, Dalton Trans. 2010, 39, 10608; i) A. Pradal, C.-M.
Chao, M. R. Vitale, P. Y. Toullec, V. Michelet, Tetrahedron 2011, 67, 4371;
j) P. Y. Toullec, V. Michelet, Top. Curr. Chem. 2011, 302, 31; k) A. Pradal, Q.
Chen, P. Faudot dit Bel, P. Y. Toullec, V. Michelet, Synlett 2012, 74.
[26] P. Y. Toullec, C.-M. Chao, Q. Chen, S. Gladiali, J.-P. GenÞt, V. Michelet, Adv.
Synth. Catal. 2008, 350, 2401.
[34] A. Togni, Angew. Chem. 1996, 108, 1581; Angew. Chem. Int. Ed. Engl.
1996, 35, 1475.
[35] P. J. Pye, K. Rossen, R. A. Reamer, N. N. Tsou, R. P. Volante, P. J. Reider, J.
Am. Chem. Soc. 1997, 119, 6207.
[36] F. Robin, F. Mercier, L. Ricard, F. Mathey, M. Spagnol, Chem. Eur. J. 1997,
3, 1365.
[37] W. S. Knowles, M. J. Sabacky, Chem. Commun. (London) 1968, 1445–
1446.
[38] Y. Uozumi, T. Hayashi, J. Am. Chem. Soc. 1991, 113, 9887.
[39] S.-F. Zhu, Y. Yang, L.-X. Wang, B. Liu, Q.-L. Zhou, Org. Lett. 2005, 7, 2333.
[40] A. M. Aguiar, C. J. Morrow, J. D. Morrison, R. E. Burnett, W. F. Masler, N. S.
Bhacca, J. Org. Chem. 1976, 41, 1545.
[41] I. Bonnaventure, A. B. Charrette, J. Org. Chem. 2008, 73, 6330.
[42] M. T. Reetz, H. Guo, J.-A. Ma, R. Goddard, R. J. Mynott, J. Am. Chem. Soc.
2009, 131, 4136.
[43] L. A. Arnold, R. Imbos, A. Mandoli, A. H. M. de Vries, R. Naasz, B. L. Ferin-
ga, Tetrahedron 2000, 56, 2865.
[44] P. W. N. M. van Leeuwen, P. C. J. Kamer, J. N. H. Reek, P. Dierkes, Chem.
Rev. 2000, 100, 2741.
[45] For a recent example of an asymmetric Rh-catalyzed enyne cycloiso-
merization reaction in which the metal center is coordinated to an achi-
ral monodentate phosphane and a chiral bidentate diene ligand, see: T.
Nishimura, T. Kawamoto, M. Nagaosa, H. Kumamoto, T. Hayashi, Angew.
Chem. 2010, 122, 1682; Angew. Chem. Int. Ed. 2010, 49, 1638.
[46] For reviews on pincer ligands and their applications in asymmetric cat-
alysis, see: a) M. Albrecht, G. van Koten, Angew. Chem. 2001, 113, 3866;
Angew. Chem. Int. Ed. 2001, 40, 3750; b) M. E. van der Boom, D. Milstein,
Chem. Rev. 2003, 103, 1759.
Received: December 6, 2013
Revised: February 17, 2014
[27] a) S. Gladiali, A. Dore, D. Fabbri, O. De Lucchi, M. Manassero, Tetrahe-
dron: Asymmetry 1994, 5, 511; b) S. Gladiali, P. Y. Toullec, J.-P. GenÞt, V.
Published online on April 22, 2014
Chem. Eur. J. 2014, 20, 7128 – 7135
www.chemeurj.org
7135
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim