Hydrogen-Bonding-Assisted Cationic Aqua Palladium(II) Complex Enables Highly Efficient Asymmetric Reactions in Water

Article abstract of DOI:10.1002/anie.202009989

Metal-bound water molecules have recently been recognized as a new facet of soft Lewis acid catalysis. Herein, a chiral palladium aqua complex was constructed that enables carbon–hydrogen bonds of indoles to be functionalized efficiently. We embraced a ch

Full text of DOI:10.1002/anie.202009989

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Accepted Article
Title: Hydrogen-Bonding-Assisted Cationic Aqua Palladium(II) Complex
Enables Highly Efficient Asymmetric Reactions in Water
Authors: Taku Kitanosono, Tomoya Hisada, Yasuhiro Yamashita, and
Shu Kobayashi
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10.1002/anie.202009989
Angewandte Chemie International Edition
COMMUNICATION
Hydrogen-Bonding-Assisted Cationic Aqua Palladium(II) Complex
Enables Highly Efficient Asymmetric Reactions in Water
_
Taku Kitanosono,* Tomoya Hisada, Yasuhiro Yamashita, Shu Kobayashi*[a]
[a]
Dr. Taku Kitanosono,* Tomoya Hisada, Dr. Yasuhiro Yamashita, Prof. Dr. S. Kobayashi*
Department of Chemistry, School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo, Japan
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Supporting information for this article is given via a link at the end of the document.
Abstract: Metal-bound water molecules have recently been
recognized as a new facet of soft Lewis acid catalysis. Herein, a
chiral palladium aqua complex was constructed that enables
carbon–hydrogen bonds of indoles to be functionalized efficiently.
We embraced a chiral 2,2¢-bipyridine as both ligand and hydrogen-
bond donor to configure a robust, yet highly Lewis acidic, chiral aqua
complex in water. Whereas the enantioselectivity could not be
controlled in organic solvents or under solvent-free conditions, the
use of aqueous environments allowed the s-indolylpalladium
intermediates to react efficiently in a highly enantioselective manner.
This work thus describes a potentially powerful new approach to the
1a). Lured by the pluripotency of chiral aqua precious metal
complexes for functionalizing carbon–hydrogen bonds in water,
we herein describe the development of a chiral palladium
complex that is highly stable and active in water.
Applications of chiral palladium complexes to reactions in
aqueous media include examples of complexes embedding into
a protein scaffold,[6a],[8] a robust PEPPSI complex,[9] a complex
supported on an amphiphilic resin,[10] and a micellar system.[11]
We envisaged a complementary approach wherein a chiral
hydrogen-bond donor associated with trifluoromethanesulfonate
(triflate) anion would furnish a charge-separated palladium aqua
complex with enhanced Lewis acidity (Scheme 1b).[13] The high
Lewis acidity and the vacant coordination site of such a complex
make it more electrophilic than the corresponding neutral
complex in coordination with carbon–carbon or carbon–
heteroatom multiple bonds.[14] The pseudo-square-planar
coordination of a chiral hydrogen-bond donor bound to the
palladium core would preclude the presence of equatorially
bound water molecules that invoke hydrolysis, resulting in
enhanced longevity in water. We sought to apply this design to
chiral 2,2¢-bipyridine ligand L bearing two OH groups, which is
often found to play a sophisticated role in catalysis exerted in
water.[15] The structure of the hydrated palladium ion in an
transformation of organometallic intermediates in
enantioselective manner under mild reaction conditions.
a
highly
Chiral aqua or hydroxo complexes of transition metals have
received increasing attention due to their immense potential for
application in catalytic processes involving carbon–carbon bond
formation, compared with the corresponding anhydrous
complexes.[1],[2] Coordinating water molecules in aqua
complexes form much stronger hydrogen bonds than free water
molecules,[3] thus participating in intramolecular hydrogen bonds
within the first hydration shell,[4] and sometimes conferring a
pronounced Brønsted acidity.[1o] Metal-bound water molecules
and hydroxides can act, inter alia, as a nucleophile to promote
transmetallation or s-metathesis.[1m],[2b],[5] That is, precious-metal
aqua complexes offer orthogonal catalysis capable of
functionalizing carbon–hydrogen bonds through the formation of
organometallic intermediates, which are not feasible with 3d
metals.[1] Because of their unique stereoelectronic properties,
these 16-electron catalysts could impart unprecedented
reactivity and selectivity to conventional Lewis acid-catalyzed
aqueous solution adopts
a
pseudo-Jahn–Teller distorted
octahedron, wherein two weakly bound water molecules occupy
axial positions with a bond length of 0.7 Å longer than
equatorially bound water molecules.[16] Given that these
properties are clearly distinct from equatorial water molecules in
the first hydration shell (Pd–Owater ca. 2.0 Å) and the second
shell (Pd–Owater >4.0 Å), the axial hydration shell is termed the
meso-shell (Pd–Owater ca. 2.8 Å).[17] Aqueous environments thus
allow facile access of electron-rich molecules, for example,
indole, to the apical position in place of readily exchangeable
water molecules. In contrast, under anhydrous conditions, the
apical occupancy of one counteranion with another occupying
the equatorial region[18] would mask the meso-shell and impose
the trajectory of indole or solvent molecules on the equatorial
plane due to the electrostatic repulsion, disrupting a coordination
geometry around palladium(II) to form dangling alcohol units.
That is, preferred palladation of indole within the meso-shell in
water would enable a highly enantioselective transformation of
indole (Scheme 1c).
reactions. While
a conceivable drawback of these aqua
complexes is their precarious activity under anhydrous
conditions caused by the liberation of a water molecule from
their primary coordination sphere, aqueous environments would
offer them improved durability. Furthermore, asymmetric
environments in water often carry transcendent performance
that cannot be exerted in organic solvents.[6] Chiral precious-
metal complexes have, however, rarely been used in aqueous
[1b,k],[6]-[10]
media,
in spite of an increasing awareness that
performing organic reactions in water meets the worldwide need
for green sustainable chemistry. The problem may lie with the
insolubility and inherent ease of hydrolysis of these complexes
in water because soft acids are reluctant to coordinate with the
hard base H2O and furthermore they exhibit low hydrolysis
constants (e.g. 2.3 for Pd2+),[11] irreversibly leading to the less
soluble µ-hydroxo-bridged dimer or oligomer[1c,h-m,o],[2e] (Scheme
1
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10.1002/anie.202009989
Angewandte Chemie International Edition
COMMUNICATION
as a trigger of the indole substitution.[20] To corroborate the
formation of the s-indolylpalladium intermediate, LPd(OTf)2
complex was incubated with indole at room temperature in D2O.
The indole was found to forthwith undergo H/D exchange
exclusively at C3 position, despite its immiscibility in D2O (Figure
1c and Table S2). In contrast, incubating under anhydrous
conditions attributed to no D incorporation. As presumed, the
occupancy of triflate anion within the second shell of the
anhydrous complex would impede the formation of the s-
indolylpalladium intermediate.
a)
H
O
OH2
OH
L
L
L
L
L
L
L
L
Base
−HX
Pd+
Pd2+
Pd2+
vs.
*
Pd2+
X
*
*
*
O
H
X
X
2
2
In anhydrous solvents
In water
accessible
b)
*
c)
L
L
blocked
OTf
OH2
Pd2+
OTf
tBu
H
O
H
tBu
O
H
O
N
Pd2+
N
H
H
N
N
Pd2+
H
O
H
H
H
O
OTf
OTf
tBu
H
O
TfO
tBu
TfO
OH2
• Increased Lewis acidity
• Effective suppression of
dimerization to stabilize
monomeric Pd2+
anhydrous form
aqua complex
D2O
a)
b)
disrupted cooridination
environments
i)
ii)
Scheme 1. a) Potential problems of palladium aqua complexes under basic
conditions. b) The concept of the hydrogen-bond-assisted cationic palladium
complex in this study. c) The design of the chiral 2,2¢-bipyridine palladium
aqua complex that is effective for indole palladation and subsequent
asymmetric reaction. The apical triflate anion is labile to exchange with meso-
shell water molecules in aqueous environments, further exchanging with
reactants. The preferred equatorial intrusion of indole or solvent molecules
under anhydrous conditions would weaken the Pd–OL bonds, disrupting the
iii)
iv)
v)
coordination environments surrounding Pd2+
.
8.0
7.0
5.0
4.0
1.0
d
(ppm)
c)
H
H/D
LPd(OTf)2
in D2O: 93% D within 10 min
in CH2Cl2 at 70 oC, 30 min then D2O: 0% D
0% D
(1 equiv)
Solvent, rt
We were encouraged by the identification of conditions that
enabled isolation of the bench-stable, anhydrous LPd(OTf)2
complex. The X-ray packing structure of the complex revealed a
herringbone packing arrangement within which the palladium ion
adopts a pseudo-square-planar structure in a tetradentate
manner with ca. 2.0 Å Pd–OL bonds (Figure 1a; see the
Supporting Information for full details of X-ray crystallography
data).[19] In the single crystal, two triflate anions occupy the
N
N
H
H
Figure 1. a) Crystal structure of anhydrous LPd(OTf)2. The site-occupancy
disorder of triflate anions is shown. b) Variable-temperature 1H NMR studies of
LPd(OTf)2 complex in D2O recorded at i) 20 °C, ii) 40 °C, iii) 60 °C, iv) 80 °C,
and v) 20 °C after cooling from 80 °C. c) Deuterium quenching experiments of
a putative s-indolylpalladium intermediate.
apical position and the equatorial position, with the Pd–OOTf
-
bond length (ca. 4.0 Å) being twofold longer than the Pd–OL
bond, and approximately equivalent to the distance to the
second hydration sphere, and forms hydrogen bonding with OH
group of L (ca. 1.8 Å). As anticipated, the occupancy of the
triflate anions within the second shell of the anhydrous
LPd(OTf)2 complex provides only an outer-sphere site for the
approaching indole, which may impede the formation of the s-
indolylpalladium complex considering that a C–Pd bond with a
bond length of 2.2 Å or shorter is required unless coordination
bonds around Pd2+ are broken.[14] The complex in solution was
characterized based on UV-vis and 1H NMR spectroscopic
studies. The NMR spectrum of the LPd(OTf)2 complex in D2O
exhibited dissymmetric configuration, with one OH group of L
unexchanged, indicating the preferential hydrogen-bond
formation with the equatorial triflate anion, as expected.
Variable-temperature 1H NMR studies revealed that the
palladium aqua complex underwent a reversible conformational
change in the range from 20 to 80 °C in D2O (Figure 1b). The
desymmetrized peaks recorded at room temperature were
The complex was then amenable to a model asymmetric
reaction that involves C–H functionalization of the privileged
indole pharmacophore (Table 1). Although there have been
several reports delineating catalytic asymmetric Friedel–Crafts
alkylation of indole 1a, b-substituents are known to have a
profound influence on enantioselection; trans-1-phenylbut-2-en-
1-one 2a has been recognized as one of the most difficult
substrates on which to impose stereoselectivity without the need
for high catalyst loadings.[21] Under the optimized reaction
conditions, the C–H bond of 1a could be functionalized with 2a
in a highly enantioselective fashion within 30 min (entry 1).
According to our definition,[6a] this reaction is classified as Type
IIIa (Figure S2). The distinguished catalytic activity of LPd(OTf)2
was apparent by comparing it with the micellar system
previously reported as Type IIb reaction,[11] with the latter
showing significantly retarded kinetics and erosion of
enantioselectivity (entry 2). Likewise, the reaction was sluggish
and less selective in the presence of the polyoxyethanyl-a-
tocopheryl succinate-based amphiphile designed by Lipshutz
and Ghorai,[22] although the field of transition-metal-catalyzed
chemistry has flourished in water with the aid of this surfactant
(entry 3). The activity was highly contingent on the ligands
coordinating to palladium, with a tetra-coordination fashion being
superior to bidentate coordination (entries 4–6). Because the µ-
hydroxo-bridged dimer is more stable than monomeric [Pd(2,2¢-
bpy)(OH2)2]2+,[23] the results underpin the importance of
hydrogen bonds between the alcohol unit of L and the triflate
superimposed to form
a C2-symmetric complex as the
temperature was raised, and the spectrum remained unaltered
upon cooling to room temperature, denoting the conformational
reversibility of the complex.
Noticeable color change was visualized upon mixing
LPd(OTf)2 complex and indole in water (Figure S2). As widely
espoused, the palladium(II) would perform an electrophilic
palladation of the indole to give an indolylpalladium intermediate
2
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10.1002/anie.202009989
Angewandte Chemie International Edition
COMMUNICATION
anion. A loss of cationicity impeded the progress of the reaction
(entry 7). Similarly, the activity of methanesulfonate deteriorated
due to the reduced cationic nature compared with triflate, with a
comparable level of enantioselectivity (entry 8). The use of
lipophilic anions which allowed the reaction to be Type IIIb, did
not alter their catalytic activities, with a poorer nucleophile being
more enantioselective (entries 9–13). The water-immiscible
perfluorooctanesulfonate, albeit with its electron-withdrawing
property, resulted in decreased enantioselectivity (entry 14).
displayed reduced levels of enantioselection under neat
conditions (entry 11). In contrast, the putative aqua complex that
would form in water enabled high enantioselection to be realized
with quantitative product formation (entry 12). The catalyst
induced decreased enantioselectivity when it was not incubated
with water but with substrates even though the reaction was
performed in water (entry 13), highlighting the conspicuous
effect of an aqua complex on the formation of
a s-
indolylpalladium intermediate and a subsequent enantioselective
control. Equally, the most effective chiral environments are
assembled
at
the
substrate-water
interface,
while
Table 1. Effect of ligands surrounding palladium cation.
enantioselectivity plunged in homogeneous reactions.
H
O
Ph
Table 2. Influence of solvents.
Catalyst (2.5 mol%)
+
O
H2O, rt, 30 min
N
H
N
H
3aa
H
1a
2a
O
LPd(OTf)2
(2.5 mol%)
Solvent, rt, 3 h
Ph
(1.2 equiv)
N
N
+
O
N
N
H
3aa
OH
HO
H
L
1a
(1.2 equiv)
2a
Entry
1
Catalyst
LPd(OTf)
PdCl , SDS, L, PhNMe
LPd(OTf)
Pd(MeCN)
Pd(2,2’-bpy)(OTf)
Pd(phen)(OTf)
LPdCl
LPd(OSO
Yield (%)[a] Ee (%)[c]
Entry
1
Solvent
Yield (%)[a] Ee (%)[b]
2
55
5
89
56
70
–
2[d]
3[e]
4
2
2
nhexane
CH2Cl2
toluene
THF
95
80
94
92
72
77
0
31
34
16
1
2
22
15[b]
3[b]
0[b]
<1
7
2
4
(OTf)2
3
5
2
–
4
6
2
–
5
Et2O
0
7
2
0
6
EtOAc
DMSO
acetone
MeCN
MeOH
– (neat)
H2O
1
8
2
CH
(4-MeC
(4-FC
(4-MeOC
(2-naph)]
(1-pyrene)]
3)2
84
53
65
37
19
4
7
–
9
LPd[OSO
LPd[OSO
LPd[OSO
LPd[OSO
LPd[OSO
2
6
H
4
)]
2
57
40
62
56
86
69
8
44
90
91
95
97
94
1
10
11
12
13
14
2
6H4)]2
9
1
2
6H4)]2
10
11
12
13[c]
2
2
2
12
90
61
2
2
LPd(OSO
2C
8F17)
2
35
H2O
[a] Isolated yield. [b] Determined by 1H NMR analysis. [c] Determined by
HPLC analysis. [d] PdCl2 (2.5 mol%), SDS (5 mol%), L (3 mol%), PhNMe2 (5
mol%). Conditions are adopted from Ref. [11] with reduced catalyst loading.
[e] Run in the presence of 2 wt% aqueous TPGS-750-M.
[a] Isolated yield. [b] Determined by HPLC analysis. [c] During the procedure,
water was added at the end.
With optimized conditions in hand, the substituent effects
with respect to both indole 1 and a,b-unsaturated ketone 2 were
appraised (Table 3). The products 3 formed in a highly
enantioselective manner, irrespective of the electronic features
of the substituents on the phenyl group of 2 (entries 1–7). The
heteroaromatic enone 2h and 2i could serve as a substrate,
giving the corresponding product 3ah and 3ai in excellent yield
with high enantioselectivity (entry 8 and 9). The reaction was
Consistent with our hypothesis and the NMR studies of the
LPd(OTf)2 complex, enantioselection deteriorated when the
reaction was run in organic solvents (entries 1–10 in Table 2).
The palladium complex LPd(OTf)2 was capable of promoting the
reaction in an anhydrous form in nonpolar solvents albeit with
reduced selectivity (entries 1–3), whereas it catalyzed the
reaction in a nonselective fashion in polar solvents (entries 4–6).
The feasible electrophilic activation of carbonyl or soft p-bond[24]
would provoke the C3-alkylation of indole in aprotic solvents
without forming a s-indolylpalladium intermediate. The use of
dimethylsulfoxide as a solvent disabled its catalytic activity (entry
7). In a solution of coordinating solvent, the Pd–L binding was
vulnerable to the superior enthalpy of solvent coordination,
inducing aggregation and formation of Pd black during the
progress of the reaction (entries 8–10). Moreover, the catalyst
applicable to
a
new candidate of optically active
ferrocene/cymantrene-indole hybrids, without Pd black formation
even in the presence of metal carbonyls (entry 10, 11).
Ferrocene and cymantrene serve as a potent organometallic
species that can endow compounds with enhanced biological
activity in areas such as antimalaria and anticancer drugs.[25]
The cyclohexyl group also provided the desired product 3ak with
good enantioselectivity (entry 12). Eroded enantioselectivity
3
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10.1002/anie.202009989
Angewandte Chemie International Edition
COMMUNICATION
might be associated with the formation of palladium black in the
course of the reaction. The addition of even small amounts of
organic solvents proved fruitless because the aqua complex
preferably undergoes water exchange reactions with these
displays high durability, high Lewis acidity, and high levels of
enantioselection through electrophilic palladation. The power of
the designed complex LPd(OTf)2 was shown to manifest
exclusively in water through the robust and enantiocontrolled
organic solvents and loses the intended performance (Table S1). functionalization of indole C–H bond, via an efficient and
These results underscore the essential use of water as a
reaction medium. The palladium complex was also applicable to
the enantioenriched formation of a fluorinated tertiary carbon
stereocenter despite a solid-solid reaction (entry 13). The
reaction with indoles substituted with electron-donating or
electron-withdrawing groups proceeded smoothly with high
enantioselectivities (entries 15–21). Noteworthy is the tolerance
of bromo groups on indole under our catalysis (entry 21). In
addition, our catalysis was applicable to challenging,
enantioselective C2-alkylation of a putative pyrrolylpalladium
species (Scheme S2).
operationally simple protocol. Noteworthily, substrates are
reacted in a highly enantioselective manner although immiscible
with water (Type IIIa reaction). The design represents a
potentially powerful method to transform highly active
organometallic intermediates in
a
highly enantioselective
manner under mild reaction conditions.
Acknowledgements
This work was supported by
a Grant-in-Aid for Science
Research (JP19H05288 and in part JP20K15262 to TK,
JP15H05698 to SK) from the Japan Society for the Promotion of
Science (JSPS).
Table 3. Substituent effects.
H
LPd(OTf)2
(2.5 mol%)
Solvent, rt, 3 h
R2
Keywords: asymmetric catalysis • Lewis acids • reaction in
O
+
O
R2
water • cationic palladium • aqua complex
N
N
R1
H
H
R1
1
2
3
[1]
For representative examples of precious metals including asymmetric
reactions, see: a) R. Gauthier, M. Mamone, J.-F. Paquin, Org. Lett.
2019, 21, 9024-9027; b) T. Kuremoto, T. Yasukawa, S. Kobayashi, Adv.
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1998, 120, 2474-2475; p) M. Sodeoka, R. Tokunoh, F. Miyazaki, E.
Hagiwara, M. Shibasaki, Synlett 1997, 463-466.
(1.2 equiv)
Entry
1
R1
1
R2
R3
2
3
Yield (%)[a] Ee (%)[b]
–
1a Ph
Me 2a 3aa 97
Me 2b 3ab 99
90
92
88
90
90
89
82
93
84
85
87
78
78
84
89
84
87
80
87
81
81
2[f]
–
1a 4-MeC6H4
3
–
1a 4-MeOC6H4 Me 2c 3ac 95
1a 4-CF3C6H4 Me 2d 3ad 90
4[c]
–
5[c]
–
1a 4-FC6H4
1a 4-ClC6H4
Me 2e 3ae 86
Me 2f 3af 82
6[d]
–
7[e,f]
8[c]
–
1a 4-NO2C6H4 Me 2g 3ag 93
–
1a 2-thienyl
1a 2-furyl
Me 2h 3ah 94
9[e,f]
10[c]
11[e,f]
12[e,f]
13[c,f]
14[e,f]
15[e]
16
–
Me 2i
3ai
3aj
92
37
–
1a 2-ferrocenyl Me 2j
[2]
For representative examples of nonprecious metals including
asymmetric reactions, see: a) M. H. Abdellattif, M. Mokhtar, Catalysts
2018, 8, 133-148; b) S. Kobayashi, T. Endo, T. Yoshino, U. Schneider,
M. Ueno, Chem. Asian J. 2013, 8, 2033-2044; c) T. Kitanosono, T.
Ollevier, S. Kobayashi, Chem. Asian J. 2013, 8, 3051-3062; d) S.
Kobayashi, T. Kitanosono, M. Ueno, Synlett 2010, 2033-2036; e) J. S.
Fossey, R. Matsubara, H. Kiyohara, S. Kobayashi, Inorg. Chem. 2008,
47, 781-783; f) M. Hatano, T. Ikeno, T. Miyamoto, K. Ishihara, J. Am.
Chem. Soc. 2005, 127, 10776-10777; g) T. Kawabata, M. Kato, T.
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Yamashita, H. Ishitani, H. Shimizu, S. Kobayashi, J. Am. Chem. Soc.
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H. Yamamoto, J. Tanaka, E. Wada, D. P. Curran, J. Am. Chem. Soc.
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J. Tanaka, E. Wada, D. P. Curran, J. Org. Chem. 1997, 62, 6454-6455;
k) W. Odenkirk, B. Bosnich, J. Chem. Soc., Chem. Commun. 1995,
1181-1182.
–
1a CpMn(CO)3 Me 2k 3ak 40
–
1a Cy
1a Ph
1a Ph
1b Ph
1c Ph
Me 2l
CF3 2m 3am >99
Et 2n 3an >99
3al
86
–
–
5-Me
6-Me
Me 2a 3ba 97
Me 2a 3ca 94
Me 2a 3da 97
Me 2a 3ea 94
17
5-MeO 1d Ph
5-BnO 1e Ph
18
19[e,f]
20[e,f]
21[e,f,g]
5-F
1f
Ph
Me 2a 3fa
>99
[3]
[4]
[5]
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aqua complex, wherein
trifluoromethanesulfonate anion as hydrogen-bond donor,
a
chiral ligand interacts with
4
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Entry for the Table of Contents
OH2
OTf
tBu
H
H
N
Pd2+
N
O
H
N
H
H
H
O
tBu
TfO
OH2
designed aqua complex
Ph
O
N
H
Ø Reduced catalyst loading
Ø Water-promoted indole C−H functionalization
Ø ”In water”-driven stereoselectivity
Metal-bound water molecules have recently been recognized as a new facet of soft Lewis acid catalysis. Herein, a chiral palladium
aqua complex was constructed and used to functionalize carbon–hydrogen bonds of indoles robustly and efficiently in a highly
enantioselective manner. The power of the designed complex was displayed exclusively in water. The inclusion of organic solvents
deteriorated the designed catalysis.
6
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