Access to a Chiral Phosphine-NHC Palladium(II) Complex via the Asymmetric Hydrophosphination of Achiral Vinyl Azoles

Article abstract of DOI:10.1021/acs.organomet.1c00262

Enantioenriched phosphine azoles were synthesized in high yields via palladium-catalyzed asymmetric hydrophosphination with excellent yields and enantioselectivities under mild reaction conditions. One of the phosphine azoles was methylated and complexed to palladium(II) cleanly to give a chiral phosphine-NHC palladium(II) complex with excellent overall conversion.

Full text of DOI:10.1021/acs.organomet.1c00262

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Article
Access to a Chiral Phosphine−NHC Palladium(II) Complex via the
Asymmetric Hydrophosphination of Achiral Vinyl Azoles
Jeffery Wee Kiong Seah, Yongxin Li, Sumod A. Pullarkat, and Pak-Hing Leung*
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ABSTRACT: Enantioenriched phosphine azoles were synthesized
in high yields via palladium-catalyzed asymmetric hydrophosphi-
nation with excellent yields and enantioselectivities under mild
reaction conditions. One of the phosphine azoles was methylated
and complexed to palladium(II) cleanly to give a chiral
phosphine−NHC palladium(II) complex with excellent overall
conversion.
ver since the first few N-heterocyclic carbenes (NHC)
overall atom economy and the use of harsh reagents and
1
2
3
Ewere developed by Arduengo, Wanzlick and Lappert, conditions, such as strong bases and prolonged heating which
NHCs have transformed into a distinctly important class of
ligands in homogeneous catalysis.4−7 As compared to
phosphines, NHCs are known to be better sigma donors but
poorer pi acceptors electronically.8 Sterically, the substituents
on the nitrogen atoms in NHCs point toward the coordination
sphere of the metal, while those on the phosphine atom point
away, creating a unique steric environment around the metal
center.9 As the chemical properties of both phosphines and
NHCs can be independently adjusted by modifying their
substituents, a new specific class of hybrid phosphine−NHC
(P-NHC) ligands has emerged over the years and proven to be
increasingly valuable in the synthesis of metal com-
plexes.8,10−13 In asymmetric catalysis where metals bearing
chiral P-NHCs are commonly utilized, the corresponding P-
NHC ligands are generally derived from their corresponding
protonated precursors and the synthesis of these chiral
phosphine azolium cations generally begins from a limited
pool of chiral amines and epoxides (Scheme 1).14−16 In
addition to the restricted pool of chiral starting materials,
disadvantages such as a tedious multistep synthesis with low
may not be compatible with ligands bearing base-sensitive
functional groups, are also frequently encountered.17−19 As
such, chiral P-NHC ligands continue to find applications in a
significant number of important asymmetric catalytic reactions
including the Pd-catalyzed Suzuki coupling and hydro-
amination,14,17 Ir-catalyzed transfer hydrogenation,15 and Rh-
catalyzed conjugate additions,18 it is paramount that the
current methodologies employed to access chelating chiral
phosphine azolium cations from a wider pool of achiral
substrates through asymmetric catalysis be expanded.
In view of these problems, we envisaged chiral mixed
phosphine azolium cations could be easily obtained via
alkylation of the corresponding chiral phosphine azoles and
proceeded to develop a new method of synthesizing chiral
phosphine azoles from simple achiral vinyl azoles. We hereby
report a novel synthesis methodology of accessing chiral
phosphine azoles from vinyl azoles through catalytic
asymmetric hydrophosphination. The benefits associated with
this protocol include excellent enantioselectivity, high atom
economy, and mild reaction conditions. Through this article,
we report the first example of a chiral mixed P-NHC palladium
complex derived from the asymmetric hydrophosphination of
Scheme 1. Synthesis of Chiral P-NHC Complexes from
Chiral Phosphine Azolium Cations
Received: April 29, 2021
Published: June 25, 2021
https://doi.org/10.1021/acs.organomet.1c00262
© 2021 American Chemical Society
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Table 1. Condition Screening for the Catalytic Asymmetric Hydrophosphination of Vinyl Azole 1a
a
b
c
entry
catalyst
cat. loading
base
NEt3
base loading
1 equiv
solvent
THF
THF
THF
THF
CH2Cl2
(CH3)2CO
NCMe
EtOH
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
T/°C
conv/%
ee/%
1
2
3
4
5
6
7
8
(R,R)-C1
(R,R)-C2
(R)-C3
(S)-C4
(R)-C3
(R)-C3
(R)-C3
(R)-C3
(R)-C3
(R)-C3
(R)-C3
(R)-C3
(R)-C3
(R)-C3
(R)-C3
(R)-C3
(R)-C3
(R)-C3
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
10 mol %
2.5 mol %
1 mol %
2.5 mol %
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
−40
−78
−78
−78
−78
−78
−78
35
93
>99
75
3
25
78
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
TMEDA
DBU
NaOAc
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
2 equiv
1 equiv
e
45
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
40
80
51
65
13
59
82
2
73
93
96
96
96
96
96
9
10
11
12
13
14
15
16
17
18
>99
0
d
19
a
Reactions were carried out with diphenylphosphine (0.0575 mmol), vinyl azole 1a (0.0575 mmol), base (0.0575 mmol, except entry 2) in the
listed solvent (575 μL) with specified catalyst (5 mol %) at the respective temperature for 8 h before being oxidized with 30% w/w aqueous
b
hydrogen peroxide at the stated temperature unless otherwise stated. Obtained via integration of 30.2 ppm from 31P{1H} NMR spectrum of crude
c
d
e
product mixture. Determined by chiral HPLC based on (S)-3a. No reaction. (R)-3a was the major enantiomer.
an achiral vinyl azole with excellent enantioselectivity and hope
that this new catalytic synthetic route employing mild reaction
conditions would prove useful for the synthesis of other hybrid
P-NHC metal complexes bearing base-labile groups.
superior when a moderately polar solvent was used (entries 3
and 5). In addition, protic EtOH resulted in the lowest
enantioselectivity (entry 8). Next, a series of bases were
screened, and it was found that in general, enantioselectivity
was not greatly affected by the bulkiness of base (entries 5 and
10). Inorganic bases such as NaOAc suffered from a marginally
reduced enantioselectivity possibly due to its poor solubility in
CH2Cl2 while the strongly basic DBU resulted in an extremely
low enantioselectivity with an enantioselectivity of just 2%
(entries 11 and 12). When the reaction temperature was
gradually reduced, a consistent increase in enantioselectivity
was observed alongside no adverse impact to the conversion
and reaction rate (entries 13 and 14). For catalyst loading, a
heightened loading of 10 mol % did not further enhance
enantioselectivity, while a lower loading below 2.5 mol %
significantly diminished the reaction rate even though the
corresponding enantioselectivity was not compromised (en-
tries 15 to 17). Base loading did not influence the conversion
and the enantioselectivity significantly (entry 18). Last, it
should be noted that in the absence of (R)-C3, substrate 1a
failed to react with HPPh2 at −78 °C (entry 19); hence, the
asymmetric hydrophosphination catalyzed by (R)-C3 produces
a true enantioselective effect in which no background reaction
occurs to lower the enantioselectivity of the asymmetric
hydrophosphination reaction.
In a preliminary trial, substrate 1a was reacted with
diphenylphosphine in the presence of a series of enantiopure
palladacycles, C1−C4, with triethylamine (except for (R,R)-
C2, where an internal basic ligand, acetate, was present) in
THF at room temperature over a standard duration of 8 h
(Table 1, entries 1−4). After 8 h, the intermediary air-sensitive
phosphine azole product, (S)-2a, was oxidized to facilitate
workup and postanalysis (chiral HPLC), and the 31P{1H}
NMR spectrum of the crude mixture showed a new resonance
signal at 30.2 ppm, corresponding to enantioenriched product
(S)-3a. Among the four catalysts screened, in general
palladacycles bearing two vacant sites yielded higher
enantioselectivity (entries 3 and 4). For tridentate pallada-
cycles, the yield and enantioselectivity were higher when the
anionic ligand was acetate instead of chloride (entries 1 and 2).
The catalyst which gave the poorest performance was (R,R)-
C1, which can be explained by the less labile Pd−Cl bond.
Consequentially, catalyst (R)-C3 was deemed the best catalyst
for the asymmetric hydrophosphination of vinyl azole 1a as it
afforded the highest yield and enantioselectivity. Reaction
yields with (R)-C3 were excellent in all the solvents screened
with a conversion of >99% as deduced from the 31P{1H} NMR
spectra of the crude mixtures. Enantioselectivity (ee) was
With the optimized set of conditions on hand, the
asymmetric hydrophosphination of substrates 1b−h was
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investigated (Table 2). The results show that electronically,
electron-withdrawing substituents generally had an accelerated
Table 3. Methylation of (S)-2g and Complexation of
Phosphine Azolium Cation (S)-4g
Table 2. Substrate Screening of Vinyl Azoles 1a−h
a
b
entry
[Pd] precursor
solvent
CH2Cl2
DMF
base
yield/%
1
2
3
PdCl2(NCMe)2
PdCl2(NCMe)2
PdCl2(NCMe)2
Li2PdCl4
Li2PdCl4
Li2PdCl4
NEt3
30
17
50
0
49
0
NaOAc
Ag2O
d
CH2Cl2
e
4
5
6
7
CH2Cl2/MeOH
CH2Cl2/MeOH
CH2Cl2/MeOH
CH2Cl2/MeOH
Ag2O
Ag2O
AgOAc
NEt3
Li2PdCl4
95
a
Reactions were carried out with (S)-2g (0.0575 mmol), 1 equiv of
[Pd] precursor, 2 equiv of halide source (if any), and 1 equiv of base
b
in the listed solvent(s) (total volume 3 mL). Crude 31P{1H} NMR
d
e
yield. Added 2 equiv of NEt4Cl. Using 0.5 equiv of Ag2O.
purification, direct attempts to form the desired chelating P-
NHC metal complex from (S)-4g were carried out. Palladium
was chosen as the metal in this study. As commonly employed
strong bases such as KOtBu, NaH, KHMDS, and nBuLi led to
the decomposition of the ligand due to the presence of the
acidic proton adjacent to the carbonyl functional group, milder
conditions were required for the formation of the desired
chelating mixed P-NHC metal complex.
a
Reactions were carried out with diphenylphosphine (0.0575 mmol),
(R)-C3 (2.5 mol %), and base (0.0575 mmol) in CH2Cl2 (575 μL)
and the listed vinyl azoles (0.0575 mmol) at stated temperature for
the stated duration before being oxidized with 30% w/w aqueous
hydrogen peroxide at the stated temperature. Using 1150 μL of
CH2Cl2. Isolated yield. Determined by chiral HPLC. Reaction was
When PdCl2(NCMe)2 was used as the metal source, the
yield increased when the basicity of the base increased (entries
1−3). In entry 3, 2 equiv of NEt4Cl were added to ensure
sufficient chloride ligands for the formation of (S)-5g.
However, when the metal source was switched to methanolic
Li2PdCl4, the stronger base Ag2O gave a lower product yield
than the weaker base NEt3 (entries 5 and 7). The weakest base
AgOAc afforded no product at all as AgOAc was too weak a
base to carry out the deprotonation (entry 6). Interestingly, the
stoichiometry of Ag2O also affected the yield drastically. When
0.5 equiv of Ag2O was used, no product formation was
observed (entry 4). The highest product yield of 95% was
obtained with NEt3 as the base and Li2PdCl4 as the palladium
precursor in a mixed solvent system CH2Cl2/MeOH (entry 7).
Notably, since the formation of the carbene and its
coordination to the palladium center occurred in the presence
of a protic solvent, MeOH, it is postulated that this
deprotonation-coordination process might be a concerted one.
The absolute stereochemistry of the chiral center in the
hydrophosphinated product was determined by X-ray
crystallography. The bond lengths of Pd(1)−Cl(1) and
Pd(1)−Cl(2) in (S)-5g are 2.368(4) and 2.335(6) Å,
respectively (Figure 1). Noticeably, the Pd−Cl bond trans to
the phosphine is longer than that trans to the NHC. As NHCs
are generally more electron-donating than phosphines, the
slightly longer Pd−Cl bond trans to the phosphine can be
attributed to steric repulsion between the methyl group on
C(2) and Cl(1).20 The Pd(1)−C(1) and Pd(1)−P(1) bonds
in five-membered chelating complex (S)-5g are also slightly
shorter as compared to those found in other chelating
complexes.21 In addition, the phosphine ligand showed no
sign of sulfurization via ligand dissociation even after (S)-5g
was heated (in a sealed tube) with 20 equiv of sulfur in CH2Cl2
at 65 °C for 3 days. Both observations translate to a stronger
b
c
d
e
f
halted after 96 h. Phosphine oxide product not formed.
rate and better enantioselectivity as compared to those of
electron-donating substituents. Highly electron-rich 1f was so
weakly electrophilic that it only managed to give a yield of 33%
after 96 h. Highly electron-withdrawing substituents on the
activated olefins such as the dicyano and triazolyl groups led to
no formation of product. This observation was supported by
1
the lack of the three characteristic proton signals in the H
NMR spectra of the oxidized crude reaction mixtures. This
decomposition might have been caused by the highly
electronegative atoms in the azole rings in substrates 1c and
1h. Sterically, bulky substituent such as diphenyl on the
activated olefin gave roughly the same enantioselectivity (ee =
91%) as those olefins with a less bulky substituent such as
hydrogen (ee = 96%), signaling that the enantioselectivity and
rate of the asymmetric hydrophosphination of such activated
olefins is more sensitive toward the electronic structure than
the steric bulk of the substrates.
Subsequently, to prove that the intermediary chiral
phosphine azole can be converted into the chiral phosphine
azolium cation, (S)-2g was reacted with methyl triflate in
CH2Cl2 at −40 °C for 5 h to give enantioenriched chiral
chelating phosphine azolium cation (S)-4g in quantitative yield
(Table 3). The formation of (S)-4g was supported by a new
resonance signal at −3.00 ppm. This is noteworthy as the
alkylation process occurred selectively at the sp2 N-terminal
rather than at the supposedly more nucleophilic sp3 P-terminal
of the ligand. Without the need for tedious workup and
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Nanyang Technological University, 637371, Singapore;
orcid.org/0000-0002-4150-2408
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00262
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research is supported by the Ministry of Education,
Singapore, under its Academic Research Fund Tier 1 (2019-
T1-001-094).
Figure 1. Molecular structure of chiral chelating P-NHC Pd(II)
chloride complex (S)-5g with thermal ellipsoids shown at 50%
probability (CCDC 2035450). Hydrogen atoms except H(C9) are
omitted for clarity.
REFERENCES
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binding affinity between the bidentate ligand and the palladium
center in (S)-5g.
In conclusion, enantioenriched phosphine azoles were
synthesized with high yields and enantioselectivity via catalytic
asymmetric hydrophosphination. One of the chiral phosphine
azoles generated via this protocol was methylated before being
coordinated to palladium(II) to give a hybrid chelating chiral
phosphine−NHC palladium(II) complex.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00262.
■
sı
General information, materials, references, synthesis
1
procedures, characterization data, H, 13C, and 31P{1H}
NMR spectra, chiral HPLC spectra, and single-crystal X-
ray diffraction data (PDF)
Accession Codes
CCDC 2035450 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Pak-Hing Leung − School of Physical and Mathematical
Sciences, Division of Chemistry and Biological Chemistry,
Nanyang Technological University, 637371, Singapore;
orcid.org/0000-0003-3588-1664; Email: pakhing@
ntu.edu.sg
Authors
Jeffery Wee Kiong Seah − School of Physical and
Mathematical Sciences, Division of Chemistry and Biological
Chemistry, Nanyang Technological University, 637371,
Singapore
Yongxin Li − School of Physical and Mathematical Sciences,
Division of Chemistry and Biological Chemistry, Nanyang
Technological University, 637371, Singapore
Sumod A. Pullarkat − School of Physical and Mathematical
Sciences, Division of Chemistry and Biological Chemistry,
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