Synthesis of Stereoprojecting, Chiral N-C(sp3)-E Type Pincer Complexes

Article abstract of DOI:10.1021/acs.organomet.8b00262

A synthetic strategy to generate chiral N-C(sp³)-E (E = S, O) pincer complexes incorporating enhanced stereoprojecting groups at the N-arm site has been established. The synthesis of the tridentate pincer ligand was carried out via palladacycle-catalyzed asymmetric hydrophosphination of N-chelating enones. The chelation properties of the substrates were initially demonstrated on C(sp²)-N type palladacycles. The extended substrate scope allows versatile structural modifications on the ligand backbone. Subsequent cyclometalation provided N-C(sp³)-E complexes in a diastereoselective reaction.

Full text of DOI:10.1021/acs.organomet.8b00262

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Synthesis of Stereoprojecting, Chiral N‑C(sp3)‑E Type Pincer
Complexes
́
́
́
Laszlo B. Balazs, Wee Shan Tay, Yongxin Li, Sumod A. Pullarkat,* and Pak-Hing Leung*
Division of Chemistry & Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
S
* Supporting Information
ABSTRACT: A synthetic strategy to generate chiral N-
C(sp3)-E (E = S, O) pincer complexes incorporating
enhanced stereoprojecting groups at the N-arm site has
been established. The synthesis of the tridentate pincer ligand
was carried out via palladacycle-catalyzed asymmetric hydro-
phosphination of N-chelating enones. The chelation proper-
ties of the substrates were initially demonstrated on C(sp2)-N
type palladacycles. The extended substrate scope allows versatile structural modifications on the ligand backbone. Subsequent
cyclometalation provided N-C(sp3)-E complexes in a diastereoselective reaction.
cases it is quite difficult, since each alteration requires an
individual, multistep ligand synthesis procedure. For instance,
one of the most commonly used chiral C(sp2)-N palladacycles,
the bis(μ-chloro) (1-naphthyl)dimethylamine palladacycle 1, is
relatively easy to synthesize; however, its structural mod-
ifications, reported by our group, require multistep syntheses,
including the need for kinetic resolution (Figure 1).9 On the
basis of these considerations, the development of a more direct
and efficient ligand synthesis for extended structural mod-
ifications is unquestionably needed for all kinds of complex
families.
INTRODUCTION
■
The development of palladacyclic compounds, bearing either a
bidentate or a tridentate pincer ligand scaffold, has attracted
interest in the last few decades, due to the extensive application
of these useful organometallic complexes.1 Among these
materials, the chiral derivatives have attracted interest since
their first discovery in asymmetric synthesis scenarios. Their
application in the chiral template-promoted cycloadditions and
hydrofunctionalization reactions has been extensively explored
over the past decade.2 In this methodology, the metal complex
is required in stoichiometric amount for the reaction. However,
it allows the generation of synthetically challenging P,P- and
P,N-bidentate ligands, which can develop five- or six-
membered-ring chelation with the metal center, circumventing
the hurdle of catalyst poisoning.3 Optically pure C(sp2)-E (E =
electron donor atom) type palladacycle complexes can be also
successfully applied in catalytic amounts for asymmetric
Michael-type addition reactions,4 including P−H addition,5
Hayashi−Miyaura arylboronic acid addition,6 [3,3]-sigma-
tropic aza-Claisen rearrangement,7 and ring-opening reactions8
just to name a few.
One of the most important features of the palladacyclic
complexes is the extensive synthetic opportunities to modify
the ligand backbone. This in turn allows enormous possibilities
for the fine tuning of the electronic properties of the metal
center as well as control of the stereochemistry around the
coordination sites. Both of these factors can have a direct effect
on reactivity as well as stereoselectivity when these complexes
are employed in asymmetric synthesis. In the aforementioned
examples, it has already been proven that each individual
complex has its own structural and electronic features that lead
to a unique performance in catalysis. Thus, some derivatives
may be more efficient in one particular catalytic reaction, while
analogues work better in another reaction. While the
importance of ligand modifications is evident, in most of the
The generation of achiral N-C(sp2)-E pincer palladacycles
has already been established, and their catalytic activity was
tested in Suzuki−Miyaura cross-coupling reactions.10 The
aliphatic derivatives of those pincer complexes were also
reported previously with the N-C(sp3)-O pincer backbone.11
However, in these early studies the catalytic activity was not
explored. Our group recently reported the synthesis of chiral
N-C(sp3)-E (E = O, S) type complexes, including bimetallic
derivatives, and the catalytic performance was evaluated in
asymmetric hydrophosphination reactions.12 The new com-
pounds provided the desired chiral phosphine products with
high enantioselectivities and regioselectivities. However, the
structural modifications of the catalyst have not yet been
investigated and the steric control around the catalytic site still
can be improved by building up projecting groups at the N site
of the complex (Figure 2). Our group is interested in exploring
further the chemistry of the relatively less explored chiral N-
C(sp3)-E pincer complexes and therefore embarked upon
developing an effective and robust synthetic strategy, which
also allows easy and convenient structural modifications on the
ligand backbone.
Received: April 24, 2018
© XXXX American Chemical Society
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Figure 1. Structural modifications of C(sp2)-N type palladacycles.
the first stereocenter is generated via an asymmetric hydro-
phosphination reaction, catalyzed by complex 5. On the basis
of our previous studies, complex 5 is still one of the most
powerful and well-established catalysts in asymmetric hydro-
phosphination reactions.5,13 In the following step, a diaster-
eoselective cyclometalation leads us to the desired, optically
active final product (4a). The cyclometalation of the
synthesized ligand is also a crucial part of our strategy, since
the synthesis of these compounds is known to be exceptionally
challenging.
One of the most important components of this aliphatic
pincer ligand scaffold is the C(sp3) unit, which is connected
directly to the metal center and imparts entirely different
features to the complexes in comparison to the C(sp2)
counterpart. These include, but are not limited to, higher
electron density around the metal center and a stereogenic
carbon donor which is directly coordinated to the metal, thus
allowing a more efficient transmission of chiral information.
These structural features may have a strong influence on the
stereochemistry when the complex is applied in a particular
catalytic transformation.
Figure 2. Structural modifications of N-C(sp3)-E complexes.
In addition, varying the groups connected to the chiral
carbon adjacent to the phosphorus atom may also have some
influence on the catalytic performance via alteration of the
conformation of the five-membered palladacyclic ring (ring A
in Figure 2). It needs to be reiterated that such sterically
enhanced, optically pure N-C(sp3)-E complexes have not yet
been reported in the literature, nor has a relatively concise and
universal synthetic strategy been found that provides easy
structural modifications on this new class of complexes. Herein
we report an effective and simple method for structural
modification, in which the first C(sp3) stereocenter is
generated in asymmetric hydrophosphination, followed by
cyclometalation which creates the second stereocenter in a
highly diastereoselective manner. This method allows us to
generate a wide range of new, optically pure N-C(sp3)-E
complexes bearing enhanced stereoprojecting units without the
need for a time-consuming and often inefficient kinetic
resolution step.
It is generally accepted that intramolecular cyclometalation
via C−H activation is preferentially favored in the case of the
aromatic ligands in comparison to the aliphatic ligands.14 One
explanation is that, although the alkylic C(sp3)−H bond is
generally weaker than the aromatic C(sp2)−H bond, the
strength of the generated M−C(sp2) bond is significantly
higher than that of the M−C(sp3) bond.15 Another important
factor in the C(sp2)−H bond activation is the possible
coordination of the π aromatic system to the metal, before the
C−H bond cleavage takes place. In the case of aliphatic
C(sp3)−H bond activation, such precoordination does not
occur.1f,c,16 In addition, the enhanced flexibility of the aliphatic
backbone complicates the selective generation of the well-
defined compounds. There are indeed only a few reports in the
literature in which the M−C(sp3) bond formation was
promoted over the M−C(sp2) formation.17
RESULTS AND DISCUSSION
■
In order to build up the steric projection at the N-site of the N-
C(sp3)-E complexes, our first attempt was to change the
pyridyl group to a quinolyl ring. For this purpose, the synthesis
route was initiated with an asymmetric P−H addition step
onto an α,β-unsaturated enone (2a) bearing a quinolyl ring
adjacent to the carbonyl functionality (Scheme 1). In this step,
Therefore, while initiating our ligand synthesis, we took all
the possible difficulties in the P−H addition into consideration.
Scheme 1. Synthetic Plan To Generate the Quinolyl-Based N-C(sp3)-E Complex (4ab)
B
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Scheme 2. Coordination Properties of N-Chelating Enones
It has been demonstrated previously that the P,N-chelating
phosphine ligands, which are generated in asymmetric
hydrophosphination, can alter the catalytic performance of
complex 5 by acting as a catalyst poison.18 However, in our P−
H addition reactions the source of the problem was not the
generated ligands but the N-chelating enone starting materials
themselves. Since the synthesis of N-C(sp3)-E pincer
complexes requires the use of these types of N-chelating
substrates during the ligand synthesis, the effect of N-chelation
also plays a crucial role in the development of our synthetic
strategy and provides fundamental insights into this aspect of
coordination in this class of compounds.
With the N-chelating enones, the source of the difficulty is
the lone pair of the N-moiety that takes part in the final
coordination in the N-C(sp3)-E complexes, as well as in the
chelation to the palladium before the P−H addition. To
explore the coordination behavior of the selected N-chelating
substrates, compound 2a was treated with 1 equiv of complex
6 and stirred at room temperature in CDCl3 for 15 min
(Scheme 2, top left).
Figure 3. ORTEP structure of complex 7. All hydrogen atoms are
omitted for clarity.
Within this time, a dynamic equilibrium was set up between
the starting materials and the product (7). Compound 7 was
generated by N chelation via the nitrogen of the quinolyl ring
to the metal center. The ratio between complex 7 and the
starting materials was found to be 0.30:1 as determined by 1H
NMR. The coordination product can be isolated via
crystallization from the solvent, and it was found to be stable
in the solid state. However, when the isolated product was
redissolved in CDCl3, the same equilibrium was reestablished.
Another proof for the existence of the equilibrium was the
presence of the same amount of complex 7 in the mixture even
after more than 10 days, without any changes in the ratio. This
experiment excludes the possibility of a one-way coordination
reaction. The single-crystal X-ray diffraction analysis of
complex 7 confirmed its structure (Figure 3).
recognized under the mentioned reaction conditions (for
NMR spectra, see the Supporting Information).
Complex 8 was generated from complex 6 by mixing it with
1 equiv of AgClO4 in acetonitrile.
After the chloride atoms were removed, the two acetonitrile
molecules provided a more hemilabile coordination to the
metal center. Introducing a stoichiometric amount of enone 2a
to compound 8 leads to the formation of complex 9 (Scheme
2, top right). After isolation of the coordination product, the
ORTEP structure revealed that the quinolyl substrate 2a can
indeed replace one acetonitrile in a position trans to the
nitrogen of the C(sp2)-N ligand while the other acetonitrile
remains coordinated to the palladium (Figure 4). Coordination
complex 9 exists in equilibrium in CDCl3, giving a 1:0.30 ratio
with the starting materials.
In a subsequent experiment, the coordination ability of the
pyridyl ring was tested by treatment of complex 8 with enone
2b (Scheme 2, bottom right). The equilibrium was also
observed in this case, giving a 1:0.20 ratio between the
coordination product and the starting materials in the same
solvent system at the same temperature. According to an X-ray
In the bis(chloro)-C(sp2)-N dimer 6, which was used for the
coordination test, the bridging chlorides make a stronger X-
type and a weaker L-type coordination to the palladium
centers. On the basis of the findings, the quinolyl enone (2a) is
strong enough to replace the L-type chloride, but the X-type
chloride stays intact. According to the NMR measurements,
significant coordination via the carbonyl oxygen was not
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carried out in an asymmetric fashion using chiral catalysts
(Table 1). As previously reported by us, a wide range of α,β-
unsaturated ketones can be effectively transformed into the
corresponding chiral phosphine ligands, catalyzed by the
C(sp2)-P type palladacycle 5. This transformation included
the pyridyl enone derivative 2b, which successfully went
through the P−H addition with 92% enantiomeric excess and
provided the desired product in quantitative yield.19 In
accordance with this study, we started our synthesis plan
with the addition reaction under the same conditions using the
quinolyl-based enone derivative 2a. In the addition reaction
the phosphine product 3aa was produced in quantitative yield;
however, the enantioselectivity dropped drastically (ee =
52.3%) (Table 1, entry 2).
By changes in the reaction conditions, several attempts were
made to improve the stereoselectivity in the reaction, but no
increase in enantioselectivity was achieved (Table 1, entries 1−
10). The optimization study was continued by using the P-
C(sp2)-P type pincer complex 12, which was also reported by
our group previously.20
Figure 4. ORTEP structure of complex 9. All hydrogen atoms are
omitted for clarity.
For complex 5, the addition of a base was necessary for the
reaction to be completed; however, complex 12 does not
require the use of triethylamine in the transformation (Table 1,
entries 12 and 13). The reason is the presence of acetate ion,
coordinated to the palladium, which can take the role of the
internal base.
analysis, in this case both coordinated acetonitrile molecules
were replaced by the substrate, leading to N,O-chelation to the
palladium center (Figure 5). Single coordination by the
nitrogen or the oxygen was not observed under the
experimental conditions.
The amount of the catalyst was also optimized, and
according to the results, the best conditions require 10 mol
% catalyst loading (Table 1, entries 12, 14, and 15). A higher
catalyst loading of 15 mol % significantly accelerated the
reaction (2 times faster than that of with 5 mol % loading);
however, the faster transformation slightly decreased the
enantioselectivity.
Modification of the temperature revealed that the highest
enantiomeric excess can be achieved at −40 °C (Table 1,
entries 11, 14, and 16−18). In general, the choice of the lower
temperature is more advantageous in asymmetric hydro-
phosphination reactions, however in this case −60 °C was
found to be too low for the transformation in terms of
selectivity. After trying out different conditions, eventually the
usage of complex 12 with 10 mol % catalyst loading at −40 °C
in acetone gave the best overall result (Table 1, entry 17).
The desired phosphine ligand was generated after 1 h
reaction time in quantitative yield with excellent (ee = 96.6%)
enantioselectivity. After a single recrystallization from the
DCM/Et2O solvent system, the enantiomerically pure (ee >
99%) compound was observed in 76% isolated yield.
The optimization showed that substrate 2a, bearing the
quinolyl ring instead of the pyridyl moiety, acts in an entirely
different way from substrate 2b during the catalysis. We have
reported the reaction mechanism of similar hydrophosphina-
tion reactions using (R,R)-12 as the catalyst for other pyridyl-
substituted substrates.20a The aforementioned coordination
studies with the C(sp2)-N palladacycles demonstrated the
different chelating properties of these two enone derivatives,
which may be one of the reasons for the unusual performance
in the addition reaction catalyzed by complex 5. However, this
finding still does not provide an explanation for the different
behavior in the hydrophosphination reactions catalyzed by
complexes 5 and 12.
Figure 5. ORTEP structure of complex 10. All hydrogen atoms are
omitted for clarity.
Treatment of the trans-chalcone (11) with the CN-
bis(acetonitrile) complex 8 did not show any coordination at
1
ambient temperature on the basis of H NMR measurements
in CDCl3. This means that, without a stronger electron donor
atom, coordination does not take place between the substrate
and the metal.
To sum up, on the basis of these experimental studies, the
nitrogen atom in the heterocyclic ring has a crucial role in
coordination to the palladium center. Coordination via the
oxygen atom was observed only upon mixing enone 2b and
complex 8, thus generating an N,O-type chelation.
The different coordination properties of the pyridyl- and
quinolyl-based substrates were thus established in these
experiments, and on the basis of these findings, their different
performances in the palladacycle-catalyzed asymmetric hydro-
phosphination were surmised.
In order to examine this aspect, substrate 2a and complex 5
were mixed in CDCl3 in equivalent amounts and stirred for 15
min. The same experiment was carried out with 1 equiv of
In order to synthesize the tridentate pincer ligands for the
N-C(sp3)-E type complexes, the first P−H addition step was
D
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a
Table 1. Optimization of P−H Addition onto Enone 2a
b
c
entry
catalyst
solvent
T (°C)
−40
t (h)
yield (%)
ee (%)
d
1
(R)-5
(R)-5
(R)-5
(R)-5
(R)-5
(R)-5
(R)-5
(R)-5
THF
THF
20
20
20
21
20
14
22
20
20
1
1.5
1.5
1.5
1
0.5
1
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
6.3
52.3
12.3
0.5
d
2
−80
−40
−40
−80
−40
−40
−80
−80
−40
room temp
0
0
0
0
−20
−40
−60
0
d
3
MeCN
toluene
toluene
CHCl3
DCM
DCM
d
4
d
5
0
d
6
25.6
14.0
41.8
3.2
d
7
d
8
d
9
(R)-5
(R)-5
DCM/MeOH (10/1)
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
de
,
10
11
12
13
14
15
16
17
18
19
20
27.1
48.9
51.0
52.6
67.8
22.6
81.1
96.6 (>99)
84.6
28.9
(R,R)-12
(R,R)-12
(R,R)-12
(R,R)-12
(R,R)-12
(R,R)-12
(R,R)-12
(R,R)-12
(R,R)-12
(R,R)-12
d
e
f
e
e
e
1
2
20
20
99 (76)
99
acetone
CHCl3
toluene
99
99
0
−40.6
a
Reaction conditions unless specified otherwise: enone 2a (85 μmol, 1.0 equiv), HPPh2 (93.5 μmol, 1.1 equiv), catalyst (4.25 μmol, 5 mol %),
b
c
solvent (2.6 mL). The yield was calculated from 31P{1H} NMR. Isolated yields after a single recrystallization are given in parentheses. The ee was
determined by chiral HPLC. The ee values after a single recrystallization are given in parentheses. Triethylamine (85 μmol, 1.0 equiv) was added
to the reaction. In the reaction, 10 mol % of catalyst was used. In the reaction 15 mol % of catalyst was used.
d
e
f
Scheme 3. Coordination Behavior of Enone 2a with (R)-5 and (R,R)-12
complex 12 as well. According to 31P{1H} and H NMR
measurements, complex 5 and substrate 2a develop a dynamic
connection, a continuous coordination, and decoordination
between the reactants, providing different possible coordina-
tion products (Scheme 3).
hemilabile (for NMR spectra, see the Supporting Information).
1
However, mixing enone 2a and complex 12 did not show any
coordination at all, which can be explained by the steric
repulsion between the phenyl groups in the P-C(sp2)-P pincer
complex and enone 2a (Figure 6). The metal center in
compound 12 is evidently much less accessible than that in 5.
We have reported previously that catalysts (R,R)-12 and
(R)-5 operate via different reaction mechanisms.13,18b
While coordination between compound 2a and the C(sp2)-
N type complex 8 developed a well-defined equilibrium (see
above), in the case of the C(sp2)-P palladacycle (5), the
coordination is far more flexible and the chelation is fairly
E
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comparison between the new ligand synthesis route and the
previously reported systems, at first, pyridyl enone 2b was used
in the addition reaction. The generated ligand 3b was observed
with 97.4% enantiomeric excess in quantitative isolated yield
after 5 h reaction time. This result is slightly better than those
in earlier studies on this substrate.21 In order to enhance the
projection in the N-C(sp3)-E complexes, not only the quinolyl
derivatives but also the 6-Me- and 6-anisyl-substituted pyridyl
enones (2c,d) were applied in the hydrophosphination
reaction.
Figure 6. Steric repulsion between enone 2a and P-C(sp2)-P complex
12. The structure of 12 is simplified for clarity.
The former enone 2c provided the corresponding ligand 3c
in quantitative yield with high enantiomeric excess (ee =
96.6%), and the latter enone 2d was transformed into the
desired product 3d in an enantiomerically pure transformation.
In the next step, the effect of different substituents on the R2
aryl ring was tested. These modifications may also alter the
catalytic performance of the final complexes, by changing the
ring conformation in the N-C(sp3)-E pincer palladacycles.
Among the modified structures (2e−i), the 4-methoxy-
substituted compound turned out to be the most challenging
in this series. The reaction proceeded with high 95.1% yield
with a longer 30 h reaction time and the enantiomeric excess
was slightly lower at 82.1%. If the substituent was changed to
another electron-donating group, such as 4-bromo, the
reaction provided high ee and yield in 6 h.
Catalyst 5 involves an intramolecular mechanism in which
the reacting phosphine and the substrate coordinate
simultaneously on the palladium catalyst. On the other hand,
catalyst (R,R)-12 adopts an intermolecular mechanism in
which only the phosphine coordinates to the palladium during
the course of the addition reaction. The substrate chelation to
complex 5 might be one explanation for the suppressed
catalytic performance in the P−H addition reaction. Since we
did not experience such chelation with complex 12, the
transfer of the chiral information is much more effective.
On application of the optimized conditions, a series of
tridentate N-C(sp3)-E type ligands were synthesized bearing
an extended group at the N-site (Scheme 4). To make a
Scheme 4. Extension of N-C(sp3)-E Pincer Ligand Synthesis
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The presence of an electron-withdrawing group, such as a p-
trifluoromethyl substituent on the aryl ring, also did not
change the efficiency of the synthesis. A sterically more
hindered group (2-naphthyl) in the R2 position was also tested
in the addition reaction onto enone 2i, and the transformation
was complete, giving similar results. Altering the position of the
N donor atom on the aryl ring also did not cause any
drawbacks to the reaction; the corresponding phosphine 3j was
observed with excellent selectivity and yield within a short
reaction time.
improved by extending the reaction time or by adding an
additional amount of base (Table 2, entry 7).
The structure and the absolute stereochemistry of (R,R)-4aa
in the solid state was confirmed by single-crystal X-ray
crystallographic analysis (Figure 7). The obtained structure
On the basis of our findings, the new synthesis system has a
very high tolerance toward substrate modifications. Overall, all
of the tridentate ligands were produced in a short reaction (less
than 6 h) in quantitative or nearly quantitative yield (97−
99%), with good to excellent enantiomeric excesses (ee =
82.1% to ee > 99%). It is worth mentioning that, after a single
recrystallization, the enantiomerically pure ligands 3aa,c,g−i
were observed in good (up to 82%) yield.
Asymmetric hydrophosphination is an extraordinary tool to
generate the chiral phosphine ligands in a single step with high
atom economy. This transformation makes our synthetic plan
certainly powerful. After the first stereocenter is generated in
this addition step, the second step is the cyclometalation of the
tridentate ligand.
Figure 7. ORTEP structure of (R,R)-4aa. Hydrogen atoms are
omitted from the structure for clarity (except on chiral carbons).
revealed that the C1−C12−P1−S1 chelate adopted the λ
conformation with the C-Ph group occupying the sterically less
favorable axial position. One of the explanations for this aspect
may be the possible steric repulsion between the C-Ph and the
P-Ph(eq) units. It needs to be noted that, while the first
stereocenter is generated via the asymmetric hydrophosphina-
tion, during cyclometalation a second chiral center is created in
a diastereoselective manner.
During the optimization process of the metalation step,
various solvents and palladium sources were tried out (Table
2). The best palladium source was found to be Li2PdCl4 in a
On application of the optimal conditions, several new N-
C(sp3)-E complexes were synthesized with enhanced steric
projection at the N site (Scheme 5). To test the extent of the
a
Table 2. Optimization of Cyclometalation of (S)-3aa
Scheme 5. Synthesis of Stereoprojecting N-C(sp3)-E
Complexes
yield
(%)
entry
palladium source
solvent
t
1
2
3
4
5
Li2PdCl4
Li2PdCl4
Li2PdCl4
Li2PdCl4
K2PdCl4
PdCl2(MeCN)2
Pd(MeCN)4(ClO4)2 MeCN
Li2PdCl4
Li2PdCl4
DCM
MeOH
acetone
MeOH/CHCl3 (2/1) 40 h
MeOH/CHCl3 (2/1) 40 h
DCM
40 h
40 h
40 h
23
26
21
40
25
33
45
44
72
b
6
7
40 h
2 h
c
8
9
MeOH/CHCl3 (2/1) 5 days
MeOH/CHCl3 (2/1) 5 days
d
a
Reaction conditions: ligand (S)-3aa (42 μmol, 1.0 equiv), reagent
b
(42 μmol, 1.0 equiv), solvent (20 mL), room temperature. NaOAc
(42 μmol, 1.0 equiv) was added to the reaction mixture. After
c
completion of the metalation, LiCl (42 μmol, 1.0 equiv) was added to
d
the reaction mixture. Triethylamine (42 μmol, 1.0 equiv) was added
to the reaction mixture.
methanol/chloroform (2/1) solvent mixture, which gave a
moderate 40% isolated yield after 40 h at ambient temperature.
Under the same conditions, a longer reaction time did not
improve the conversion significantly (Table 2, entries 4 and 8).
However, if 1 equiv of triethylamine was introduced to the
system, the yield increased to 72% after a reaction time of 5
days (Table 2, entry 9). Applying Pd(MeCN)4(ClO4)2 as a
metal source accelerated the reaction, and after 2 h the isolated
yield was 45%. However, this result could not be further
synthetic route, the N-C(sp3)-O derivative of the quinolyl
ligand 3ab was also successfully utilized in the cyclometalation
reaction, giving 70% yield in the reaction. The N-C(sp3)-S type
ligand bearing the 6-methylpyridyl ring 3c provided the final
complex with a slightly lower isolated yield (63%); however,
the generation of the 6-anisylpyridyl complex 4da was found to
be even more difficult. In the test reactions, different
modifications on the aryl group, connected to the carbon
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Figure 8. Explanation of diastereoselectivity in cyclometalation.
next to phosphorus, were also performed by introducing 4-
CF3-phenyl and naphthyl groups in the ligands 3h,i. These
reactions were carried out in a shorter time and generated the
desired complexes in moderate to good yields. In all syntheses,
the applied pincer ligands were used in their enantiomerically
pure form and the transformation provided only one of the
possible diastereomers without loss of enantiopurity.
On the basis of the experimental results, if the generated N-
C(sp3)-E type ligands are enantiomerically pure, the
diastereoselective metalation step provides the optically pure
complexes without the loss of chiral purity. The diaster-
eoselectivity can be explained by steric effects during the
metalation process (Figure 8). The chiral phosphine ligands in
solution may exist as different conformers (A and B). Due to
the steric repulsion between the phenyl group on C1 and the
oxygen of the carbonyl group, the bond between C1 and C2
may undergo rotation to develop the sterically more favorable
conformer B. In the cyclometalation step, as a result of the
Pd−C σ-bond formation and the rotation between C3 and the
quinolyl ring, two five-membered palladacycle rings are
generated. Since the stereochemistry of the ligand is fixed,
after metalation, one stereocenter out of two is always fixed,
corresponding to the chirality on C1. In other words, when the
synthesis is started with the S ligand, the possible
diastereomers have the R,X general chirality (R defines the
stereochemistry on C1 and X belongs to C2, which can be
either R or S). Considering the structure of the two possible
diastereomers R,R or R,S, complex 4 with the same
configuration on C1 and C2 chiral centers has a much more
favorable orientation, in comparison to that having alternate
stereochemistry. On the basis of experimental results, the R,S
diastereomer is not generated during the syntheses.
If the metalation step was carried out by using the phosphine
sulfide ligand (R)-3 with the opposite chirality, the obtained
N-C(sp3)-E complex acquired the reverse S,S stereochemistry.
The transformation of (R)-3ab to (S,S)-4ab established the
simple switch between the different enantiomers. The X-ray
structure of (S,S)-4ab confirmed the structure and the chirality
(Figure 9). In this case, the C11−C12−P1−O1 chelate
developed the δ conformation, once again with the C-Ph
moiety located in the unexpected axial position.
The result of the cyclometalation is the generation of two
slightly distorted square planar palladacycle rings. The
metalation of ligand 3j, bearing a 3-quinolyl ring instead of
the 2-quinolyl moiety, could provide the formation of a six-
membered palladacycle ring, on the basis of the structural
features. However, even after trying different palladium
sources, such a transformation was not observed.
Figure 9. ORTEP structure of (S,S)-4ab. Hydrogens are omitted
from the structure for clarity (except on chiral carbons).
The tridentate pincer backbone provides extraordinary
stability to the generated N-C(sp3)-E complexes. Complex
4aa was dissolved and heated to reflux temperature in toluene
for more than 10 h without any observed thermal
decomposition.
If we consider the stereochemical stability, it is known in the
literature that aliphatic C(sp3)-type pincer complexes can
undergo α-hydrogen abstraction, which results in the
formation of palladium carbene complexes,22 as well as α- or
β-H elimination.1b,d−f,l,j These transformations could result in
racemization in our case (since the two chiral centers in the
final complexes are located exactly in the positions α and β to
the palladium center), if a reversible elimination/insertion or
abstraction/C−H bond activation would occur. In order to
examine this possibility, the optical rotation of the final
complexes was monitored over a 2 week period, and no such
process was observed. As a result of a reversible α- or β-H
elimination, the possible generation of the other diastereomer,
with the alternate chirality, could take place. In a test of the
stability of pure (R,R)-4aa in this regard, the 31P{1H} NMR
was monitored over a period of 1 month with once again no
formation of the other R,S diastereomer.
CONCLUSIONS
■
In conclusion, an effective and extensive synthetic method-
ology was demonstrated to produce new, stereoprojecting N-
C(sp3)-E complexes. The first step of our strategy, the catalytic
asymmetric hydrophosphination reaction, was carried out on
the more challenging, N-chelating substrates, giving the desired
chiral phosphine ligands in quantitative yield with up to ee >
99%. The N-chelating effect was examined by coordination
studies on C(sp2)-N, C(sp2)-P, and P-C(sp2)-P palladacycles.
The different chelation properties between the 2b pyridyl and
H
DOI: 10.1021/acs.organomet.8b00262
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(S)-3-(Diphenylphosphorothioyl)-3-phenyl-1-(quinolin-2-yl)-
2a quinolyl enones were established, as well as the different
performances in catalytic asymmetric hydrophosphination,
leading to the reported 3b and the new 3a chiral ligands.
The complexation of the new N-C(sp3)-E type tridentate
ligands was also discussed, and all of the generated complexes
bear a sterically enhanced group at the N site of the
compound. This enhanced stereoprojection may alter the
catalytic performance of the N-C(sp3)-E compounds, and
studies on this aspect are currently in progress. Overall, the
newly developed synthetic pathway allows us to perform easy
structural modifications on the enantiomerically pure chiral
complexes, within a relatively fast, selective transformation,
without the need for time-consuming and wasteful resolution.
propan-1-one ((S)-3aa). White solid material was produced in 99%
20
yield and ee = 96.6%. [α]D = −230 (c 0.5, CH2Cl2) for ee > 99%.
Mp: 203.5−204.0 °C. 31P{1H} NMR (162 MHz, CDCl3): δ 51.52 (s,
1
1P). H NMR (400 MHz, CDCl3): δ 8.32−8.22 (m, 3H, ArH), 8.16
(d, J = 8.5 Hz, 1H, ArH), 7.91 (d, J = 8.5 Hz, 1H, ArH), 7.83−7.78
(m, 2H, ArH), 7.64 (t, J = 7.3 Hz, 1H, ArH), 7.58−7.49 (m, 4H,
ArH), 7.36−7.20 (m, 6H, ArH), 7.08 (s, 3H, ArH), 4.94 (td, J = 10.7,
2.0 Hz, 1H, PCHCH2), 4.73−4.59 (m, 1H, C(O)CH2), 3.66 (ddd, J =
17.6, 11.1, 2.2 Hz, 1H, C(O)CH2). 13C NMR (101 MHz, CDCl3): δ
199.38 (d, J = 15.5 Hz, 1C, CO), 152.59−118.32 (27C, Ar), 42.56
1
2
(d, JPC = 52.4 Hz, 1C, PCH), 38.83 (d, JPC = 3.5 Hz, 1C, C(O)
CH2). Anal. Calcd for C30H24NOPS: C, 75.45; H, 5.07; N, 2.93.
Found: C, 75.31; H, 4.93; N, 2.81. HRMS (+ESI) m/z: (M + H)+
calcd for C30H25NOPS, 478.1394; found, 478.1389.
(S)-3-(Diphenylphosphoryl)-3-phenyl-1-(quinolin-2-yl)propan-1-
one ((S)-3ab). White solid material was produced in 99% yield and ee
EXPERIMENTAL SECTION
■
20
= 96.6%. [α]D = −121 (c 0.5, CH2Cl2) for ee > 99%. Mp: 172.0−
All air-sensitive manipulations were carried out under a positive
pressure of nitrogen using Schlenk techniques. Solvents were degassed
prior to use. Solvents were obtained from the following sources:
chloroform (AR), acetonitrile (AR), methanol (AR), dichloro-
methane (HPLC), acetone (AR), ethyl acetate (AR), and n-hexane
(HPLC) VWR; 2-propanol (HPLC), n-hexane (AR), and toluene
(AR) from Avantor; diethyl ether (AR) from Fischer Scientific; THF
from TEDIA Co. THF was distilled from sodium/benzophenone
before use. NMR spectra were recorded on Bruker AV 300, AV 400,
AV 500, and BBFO 400 spectrometers. Chemical shifts are reported
in ppm and referenced to an internal SiMe4 standard (0 ppm) for 1H
NMR, chloroform-d (77.22 ppm) for 13C NMR, and external 85%
H3PO4 for 31P{1H} NMR. A PSL-1800 Low Temp Pairstirrer was
used for low-temperature reactions. Column chromatography was
performed with silica gel 60 (purchased from Merck). Melting points
were measured using the SRS Optimelt Automated Point System SRS
MPA100. Elemental analysis was performed on the EuroVector Euro
EA elemental analyzer. In case if elemental analysis measurements
were not performed, the purity was determined by other measure-
ments stated below. HRMS using electrospray ionization (ESI) was
performed on the Waters Q-Tof Premier spectrometer. Optical
rotations were examined with the JASCO P-1030 polarimeter in
DCM in a 0.1 dm cell at the specified temperatures. The
enantioselectivities of the asymmetric hydrophosphination reactions
were determined with an Agilent 1200 Series HPLC machine fitted
with the specified Daicel Chiralpak columns with an n-hexane/2-
propanol mixture as eluent at 23 °C.
173.0 °C (dec). 31P{1H} NMR (162 MHz, CDCl3): δ 34.04 (s, 1P).
1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.4 Hz, 1H, ArH), 8.16
(d, J = 8.5 Hz, 1H, ArH), 8.09−8.01 (m, 2H, ArH), 7.92 (d, J = 8.5
Hz, 1H, ArH), 7.83−7.75 (m, 2H, ArH), 7.63 (t, J = 7.4 Hz, 1H,
ArH), 7.56−7.44 (m, 5H, ArH), 7.39−7.32 (m, 3H, ArH), 7.29−7.22
(m, 2H, ArH), 7.16−7.04 (m, 3H, ArH), 4.69−4.57 (m, 1H,
PCHCH2), 4.54−4.48 (m, 1H, C(O)CH2), 3.71 (ddd, J = 17.9, 10.7,
2.4 Hz, 1H, C(O)CH2). 13C NMR (101 MHz, CDCl3): δ 199.33 (d, J
1
= 13.7 Hz, 1C, CO), 151.82−118.22 (27C, Ar), 41.49 (d, JPC
=
77.3 Hz, 1C, PCH), 38.26 (s, 1C, C(O)CH2). Anal. Calcd for
C30H24NO2P: C, 78.08; H, 5.24; N, 3.04. Found: C, 78.27; H, 5.35;
N, 3.24. HRMS (+ESI) m/z: (M + H)+ calcd for C30H25NO2P,
462.1623; found, 462.1625.
(S)-3-(Diphenylphosphorothioyl)-3-phenyl-1-(pyridin-2-yl)-
propan-1-one ((S)-3b). White solid material was produced in 99%
yield and ee = 97.4%. The obtained characterization data were
consistent with the literature report.12b [α]D = −241 (c 0.1,
20
CH2Cl2) for ee > 99%. Mp: 94.0−96.0 °C. 31P{1H} NMR (CDCl3,
162 MHz): δ 51.5 (s, 1P). 1H NMR (CDCl3, 400 MHz): δ 8.63−8.61
(m, 1H, ArH), 8.23−8.18 (m, 2H, ArH), 7.80 (d, 1H, J = 7.8 Hz,
ArH), 7.68 (td, 1H, J = 7.7 Hz, J = 1.7 Hz, ArH), 7.54−7.49 (m, 5H,
ArH), 7.39−7.35 (m, 1H, ArH), 7.33−7.25 (m, 3H, ArH), 7.23−7.19
(m, 2H, ArH), 7.08−7.05 (m, 3H, ArH), 4.87 (td, 1H, J = 10.6 Hz, J
= 2.6 Hz, PCHCH2), 4.51 (ddd, 1H, J = 18.2 Hz, J = 10.9 Hz, J = 6.2
Hz, C(O)CH2), 3.51 (ddd, 1H, J = 18.4 Hz, J = 11.6 Hz, J = 2.7 Hz,
C(O)CH2). 13C NMR (CDCl3, 100 MHz): δ 198.8 (d, J = 15.1 Hz,
1
1C, CO), 152.9−121.8 (23C, Ar), 42.1 (d, JPC = 52.9 Hz, 1C,
(R)-C(sp2)-P complex 5,5c,9c C(sp2)-N achiral palladacycles 623
and 8,24 and (R,R)-P-C(sp2)-P pincer complex 1220 were prepared
according to literature methods. The N-chelating chalcone derivatives
2 were prepared according to modified literature procedures25 (for
details see the Supporting Information). All other reactants and
reagents were used as supplied without further purification unless
stated otherwise.
PCH), 38.6 (s, 1C, C(O)CH2). Anal. Calcd for C26H22NOPS: C,
73.05; H, 5.19; N, 3.28. Found: C, 72.87; H, 5.02; N, 3.60. HRMS
(+ESI) m/z: (M + H)+ calcd for C26H23NOPS, 428.1238; found,
428.1235.
(S)-3-(Diphenylphosphorothioyl)-1-(6-methylpyridin-2-yl)-3-phe-
nylpropan-1-one ((S)-3c). White solid material was produced in 99%
20
yield and ee = 96.6%. [α]D = −245 (c 1.0, CH2Cl2) for ee > 99%.
Typical Experimental Procedure of N-C(sp3)-E Pincer Ligand
Synthesis via Asymmetric Hydrophosphination. A nitrogen-
flushed two-neck flask was charged with diphenylphosphine (17.4 mg,
93.5 μmol, 1.1 equiv) and degassed solvent (2 mL) at room
temperature, followed by the addition of (R)-5 (2.7 mg, 4.25 μmol, 5
mol %) or (R,R)-12 catalyst (7.6 mg, 8.5 μmol, 10 mol %). The setup
was brought to −40 °C and the mixture stirred for 10 min before
introducing enone 2 (85 μmol, 1.0 equiv). In case of the (R)-5-
catalyzed reactions, triethylamine (8.6 mg, 85 μmol, 1.0 equiv),
dissolved in 0.5 mL of degassed solvent, was added dropwise to the
mixture. The reaction mixture was stirred at low temperature and
monitored by 31P{1H} NMR. Upon completion, H2O2 (31% w/w, 0.1
mL) or S8 (10.9 mg, 42.5 μmol, 0.5 equiv) was placed in the flask and
the reaction mixture was warmed to room temperature and stirred for
30 min. Evaporation of the solvent under reduced pressure generated
a crude mixture, which was purified by silica gel column
chromatography, with an n-hexane/EtOAc (97/3 to 70/30) solvent
system as eluent.
Mp: 144.0−146.0 °C. 31P{1H} NMR (CDCl3, 162 MHz): δ 51.59 (s,
1
1P). H NMR (400 MHz, CDCl3): δ 8.27−8.18 (m, 2H, ArH), 7.60
(d, J = 7.6 Hz, 1H, ArH), 7.57−7.45 (m, 6H, ArH), 7.33−7.24 (m,
3H, ArH), 7.24−7.14 (m, 3H, ArH), 7.10−7.01 (m, 3H, ArH), 4.91
(td, J = 10.7 Hz, J = 2.3 Hz, 1H, PCHCH2), 4.46 (ddd, J = 17.5, 11.0,
6.1 Hz, 1H, C(O)CH2), 3.50 (ddd, J = 17.7, 11.4, 2.1 Hz, 1H,
C(O)CH2), 2.58 (s, 3H, ArCH3). 13C NMR (101 MHz, CDCl3): δ
199.00 (d, J = 15.5 Hz, 1C, CO), 158.09−119.01 (23C, Ar), 42.17
1
2
(d, JPC = 52.5 Hz, 1C, PCH), 38.84 (d, JPC = 3.4 Hz, 1C, C(O)
CH2), 24.44 (s, 1C, ArCH3). Anal. Calcd for C27H24NOPS: C, 73.45;
H, 5.48; N, 3.17. Found: C, 73.76; H, 5.84; N, 3.30. HRMS (+ESI)
m/z: (M + H)+ calcd for C27H25NOPS, 442.1394; found, 442.1390.
(S)-3-(Diphenylphosphorothioyl)-1-(6-(4-methoxyphenyl)-
pyridin-2-yl)-3-phenylpropan-1-one ((S)-3d). White solid material
20
was produced in 98% yield and ee > 99%. [α]D = −259 (c 0.5,
CH2Cl2) for ee > 99%. Mp: 210.8−211.2 °C. 31P{1H} NMR (CDCl3,
1
162 MHz): δ 51.38 (s, 1P). H NMR (400 MHz, CDCl3): δ 8.18
(ddd, J = 12.0, 7.5, 1.9 Hz, 2H, ArH), 8.04 (d, J = 8.8 Hz, 2H, ArH),
I
DOI: 10.1021/acs.organomet.8b00262
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
7.79 (dd, J = 7.7, 1.2 Hz, 1H, ArH), 7.76−7.65 (m, 2H, ArH), 7.58−
7.43 (m, 5H, ArH), 7.37−7.27 (m, 3H, ArH), 7.27−7.19 (m, 2H,
ArH), 7.13−7.02 (m, 5H, ArH), 4.89 (td, J = 10.5, 2.8 Hz, 1H,
PCHCH2), 4.64 (ddd, J = 17.6, 10.8, 6.5 Hz, 1H, C(O)CH2), 3.90 (s,
3H, OCH3), 3.58 (ddd, J = 18.2, 11.6, 2.8 Hz, 1H, C(O)CH2). 13C
NMR (101 MHz, CDCl3): δ 199.46 (d, J = 14.9 Hz, 1C, CO),
161.14−114.53 (29C, Ar), 55.64 (s, 1C, OCH3), 42.43 (d, 1JPC = 52.5
2H, ArH), 4.99 (td, J = 10.9, 2.4 Hz, 1H, PCHCH2), 4.70 (ddd, J =
17.6, 11.2, 6.0 Hz, 1H, C(O)CH2), 3.65 (ddd, J = 18.1, 11.0, 2.5 Hz,
1H, C(O)CH2). 13C NMR (101 MHz, CDCl3): δ 199.08 (d, J = 15.2
1
Hz, 1C, CO), 152.31−118.22 (28C, Ar + CF3), 42.51 (d, JPC
=
2
51.9 Hz, 1C, PCH), 38.62 (d, JPC = 3.1 Hz, 1H, C(O)CH2). Anal.
Calcd for C31H23NOPSF3: C, 68.25; H, 4.25; N, 2.57. Found: C,
68.12; H, 4.19; N, 2.44. HRMS (+ESI) m/z: (M + H)+ calcd for
C31H24NOPSF3, 546.1268; found, 546.1267.
2
Hz, 1C, PCH), 38.70 (d, JPC = 3.6 Hz, 1C, C(O)CH2). Anal. Calcd
for C33H28NO2PS: C, 74.28; H, 5.29; N, 2.62. Found: C, 74.06; H,
5.11; N, 2.40. HRMS (+ESI) m/z: (M + H)+ calcd for C33H29NO2PS,
534.1657; found, 534.1652.
(S)-3-(Diphenylphosphorothioyl)-3-(naphthalen-2-yl)-1-(quino-
lin-2-yl)propan-1-one ((S)-3i). White solid material was produced in
20
98% yield and ee = 94.3%. [α]D = −294 (c 1.0, CH2Cl2) for ee >
99%. Mp: 208.0−210.0 °C (dec). 31P{1H} NMR (CDCl3, 162 MHz):
(S)-3-(Diphenylphosphorothioyl)-1-(quinolin-2-yl)-3-(p-tolyl)-
propan-1-one ((S)-3e). White solid material was produced in 98%
yield and ee = 86.7%. [α]D20 = −273 (c 1.0, CH2Cl2) for ee = 86.7%.
Mp: 167.6−168.0 °C. 31P{1H} NMR (CDCl3, 162 MHz): δ 51.37 (s,
1
δ 51.24 (s, 1P). H NMR (400 MHz, CDCl3): δ 8.35−8.24 (m, 3H,
ArH), 8.12 (d, J = 8.5 Hz, 1H, ArH), 7.86 (d, J = 8.5 Hz, 1H, ArH),
7.83−7.77 (m, 2H, ArH), 7.74 (s, 1H, ArH), 7.69−7.59 (m, 3H,
ArH), 7.58−7.49 (m, 6H, ArH), 7.41 (d, J = 8.5 Hz, 1H, ArH), 7.38−
7.32 (m, 2H, ArH), 7.32−7.26 (m, 1H, ArH), 7.17 (td, J = 7.6, 3.1
Hz, 2H, ArH), 5.11 (td, J = 10.8, 2.7 Hz, 1H, PCHCH2), 4.79 (ddd, J
= 17.6, 11.1, 6.2 Hz, 1H, C(O)CH2), 3.74 (ddd, J = 18.0, 11.0, 2.7
Hz, 1H, C(O)CH2). 13C NMR (101 MHz, CDCl3): δ 199.33 (d, J =
15.5 Hz, 1C, CO), 152.52−118.28 (31C, Ar), 42.77 (d, 1JPC = 52.3
1
1P). H NMR (400 MHz, CDCl3): δ 8.31−8.20 (m, 3H, ArH), 8.15
(d, J = 8.5 Hz, 1H, ArH), 7.90 (d, J = 8.5 Hz, 1H, ArH), 7.84−7.76
(m, 2H, ArH), 7.66−7.60 (m, 1H, ArH), 7.60−7.50 (m, 5H, ArH),
7.34 (td, J = 7.2, 1.6 Hz, 1H, ArH), 7.29−7.20 (m, 2H, ArH), 7.16
(dd, J = 8.2, 2.1 Hz, 2H, ArH), 6.87 (d, J = 8.0 Hz, 2H, ArH), 4.92
(td, J = 10.8, 2.7 Hz, 1H, PCHCH2), 4.62 (ddd, J = 17.6, 11.1, 6.3 Hz,
1H, C(O)CH2), 3.64 (ddd, J = 17.9, 11.1, 2.7 Hz, 1H, C(O)CH2),
2.18 (d, J = 1.8 Hz, 3H, ArCH3). 13C NMR (101 MHz, CDCl3): δ
199.43 (d, J = 16.2 Hz, 1C, CO), 152.60−118.33 (27C, Ar), 42.16
2
Hz, 1C, PCH), 38.88 (d, JPC = 3.5 Hz, 1C, C(O)CH2). Anal. Calcd
for C34H26NOPS: C, 77.40; H, 4.97; N, 2.65. Found: C, 77.45; H,
5.13; N, 2.76. HRMS (+ESI) m/z: (M + H)+ calcd for C34H27NOPS,
528.1551; found, 528.1552.
1
2
(d, JPC = 52.5 Hz, 1C, PCH), 38.78 (d, JPC = 4.0 Hz, 1C, C(O)
CH2), 21.22 (s, 1C, ArCH3). Anal. Calcd for C31H26NOPS: C, 75.74;
H, 5.33; N, 2.85. Found: C, 75.93; H, 5.64; N, 3.02. HRMS (+ESI)
m/z: (M + H)+ calcd for C31H27NOPS, 492.1551; found, 492.1554.
(S)-3-(Diphenylphosphorothioyl)-3-(4-methoxyphenyl)-1-(quino-
lin-2-yl)propan-1-one ((S)-3f). White solid material was produced in
95.1% yield and ee = 86.7%. [α]D20 = −225 (c 0.5, CH2Cl2) for ee =
82.1%. Mp: 137.6−138.0 °C. 31P{1H} NMR (CDCl3, 162 MHz): δ
(S)-3-(Diphenylphosphorothioyl)-3-phenyl-1-(quinolin-3-yl)-
propan-1-one ((S)-3j). White solid material was produced in 99%
yield and ee = 95.2%. [α]D20 = −268 (c 1.0, CH2Cl2) for ee = 95.2%.
Mp: 194.6−195.0 °C. 31P{1H} NMR (CDCl3, 121 MHz): δ 51.67 (s,
1
1P). H NMR (300 MHz, CDCl3): δ 9.28 (d, J = 2.2 Hz, 1H, ArH),
8.63 (d, J = 2.0 Hz, 1H, ArH), 8.25−8.14 (m, 2H, ArH), 8.10 (d, J =
8.5 Hz, 1H, ArH), 7.90 (d, J = 8.2 Hz, 1H, ArH), 7.86−7.75 (m, 1H,
ArH), 7.65−7.57 (m, 1H, ArH), 7.57−7.46 (m, 5H, ArH), 7.40−7.30
(m, 3H, ArH), 7.29−7.19 (m, 2H, ArH), 7.16−7.06 (m, 3H, ArH),
4.90 (td, J = 10.0, 2.8 Hz, 1H, PCHCH2), 4.20 (ddd, J = 17.9, 10.1,
6.2 Hz, 1H, C(O)CH2), 3.49 (ddd, J = 18.0, 12.1, 2.8 Hz, 1H,
C(O)CH2). 13C NMR (75 MHz, CDCl3): δ 196.05 (d, J = 14.6 Hz,
1C, CO), 150.00−126.77 (27C, Ar), 41.69 (d, 1JPC = 52.9 Hz, 1C,
1
51.27 (s, 1P). H NMR (400 MHz, CDCl3): δ 8.32−8.22 (m, 3H,
ArH), 8.16 (d, J = 8.5 Hz, 1H, ArH), 7.91 (d, J = 8.5 Hz, 1H, ArH),
7.85−7.76 (m, 2H, ArH), 7.64 (t, J = 7.5 Hz, 1H, ArH), 7.59−7.50
(m, 5H, ArH), 7.34 (td, J = 7.0, 1.2 Hz, 1H, ArH), 7.29−7.26 (m, 1H,
ArH), 7.25−7.22 (m, 1H, ArH), 7.19 (dd, J = 8.8, 2.2 Hz, 2H, ArH),
6.61 (d, J = 8.6 Hz, 2H, ArH), 4.90 (td, J = 11.1, 2.6 Hz, 1H,
PCHCH2), 4.60 (ddd, J = 17.6, 11.2, 6.3 Hz, 1H, C(O)CH2), 3.67 (s,
3H, OCH3), 3.61 (ddd, J = 17.7, 10.7, 2.7 Hz, 1H, C(O)CH2). 13C
NMR (101 MHz, CDCl3): δ 199.52 (d, J = 15.8 Hz, 1C, CO),
159.03−113.40 (27C, Ar), 55.26 (s, 1C, OCH3), 41.81 (d, 1JPC = 53.0
Hz, 1C, PCH), 38.83 (d, 2JPC = 4.1 Hz, 1C, C(O)CH2). Anal. Calcd
for C31H26NO2PS: C, 73.35; H, 5.16; N, 2.76. Found: C, 73.27; H,
5.09; N, 2.62. HRMS (+ESI) m/z: (M + H)+ calcd for C31H27NO2PS,
508.1500; found, 508.1495.
2
PCH), 40.03 (d, JPC = 3.9 Hz, 1C, C(O)CH2). Anal. Calcd for
C30H24NOPS: C, 75.45; H, 5.07; N, 2.93. Found: C, 75.22; H, 4.93;
N, 2.88. HRMS (+ESI) m/z: (M + H)+ calcd for C30H25NOPS,
478.1394; found, 478.1393.
Typical Experimental Procedure of N-C(sp3)-E Complex
Synthesis via Cyclometalation of Ligand 3. A mixture of PdCl2
(7.4 mg, 42 μmol, 1.0 equiv) and LiCl (7.1 mg, 168 μmol, 4.0 equiv)
in 20 mL of solvent was stirred for 30 min. Then, the ligand (S)-3 (42
μmol, 1.0 equiv) was added and this mixture was stirred at room
temperature for 2−5 days. The reaction was monitored by thin-layer
chromatography (ethyl acetate/n-hexanes 2/1) and confirmed by
31P{1H} NMR. After completion the solvent was removed under
(S)-3-(4-Bromophenyl)-3-(diphenylphosphorothioyl)-1-(quino-
lin-2-yl)propan-1-one ((S)-3g). White material was produced in 98%
20
yield and ee = 95.6%. [α]D = −291 (c 1.0, CH2Cl2) for ee > 99%.
Mp: 203.5−204.0 °C. 31P{1H} NMR (CDCl3, 162 MHz): δ 50.93 (s,
1
1P). H NMR (400 MHz, CDCl3): δ 8.31−8.20 (m, 3H, ArH), 8.17
reduced pressure and the crude material was purified via column
chromatograpy by using an n-hexane/ethyl acetate (from 80/20 to
20/80) eluent system.
(d, J = 8.5 Hz, 1H, ArH), 7.91 (d, J = 8.5 Hz, 1H, ArH), 7.84−7.75
(m, 2H, ArH), 7.68−7.61 (m, 1H, ArH), 7.61−7.50 (m, 5H, ArH),
7.41−7.33 (m, 1H, ArH), 7.33−7.23 (m, 2H, ArH), 7.23−7.12 (m,
4H, ArH), 4.90 (td, J = 11.0, 2.6 Hz, 1H, PCHCH2), 4.62 (ddd, J =
17.6, 11.2, 6.1 Hz, 1H, C(O)CH2), 3.61 (ddd, J = 17.9, 10.7, 2.7 Hz,
1H, C(O)CH2). 13C NMR (101 MHz, CDCl3): δ 199.20 (d, J = 15.4
Hz, 1C, CO), 152.39−118.25 (27C, Ar), 42.10 (d, 1JPC = 52.4 Hz,
((1R,2R)-1-(Diphenylphosphorothioyl)-3-oxo-1-phenyl-3-(quino-
lin-2-yl)propan-2-yl)palladium(II) Chloride ((R,R)-4aa). Yellow solid
20
material was produced in 72% yield. [α]D = −90 (c 1.0, CH2Cl2).
Mp: 214.2−215.5 °C (dec). 31P{1H} NMR (CDCl3, 162 MHz): δ
1
2
67.23 (s, 1P). H NMR (400 MHz, CDCl3): δ 9.47 (d, J = 8.8 Hz,
1C, PCH), 38.61 (d, JPC = 3.4 Hz, 1C, C(O)CH2). Anal. Calcd for
1H, ArH), 8.37 (d, J = 8.3 Hz, 1H, ArH), 7.97−7.88 (m, 3H, ArH),
7.85 (d, J = 7.8 Hz, 1H, ArH), 7.76 (d, J = 8.3 Hz, 1H, ArH), 7.71−
7.62 (m, 4H, ArH), 7.62−7.51 (m, 3H, ArH), 7.42 (td, J = 7.8, 3.3
Hz, 2H, ArH), 7.25−7.19 (m, 1H, ArH), 7.15 (t, J = 7.6 Hz, 2H,
ArH), 7.02 (d, J = 7.4 Hz, 2H, ArH), 5.34 (dd, J = 14.8, 8.8 Hz, 1H,
PCH), 4.96 (dd, J = 8.7, 6.1 Hz, 1H, PdCH). 13C NMR (101 MHz,
CDCl3): δ 189.15 (d, J = 14.6 Hz, 1C, CO), 158.23−118.33 (27C,
C30H23NOPSBr: C, 64.75; H, 4.17; N, 2.52. Found: C, 64.90; H,
4.39; N, 2.77. HRMS (+ESI) m/z: (M + H)+ calcd for
C30H24NOPSBr, 556.0500; found, 556.0493.
(S)-3-(Diphenylphosphorothioyl)-1-(quinolin-2-yl)-3-(4-
(trifluoromethyl)phenyl)propan-1-one ((S)-3h). White solid material
20
was produced in 97% yield and ee = 94.6%. [α]D = −226 (c 1.0,
CH2Cl2) for ee > 99%. Mp: 121.9−122.6 °C. 31P{1H} NMR (CDCl3,
2
1
1
Ar), 57.53 (d, JPC = 5.9 Hz, 1C, PdCH), 53.37 (d, JPC = 58.8 Hz,
1C, PCH). Anal. Calcd for C30H23NOPPdSCl: C, 58.27; H, 3.75; N,
2.26. Found: C, 58.04; H, 3.65; N, 2.41. HRMS (+ESI) m/z: (M +
H)+ calcd for C30H24NOP108PdSCl, 620.0044; found, 620.0032.
162 MHz): δ 51.27 (s, 1P). H NMR (400 MHz, CDCl3): δ 8.32−
8.21 (m, 3H, ArH), 8.17 (d, J = 8.5 Hz, 1H, ArH), 7.91 (d, J = 8.5 Hz,
1H, ArH), 7.88−7.74 (m, 2H, ArH), 7.64 (t, J = 7.5 Hz, 1H, ArH),
7.61−7.48 (m, 5H, ArH), 7.45−7.30 (m, 5H, ArH), 7.30−7.19 (m,
J
DOI: 10.1021/acs.organomet.8b00262
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
((1R,2R)-1-(Diphenylphosphoryl)-3-oxo-1-phenyl-3-(quinolin-2-
(t, J = 7.6 Hz, 1H, ArH), 7.66−7.62 (m, 2H, ArH), 7.61−7.51 (m,
4H, ArH), 7.47−7.37 (m, 4H, ArH), 7.34 (s, 1H, ArH), 7.15 (d, J =
8.5 Hz, 1H, ArH), 5.51 (dd, J = 15.3, 9.3 Hz, 1H, PCH), 5.06 (dd, J =
yl)propan-2-yl)palladium(II) Chloride ((R,R)-4ab). Yellow solid
20
material was produced in 70% yield. [α]D = −117 (c 1.0,
CH2Cl2). Mp: 179.0−180.0 °C (dec). 31P{1H} NMR (CDCl3, 162
9.3, 5.4 Hz, 1H, PdCH). 13C NMR (126 MHz, CDCl3): δ 189.11 (d,
1
2
MHz): δ 73.24 (s, 1P). H NMR (400 MHz, CDCl3): δ 9.44 (d, J =
J = 15.5 Hz, 1C, CO), 158.22−118.38 (31C, Ar), 57.97 (d, JPC
=
6.3 Hz, 1C, PdCH), 54.04 (d, 1JPC = 59.0 Hz, PCH). Anal. Calcd for
C34H25NOPPdSCl: C, 61.09; H, 3.77; N, 2.10. Found: C, 61.36; H,
3.90; N, 2.24. HRMS (+ESI) m/z: (M + H)+ calcd for
C34H26NOP106PdSCl, 668.0196; found, 668.0215.
8.8 Hz, 1H, ArH), 8.36 (d, J = 8.3 Hz, 1H, ArH), 8.01 (dd, J = 11.2,
7.9 Hz, 2H, ArH), 7.91 (t, J = 7.7 Hz, 1H, ArH), 7.81 (d, J = 8.0 Hz,
1H, ArH), 7.72−7.48 (m, 8H, ArH), 7.44−7.33 (m, 2H, ArH), 7.21−
7.06 (m, 5H, ArH), 5.27 (dd, J = 7.4, 5.4 Hz, 1H, PdCH), 4.96 (dd, J
= 14.1, 7.7 Hz, 1H, PCH). 13C NMR (101 MHz, CDCl3): δ 188.58
(d, J = 10.1 Hz, 1C, CO), 159.52−118.20 (27C, Ar), 59.70 (s, 1C,
PdCH), 48.06 (d, J = 71.7 Hz, 1C, PCH). Anal. Calcd for
C30H23NO2PPdCl: C, 59.82; H, 3.85; N, 2.33. Found: C, 59.99; H,
4.05; N, 2.58. HRMS (+ESI) m/z: (M + H)+ calcd for
C30H24NO2P106PdCl, 602.0268; found, 602.0281.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00262.
■
S
((1R,2R)-1-(Diphenylphosphorothioyl)-3-(6-methylpyridin-2-yl)-
3-oxo-1-phenylpropan-2-yl)palladium(II) Chloride ((R,R)-4ca). Yel-
General methods, NMR spectra, coordination study,
HPLC spectra, and X-ray measurement data (PDF)
20
low material was produced in 63% yield. [α]D = −77 (c 1.0,
CH2Cl2). Mp: 210.5−212.0 °C (dec). 31P{1H} NMR (CDCl3, 162
1
Accession Codes
MHz): δ 67.30 (s, 1P). H NMR (400 MHz, CDCl3): δ 7.94−7.85
(m, 2H, ArH), 7.75 (t, J = 7.7 Hz, 1H, ArH), 7.69−7.50 (m, 7H,
ArH), 7.42 (td, J = 7.9, 3.3 Hz, 2H, ArH), 7.29 (d, J = 7.8 Hz, 1H,
ArH), 7.24−7.17 (m, 1H, ArH), 7.14 (t, J = 7.6 Hz, 2H, ArH), 7.02−
6.97 (m, 2H, ArH), 5.28 (dd, J = 14.9, 8.8 Hz, 1H, PCH), 4.79 (dd, J
= 8.7, 6.1 Hz, 1H, PdCH), 3.09 (s, 3H, ArCH3). 13C NMR (101
MHz, CDCl3): δ 189.04 (d, J = 14.7 Hz, 1C, CO), 162.46−119.61
(23C, Ar), 56.37 (d, 2JPC = 6.0 Hz, 1C, PdCH), 53.59 (d, 1JPC = 59.0
Hz, 1C, PCH), 26.04 (s, 1C, ArCH3). Anal. Calcd for
C27H23NOPPdSCl: C, 55.68; H, 3.98; N, 2.41. Found: C, 55.51; H,
3.86; N, 2.69. HRMS (+ESI) m/z: (M + H)+ calcd for
C27H24NOPPdSCl, 582.0040; found, 582.0022
CCDC 1835818−1835819, 1835822−1835827, 1836590, and
1836617 contain 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
*Email for S.A.P.: sumod@ntu.edu.sg.
*e-mail for P.-H.L.: pakhing@ntu.edu.sg.
■
((1R,2R)-1-(Diphenylphosphorothioyl)-3-(6-(4-methoxyphenyl)
pyridin-2-yl)-3-oxo-1-phenylpropan-2-yl)palladium(II) Chloride
((R,R)-4da). Yellow solid material was produced in 31% yield.
20
[α]D = −94 (c 1.0, CH2Cl2). Mp: 200.0−201.5 °C (dec). 31P{1H}
ORCID
1
́
́
́
Laszlo B. Balazs: 0000-0002-2625-3423
Sumod A. Pullarkat: 0000-0002-4150-2408
Pak-Hing Leung: 0000-0003-3588-1664
NMR (CDCl3, 162 MHz): δ 67.35 (s, 1P). H NMR (400 MHz,
CDCl3): δ 8.04 (d, J = 8.8 Hz, 2H, ArH), 7.93−7.84 (m, 3H, ArH),
7.83−7.74 (m, 2H, ArH), 7.69−7.57 (m, 4H, ArH), 7.57−7.44 (m,
4H, ArH), 7.25−7.15 (m, 3H, ArH), 7.12 (d, J = 8.8 Hz, 2H, ArH),
7.10−7.04 (m, 2H, ArH), 5.29 (dd, J = 14.9, 8.7 Hz, 1H, PCH), 4.93
(dd, J = 8.7, 6.4 Hz, 1H, PdCH), 3.93 (s, 3H, OCH3). 13C NMR (75
MHz, CDCl3): δ 187.81 (d, J = 14.7 Hz, 1C, CO), 161.72−114.28
(29C, Ar), 56.27 (d, 2JPC = 5.6 Hz, 1C, PdCH), 55.57 (s, 1C, OCH3),
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
53.51 (d, JPC = 59.3 Hz, 1C, PCH). Anal. Calcd for
We thank Nanyang Technological University for supporting
this research (MOE Tier I grant # RG108/15) and for a
SINGA scholarship to L.B.B.
C33H27NO2PPdSCl: C, 58.77; H, 4.04; N, 2.08. Found: C, 58.76;
H, 3.96; N, 2.09. HRMS (+ESI) m/z: (M + H)+ calcd for
C33H28NO2P108PdSCl, 676.0306; found, 676.0338.
((1R,2R)-1-(Diphenylphosphorothioyl)-3-oxo-3-(quinolin-2-yl)-1-
(4-(trifluoromethyl)phenyl)propan-2-yl)palladium(II) Chloride
((R,R)-4ha). Yellow solid material was produced in 58% yield.
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NMR (CDCl3, 162 MHz): δ 67.63 (s, 1P). H NMR (300 MHz,
CDCl3): δ 9.47 (d, J = 8.7 Hz, 1H, ArH), 8.39 (d, J = 8.4 Hz, 1H,
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1
MHz): δ 68.07 (s, 1P). H NMR (500 MHz, CDCl3): δ 9.49 (d, J =
́
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