Design of Benzimidazolyl Phosphines Bearing AlterableP,OorP,N-Coordination: Synthesis, Characterization, and Insights into Their Reactivity

Article abstract of DOI:10.1021/acs.organomet.0c00816

A new series of hemilabile benzimidazolyl phosphines is reported. Entities in this ligand family can be easily assembled and prepared on a large scale via a simple one-pot procedure. X-ray crystallographic analyses show that the Pd metal center can coordinate in different fashions, where it relies on the size of the ?PR₂group. With the same ligand scaffold, the ligand having a ?PCy₂moiety displays better efficiency in expediting aromatic C-C bond-coupling reactions, while the ligand associated with a ?P-t-Bu₂group, in contrast, promotes C-N bond-forming reactions.

Full text of DOI:10.1021/acs.organomet.0c00816

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Article
Design of Benzimidazolyl Phosphines Bearing Alterable P,O or
P,N‑Coordination: Synthesis, Characterization, and Insights into
Their Reactivity
Shun Man Wong, Pui Ying Choy, Qingyang Zhao, On Ying Yuen, Chung Chiu Yeung, Chau Ming So,
and Fuk Yee Kwong*
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Supporting Information
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ABSTRACT: A new series of hemilabile benzimidazolyl phos-
phines is reported. Entities in this ligand family can be easily
assembled and prepared on a large scale via a simple one-pot
procedure. X-ray crystallographic analyses show that the Pd metal
center can coordinate in different fashions, where it relies on the
size of the −PR2 group. With the same ligand scaffold, the ligand
having a −PCy2 moiety displays better efficiency in expediting
aromatic C−C bond-coupling reactions, while the ligand associated
with a −P-t-Bu2 group, in contrast, promotes C−N bond-forming
reactions.
palladium complexes would dramatically influence the catalytic
INTRODUCTION
■
activity.
Palladium-catalyzed cross-couplings have constituted numer-
ous applications in pharmaceutical and natural product
syntheses.1 In the past few decades, substantial efforts have
been undertaken by scientists aiming to explore unique
phosphine ligands that allow a specific coupling reaction to
proceed efficiently and smoothly.2 Yet, the synthetic routes for
attaining specially designed ligands often require multiple steps
and/or employ relatively expensive reagents (e.g. requires −Br
group(s) for Br/Li exchange at the synthetic precursor) and, in
some cases, involve chromatographic purification. Thus, the
creation of a synthetic procedure featuring easy, straightfor-
ward, and streamlined synthetic route advantages is highly
desirable.
We recently reported the heterocyclic hemilabile P,O- and
P,N-type phosphine ligands Bphos,10 PhMezole-phos,11 and
PhenCar-Phos12 for palladium catalysis (Figure 1A). In a
continuation of our research interest of developing heterocyclic
phosphines,13 herein we report our exploration of a new family
of benzimidazolyl phosphines with a unique coordination
Distinctive ligand skeletons have been highlighted to be
important for facilitating cross-coupling reactions. They
generally possess an electron-rich nature (to promote OA,
i.e. oxidative addition) and a sterically congested characteristic
(to improve RE, i.e. reductive elimination). Particularly, a
phosphine ligand associated with a proximal hemilabile
coordinating group would beneficially offer additional catalyst
longevity.3
Figure 1. Previous ligand structures/coordination modes and the
present investigations.
The Guram and Bei group reported P,O-type ligands for
Suzuki−Miyaura coupling and Buchwald−Hartwig amination
of aryl chlorides in 1999.4 Later, Hor,5 Singer,6 Stradiotto,7
and other research groups8 showed new examples of mixed-
donor chelating ligands, which were able to tackle difficult
cross-coupling processes. In 2011, McNulty reported P,O- and
P,N-type heterocyclic phosphines.9 It was suggested that
different conformational features of the corresponding
Special Issue: Organometallic Solutions to Challenges
in Cross-Coupling
Received: December 31, 2020
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manner, which can be altered by the steric bulkiness of the
Table 1. Evaluation of Ligand Efficacy (Selected) in
Suzuki−Miyaura Coupling and Buchwald−Hartwig
−PR2 group (Figure 1B).14
a
Amination of Aryl Chlorides
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Benzimidazolyl-
Based Phosphine Ligand. We designed a phosphine ligand
family on the basis of the criteria of easy diversification and
simple synthetic procedure. Thus, we chose a modular
assembly approach across three commercially available starting
components: (1) a main ligand scaffold, (2) a phosphino
group, and (3) a tunable hemilabile framework (Figure 2).
Figure 2. Features of a proposed simple and easily diversified
phosphine ligand family.
This strategy allowed plentiful modification of the ligand
structure. It is of note that these ligands can be easily accessed
via a simple one-pot synthetic pathway (Figure 3). This
a
Reaction conditions: for Suzuki−Miyaura coupling, 2-chlorotoluene
(1.0 mmol), phenylboronic acid (1.5 mmol), K3PO4·H2O (3.0
mmol), 0.05 mol % Pd(OAc)2, Pd/L = 1/2, and THF (3 mL) were
stirred for 24 h at 110 °C under a nitrogen atmosphere; for the
amination reaction, 4-chlorotoluene (1.0 mmol), N-methylaniline (1.5
mmol), K2CO3 (2.5 mmol), 0.5 mol % Pd(OAc)2, Pd/L = 1/4,
PhB(OH)2 (0.02 mmol), and toluene (3 mL) were stirred for 24 h at
110 °C under a nitrogen atmosphere. Calibrated GC yields are
reported using dodecane as the internal standard. All entries are an
average of two runs.
value in 31P NMR in comparison to L1 (see Table S1 in the
Supporting Information). In a C−N bond-forming reaction, 4-
chlorotoluene and N-methylaniline were chosen as exemplary
substrates to evaluate the ligand efficacy (selected examples are
shown in Table 1B; see Table S3 in the Supporting
Information for details). Interestingly, a reversal of activity
(L1/L8 versus L2/L9) was observed in this reaction.
In addition to a ligand survey, various bases and solvents
were examined to obtain the best reaction conditions in the
Suzuki−Miyaura coupling of aryl chlorides (Table 2; see Table
S2 in the Supporting Information for details). Among the bases
commonly used for screening (entries 1−5), K3PO4·H2O was
found to be the best choice for the reaction (entry 1). THF
gave a better result in comparison to dioxane and toluene
(entries 1 and 6−8). Further investigations of the Pd to ligand
ratio (entries 1 and 9−11) indicated that a ratio of 1/3 gave
the best yield (75%). The product yield was greatly improved
by increasing the reaction temperature to 110 °C to afford a
93% yield (entry 1 vs entry 12).
Figure 3. Simple synthetic pathways for the benzimidazolyl
phosphine ligand family.
synthetic route even allowed scale-up to a sub-kilogram level
(∼0.2 kg) without deleterious effects. Upon purification of the
product by crystallization, a variety of new air-stable phosphine
ligands were conveniently afforded (Figure 3).
Catalytic Studies of Pd/L Catalyst. With the newly
developed phosphine ligands in hand, we then investigated
their efficacy, with respect to their ligand scaffold in Pd-
catalyzed C−C and C−N coupling of aryl chlorides (Table 1).
In Suzuki−Miyaura coupling, L1 and L8 bearing a carbamoyl
group with a −PCy2 moiety exhibited the best catalytic
performance, while L2 and L9 (with a −P-t-Bu2 group) did not
(selected examples are shown in Table 1A; see Table S1 in the
Supporting Information for details). Ligand L8 with dimethyl
substitution on the 5,6-positions of the benzimidazole ring
made an improvement in the coupling reactions. This can
possibly be attributed to ligand L8 showing a more upfield
Encouraged by the favorable screening results, we next
examined a variety of aryl chlorides and arylboronic acids
B
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Table 2. Optimization of Reaction Conditions in Suzuki−
Scheme 1. Pd-Catalyzed Suzuki−Miyaura Coupling of Aryl
a
a
Miyaura Coupling of Aryl Chlorides
Chlorides
b
entry
Pd (Pd/L ratio)
base
solvent
yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 (1/3)
Pd(OAc)2 (1/3)
Pd(OAc)2 (1/3)
Pd(OAc)2 (1/3)
Pd(OAc)2 (1/3)
Pd(OAc)2 (1/3)
Pd(OAc)2 (1/3)
Pd(OAc)2 (1/3)
Pd(OAc)2 (1/1)
Pd(OAc)2 (1/2)
Pd(OAc)2 (1/4)
Pd(OAc)2 (1/3)
K3PO4·H2O
K3PO4
K2CO3
NaO-t-Bu
Cs2CO3
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
THF
THF
THF
THF
75
55
62
0
THF
4
dioxane
toluene
t-BuOH
THF
THF
THF
35
17
13
14
57
34
93
9
10
11
c
12
THF
a
Reaction conditions unless specified otherwise: 2-chlorotoluene (1.0
mmol), phenylboronic acid (1.5 mmol), base (3.0 mmol), Pd source
(0.05 mol %), L8 (indicated in Table 1), and solvent (3 mL) were
b
stirred for 24 h at 100 °C under a nitrogen atmosphere. Calibrated
GC yields are reported using dodecane as the internal standard,
c
average of two runs. At 110 °C.
under the optimized reaction conditions (Scheme 1).
Deactivated and functionalized aryl/heteroaryl chlorides were
compatible with the Pd/L8 catalyst system, and the Pd catalyst
loading was able to be lowered to 0.01 mol %. A sterically
hindered tri-ortho-substituted biaryl compound was afforded
smoothly with 0.5 mol % catalyst loading. The bulky 4-chloro-
3-methylquinoline was a feasible coupling partner for the
reaction to give the desired product in excellent yield (91%).
Notably, the coupling of β-hydrogen-containing alkylboronic
acid with aryl chloride was also successful.
Upon a change in the phosphino moiety of the ligand from
−PCy2 to −P-t-Bu2 (e.g., L8 to L9), a variety of aryl/heteroaryl
chlorides and primary/secondary amines were coupled
smoothly in this N-arylation process (Table 1B). To further
investigate the ligand efficacy, an optimization of the reaction
conditions for the amination reaction of 4-chlorotoluene was
carried out (Table 3; see Table S4 in the Supporting
Information for details). K2CO3 showed the best performance
among the other bases investigated (entries 1−5). Upon a
survey of commonly used organic solvents, toluene gave the
best yields. Remarkably, a 92% yield was observed when the
metal to ligand ratio was 1/5. Further increasing the ratio to 1/
6 resulted in a decrease in the product yield (entries 2 and 9−
13).
Aryl or heteroaryl chlorides were applicable coupling
partners in this N-arylation process. Most aniline substrates
were allowed to couple with aryl chlorides in good yields when
the Pd/L9 system was employed (Scheme 2). To further
investigate the efficiency of the new benzimidazolyl-phosphine
ligands, a more challenging amination reaction was tested using
sterically congested aryl chlorides and sterically hindered
anilines as the coupling partners. The amination reactions
proceeded well with the sterically demanding aryl chlorides
with an aniline containing di-o-methyl groups, or even 2,6-
diisopropyl substituents, with 1.0 mol % Pd loading. The ortho-
substituted, electron-poor anilines were seldom able to couple
a
Reaction conditions unless specified otherwise: ArCl (1.0 mmol),
Ar′B(OH)2 (1.5 mmol), K3PO4·H2O (3.0 mmol), Pd(OAc)2/L8 = 1/
3, and THF (3 mL) were stirred for 24 h at 110 °C under a nitrogen
atmosphere. Isolated yields are reported. A gram-scale synthesis (ArCl
(8.0 mmol), Ar′B(OH)2 (20.0 mmol), K3PO4·H2O (24.0 mmol),
Pd(OAc)2/L8 = 1/3, and THF (15 mL) were stirred for 24 h at 75
°C under a nitrogen atmosphere) is shown in parentheses. L1 was
used as the ligand. n-BuB(OH)2 (2.0 mmol) and toluene (3 mL)
b
c
were used.
with ortho-substituted aryl chlorides, as electron-deficient
anilines are poor nucleophiles.15 Herein, we successfully
demonstrated the C−N coupling of sterically hindered 2-
chloro-3-methylbenzonitrile with 3-fluoro-2-methylaniline
using 3.0 mol % Pd loading.
Metal Complex of Pd/L Catalyst. To further investigate
the unique binding properties of the ligand L series, single
crystals of Pd complexes from PdCl2(CH3CN)2 and the
ligands were grown. Single crystals of complexes 3 and 4 for X-
ray diffraction studies were obtained by vapor diffusion of
hexane into a dichloromethane solution containing the PdCl2·
L complex. Interestingly, the crystal structure of PdCl2·L9 with
the bulky −P-t-Bu2 moiety was found to coordinate in a κ2-P,N
fashion (Figure 4), while PdCl2·L8 with the less sterically
congested −PCy2 group was a dimeric complex, in which the
bottom carbamoyl oxygen pointed toward the Pd center and
exhibited a potential P,O-hemilabile ability (Figure 5). These
results indicated that the metal−ligand coordination depends
C
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Table 3. Optimization of Reaction Conditions in Amination
of Aryl Chlorides
Scheme 2. Pd-Catalyzed Buchwald−Hartwig Amination of
a
a
Aryl Chlorides
b
entry
Pd (Pd/L ratio)
base
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
Pd(OAc)2 (1/4)
Pd(OAc)2 (1/4)
Pd(OAc)2 (1/4)
Pd(OAc)2 (1/4)
Pd(OAc)2 (1/4)
Pd(OAc)2 (1/4)
Pd(OAc)2 (1/4)
Pd(OAc)2 (1/4)
Pd(OAc)2 (1/1)
Pd(OAc)2 (1/2)
Pd(OAc)2 (1/3)
Pd(OAc)2 (1/5)
Pd(OAc)2 (1/6)
K3PO4·H2O
K3PO4
toluene
toluene
toluene
toluene
toluene
dioxane
THF
t-BuOH
THF
THF
19
18
30
3
K2CO3
NaO-t-Bu
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
8
17
14
13
34
67
70
92
72
c
c
c
THF
THF
THF
c
c
13
a
Reaction conditions unless specified otherwise: 4-chlorotoluene (1.0
mmol), N-methylaniline (1.5 mmol), base (3.0 mmol), Pd source (0.2
mol %), L9 (indicated in Table 1), PhB(OH)2 (0.02 mmol), and
solvent (3 mL) were stirred for 24 h at 100 °C under a nitrogen
b
atmosphere. Calibrated GC yields are reported using dodecane as
c
the internal standard, average of two runs. 0.5 mol % of Pd(OAc)2
was used.
on the steric bulk of the phosphino moiety. The coordination
mode of the ligand to the metal can be changed by varying the
bulkiness of the phosphino group.
a
Reaction conditions: ArCl (1.0 mmol), amine (1.5 mmol), K2CO3
(2.5 mmol), Pd(OAc)2/L9 = 1/5, PhB(OH)2 (0.02 mmol) and
toluene (3 mL) were stirred for 24 h at 110 °C under nitrogen
atmosphere. Isolated yields are reported. A gram-scale reaction (8.0
CONCLUSIONS
■
In summary, we have developed a new family of hemilabile
benzimidazolyl phosphines L, which can be easily accessed and
readily fine tuned by an intended matching of three fragments
via a one-pot synthetic procedure. The X-ray structures of the
palladium complex in this ligand family showed possible static
P,O or P,N coordination to palladium. A molecular dynamics
study using computational means has yet to be conducted at
this stage. To the best of our knowledge, we have succeeded in
showing the first examples of a ligand family that have both
P,O and P,N hemilabile features. We showed that a unique
ligand structure is particularly suitable for either Pd-catalyzed
Suzuki−Miyaura cross-coupling or Buchwald−Hartwig amina-
tion. We anticipate that these interesting results will provide an
alternative direction of future ligand design for specific cross-
coupling reactions.
b
mmol) was carried out, which is shown in parentheses. No solvent
c
was used. L8 was used as the ligand and NaO-t-Bu was used as the
base.
EXPERIMENTAL SECTION
■
Figure 4. ORTEP drawing of PdCl2·L9, complex 3 (CCDC 905710).
General Considerations. Unless otherwise noted, all reagents
were purchased from commercial suppliers without purification. All
catalytic reactions were performed in resealable screw-capped Schlenk
tubes (approximately 20 mL volume) in the presence of a Teflon-
coated magnetic stirrer bar (3 mm × 10 mm). Toluene,
tetrahydrofuran (THF), and 1,4-dioxane were distilled from sodium
and sodium benzophenone ketyl under nitrogen, respectively.16
Commercially available aryl chlorides (solid form) were used as
received, and those in liquid form were purified by passing through a
short plug (0.5 cm width × 4 cm height) of neutral alumina or
distillation. Commercially available arylboronic acids were used as
received. Commercially available amines were purified by distillation.
All hydrogen atoms have been omitted for clarity.
All bases were used without grinding. A new bottle of n-butyllithium
was used (note: since the concentration of n-BuLi from an old bottle
may vary, a titration is highly recommended prior to use). Thin-layer
chromatography was performed on precoated silica gel 60 F254 plates.
Silica gel (70−230 and 230−400 mesh) was used for column
chromatography. Melting points were recorded on an uncorrected
1
1
instrument. H NMR was recorded on a 400 MHz spectrometer. H
NMR spectra were referenced internally to the residual proton
resonance in CDCl3 (δ 7.26 ppm) or with tetramethylsilane (TMS, δ
D
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1208.02, 1157.10, 1035.95, 810.58, 626.04. HRMS (ESI-TOF): m/z
[M + H]+ calcd for C28H45N3OP+ 470.3300, found 470.3292.
General Procedure for Synthesis of 2-(Di-tert-butylphos-
phino)-N,N-diisopropyl-5,6-dimethyl-1H-benzo[d]imidazole-
1-carboxamide (L9). 5,6-Dimethylbenzimidazole (0.73 g, 5.0
mmol) was dissolved in anhydrous THF (30 mL) and added
dropwise to a THF (10 mL) solution containing 1.1 equiv of NaH
(60% in mineral oil, 0.22 g, 5.5 mmol) at 0 °C (note: NaH was
prewashed with dry hexane under nitrogen). The mixture was stirred
for 20 min at room temperature. Then, 1.1 equiv of N,N-
diisopropylcarbamoyl chloride (0.90 g, 5.5 mmol) was added directly
to the reaction mixture, which was then refluxed for 30 min. After the
completion of the reaction as confirmed by GC-MS analysis, the
solution was cooled to −78 °C in a dry ice/acetone bath. Titrated n-
BuLi (6.0 mmol) was added dropwise by syringe. The reaction
mixture was further stirred for 10 min at −78 °C, and di-tert-
butylchlorophosphine (1.14 mL, 6.0 mmol) was then added dropwise
by syringe. The reaction mixture was warmed to room temperature
and stirred for 3 h. MeOH (∼10 mL) was added slowly to quench the
reaction. The solvent was removed under reduced pressure. Ethyl
acetate (∼100 mL) and water (∼50 mL) were added to the mixture,
and the aqueous phase was separated. The organic phase was further
washed with brine (∼25 mL × 3), dried by Na2SO4, and
concentrated. The concentrated mixture was applied to a 1 × 1 in.
silica pad and eluted with diethyl ether. After the solvent was removed
under vacuum, a white solid (L9) (30%) was obtained after
Figure 5. ORTEP drawing of PdCl2·L8, complex 4 (CCDC 905709).
All hydrogen atoms have been omitted for clarity.
0.00 ppm) as the internal standard. Chemical shifts (δ) are reported
in parts per million (ppm) on the δ scale downfield from TMS. 13C
NMR spectra were recorded on a 100 MHz spectrometer and
referenced to CDCl3 (δ 77.00 ppm, the middle peak). 31P NMR
spectra were recorded on a 202 MHz spectrometer and referenced to
external 85% H3PO4. Coupling constants (J) are reported in hertz
(Hz). Mass spectra (EI-MS and ES-MS) were recorded on a mass
spectrometer. High-resolution mass spectra (HRMS) were obtained
on a ESI-Q Exactive Focus Orbitrap mass spectrometer in which the
ionization method is electrospray ionization (ESI). The GC yields
described for the products were in accord with the authentic samples/
dodecane calibration standard from the GC-FID system. All yields
reported refer to isolated yields of compounds estimated to be greater
than 95% purity as determined by capillary gas chromatography (GC)
or 1H NMR. Compounds described in the literature were
1
recrystallization from ether/hexane. Mp: 179.2−181.7 °C. H NMR
(400 MHz, CDCl3): δ 1.12−1.68 (m, 30H), 2.41 (s, 6H), 3.64 (bs,
2H), 7.13 (s, 1H), 7.59 (s, 1H). 13C NMR (100 MHz, CDCl3): δ
20.2, 20.5, 30.3, 30.4, 33.7, 110.3, 120.2, 131.4, 132.4, 132.8, 142.6,
150.1, 151.8, 152.1 (complex unresolved C−P splitting was
observed). 31P NMR (202 MHz, CDCl3): δ 14.35. IR (cm−1):
2966.55, 1698.01, 1467.64, 1436.03, 1369.71, 1320.08, 1257.55,
1200.60, 1072.82, 1029.41, 914.88, 827.80, 748.38, 596.73, 546.15.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C24H41N3OP+ 418.2987,
found 418.2992.
1
characterized by a comparison of their H and/or 13C NMR spectra
to the previously reported data. The procedures in this section are
representative, and thus the yields may differ from those reported in
the tables.
Synthesis and Characterization of Benzimidazolyl-Based
Phosphine Ligand L. General Procedure for Synthesis of 2-
(Dicyclohexylphosphino)-N,N-diisopropyl-5,6-dimethyl-1H-
benzo[d]imidazole-1-carboxamide (L8). 5,6-Dimethylbenzimida-
zole (1.46 g, 10.0 mmol) was dissolved in anhydrous THF (50 mL)
and added dropwise to a THF (20 mL) solution containing 1.1 equiv
of NaH (60% in mineral oil, 0.44 g, 11.0 mmol) at 0 °C (note: NaH
was prewashed with anhydrous hexane under nitrogen). The mixture
was stirred for 20 min at room temperature. Then, 1.1 equiv of N,N-
diisopropylcarbamoyl chloride (1.80 g, 11.0 mmol) was added directly
to the reaction mixture, which was then refluxed for 30 min. After the
completion of the reaction as confirmed by a GC-MS analysis, solvent
was removed under reduced pressure. THF (4 mL) and toluene (80
mL) (THF/toluene = 1/20) were added. The solution was cooled to
−98 °C in a methanol/liquid N2 bath. Titrated n-BuLi (11.0 mmol)
was added dropwise by syringe. The reaction mixture was further
stirred for 10 min at −98 °C, and chlorodicyclohexylphosphine (2.65
mL, 12.0 mmol) was then added dropwise by syringe. The reaction
mixture was warmed to room temperature and stirred for 3 h. MeOH
(∼10 mL) was added slowly to quench the reaction. The solvent was
removed under reduced pressure. Ethyl acetate (∼200 mL) and water
(∼100 mL) were added to the mixture, and the aqueous phase was
separated. The organic phase was further washed with brine (∼50 mL
× 3), dried by Na2SO4, and concentrated. The concentrated mixture
was applied to a 1 × 1 in. silica pad and eluted with diethyl ether.
After the solvent was removed under vacuum, white crystals (L8)
(65%) were obtained after recrystallization from ether/hexane. Mp:
General Procedure for Ligand Screenings for Suzuki−
Miyaura Cross-Coupling. A stock solution of Pd(OAc)2 (2.3 mg)
with the ligand in freshly distilled solvent (10 mL) was initially
prepared with continuous stirring at room temperature. Phenyl-
boronic acid (0.1829 g), base (3.0 equiv), and a magnetic stirrer bar
(3 mm × 8 mm) were charged to an array of Schlenk tubes. Each tube
was carefully evacuated and backfilled with nitrogen (three cycles). 2-
Chlorotoluene (0.117 mL) and a stock solution of the palladium
complex (0.5 mL, 0.05 mol % Pd) were added by syringe. A further
2.5 mL of solvent was added by syringe (final volume: 3 mL). These
Schlenk tubes were resealed and magnetically stirred in a preheated
oil bath. The reaction mixtures were warmed to room temperature.
Ethyl acetate (∼10 mL), dodecane (227 μL, internal standard), and
water (∼5 mL) were added. The organic layer was subjected to GC
analysis. The GC yield was previously calibrated by an authentic
sample/dodecane calibration curve.
General Procedure for Ligand Screenings for Buchwald−
Hartwig Amination. A stock solution of Pd(OAc)2 (2.3 mg) with
the ligand in freshly distilled solvent (4 mL) was initially prepared
with continuous stirring at room temperature. K2CO3 (2.5 equiv) and
a magnetic stirrer bar (3 mm × 8 mm) were charged to an array of
Schlenk tubes. Each tube was carefully evacuated and backfilled with
nitrogen (three cycles). 4-Chlorotoluene (0.118 mL), N-methylani-
line (0.163 mL), phenylboronic acid (0.02 mmol), and a stock
solution of the palladium complex (2.0 mL, 0.5 mol % Pd or 0.8 mL,
0.2 mol %) were added by syringe. Further solvent was added by
syringe (final volume: 3 mL). These Schlenk tubes were resealed and
magnetically stirred in a preheated 110 °C oil bath. The reaction
mixtures were warmed to room temperature. Ethyl acetate (∼10 mL),
dodecane (227 μL, internal standard), and water (∼5 mL) were
added. The organic layer was subjected to GC analysis. The GC yield
was previously calibrated by an authentic sample/dodecane
calibration curve.
1
162.5−165.3 °C. H NMR (400 MHz, CDCl3): δ 1.26−1.95 (m,
34H), 2.39 (d, J = 3.6 Hz, 6H), 3.49 (m, 2H), 7.09 (s, 1H), 7.65 (s,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 19.9, 20.2, 20.4, 20.5,
20.6, 46.2, 50.6, 110.4, 120.7, 131.0, 132.2, 133.6, 139.9, 146.8, 149.2,
160.5 (complex unresolved C−P splitting was observed). 31P{1H}
NMR (202 MHz, CD2Cl2): δ −16.55. IR (cm−1): 2970.33, 1697.80,
1634.45, 1515.61, 1438.33, 1373.10, 1331.74, 1298.93, 1234.28,
E
https://doi.org/10.1021/acs.organomet.0c00816
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
General Procedure for Pd-Catalyzed Suzuki−Miyaura
Cross-Coupling of Aryl Chlorides. A stock solution of Pd(OAc)2
(2.3 mg) with the ligand (Pd/L = 1/3) in 10 mL of freshly distilled
THF (0.1 mol % of Pd per 1 mL of stock solution) was initially
prepared with continuous stirring at room temperature. Arylboronic
acid (1.5 mmol), K3PO4·H2O (3.0 mmol), and a magnetic stirrer bar
(3 mm × 8 mm) were charged to an array of Schlenk tubes. Each tube
was carefully evacuated and backfilled with nitrogen (three cycles).
The aryl chloride (1.0 mmol) was then placed in the Schlenk tubes.
The stock solution was further diluted to give different concentrations
of palladium complex. The diluted solutions were then transferred to
Schlenk tubes via syringes. Further solvent was added (final volume: 3
mL). These Schlenk tubes were resealed and magnetically stirred in a
preheated 110 °C oil bath. After the completion of the reaction as
judged by GC or TLC analysis, the reaction mixtures were warmed to
room temperature. Water (∼3 mL) and ethyl acetate (∼10 mL × 3)
were added. The organic layers were combined and concentrated. The
crude products were purified by column chromatography on silica gel
(230−400 mesh).
General Procedure for Pd-Catalyzed Buchwald−Hartwig
Amination of Aryl Chlorides. Pd(OAc)2 (2.3 mg, 0.010 mmol)
and the ligand (Pd/L = 1/5) were loaded into a Schlenk tube
equipped with a magnetic stirrer bar (3 mm × 8 mm). The tube was
evacuated and flushed several times with nitrogen. Precomplexation
was applied by adding freshly distilled toluene (1 mL) and stirring for
5 min. The aryl chloride (1.0 mmol), amine (1.5 mmol), and K2CO3
(2.5 mmol) were loaded into an array of Schlenk tubes. Further
solvents were added (final volume: 3 mL). These Schlenk tubes were
resealed and magnetically stirred in a preheated 110 °C oil bath. After
the completion of the reaction as judged by GC or TLC analysis, the
reaction mixtures were warmed to room temperature. Water (∼3 mL)
and ethyl acetate (∼10 mL × 3) were added. The organic layers were
combined and concentrated. The crude products were purified by
column chromatography on silica gel (230−400 mesh).
Hong Kong SAR, China; orcid.org/0000-0001-9105-
1740; Email: fykwong@cuhk.edu.hk
Authors
Shun Man Wong − Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic
University, Kowloon, Hong Kong SAR, China
Pui Ying Choy − State Key Laboratory of Synthetic Chemistry
and Department of Chemistry, The Chinese University of
Hong Kong, Shatin, Hong Kong SAR, China; orcid.org/
0000-0003-2765-0110
Qingyang Zhao − State Key Laboratory of Synthetic
Chemistry and Department of Chemistry, The Chinese
University of Hong Kong, Shatin, Hong Kong SAR, China;
orcid.org/0000-0001-8259-4321
On Ying Yuen − State Key Laboratory of Synthetic Chemistry
and Department of Chemistry, The Chinese University of
Hong Kong, Shatin, Hong Kong SAR, China
Chung Chiu Yeung − Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic
University, Kowloon, Hong Kong SAR, China
Chau Ming So − Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic
University, Kowloon, Hong Kong SAR, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.0c00816
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Synthesis of Metal Complexes 3 and 4. PdCl2(CH3CN)2
(0.0065 g, 0.025 mmol) and L8 or L9 (0.025 mmol) were dissolved
in freshly distilled dichloromethane (5 mL) under nitrogen at room
temperature. The yellow solution was stirred for 1 h. Anhydrous
hexane (2 mL) was then slowly added to recrystallize the pure
product.
■
This paper is dedicated to Prof. Albert S. C. Chan on the
occasion of his 70th birthday. We thank the Research Grants
Council of Hong Kong (GRF: 14304519-19P), and CUHK
Direct Grants (4053388 and 4442353) for financial support.
We are grateful for financial support from the Innovation and
Technology Commission (HKSAR, China) to the State Key
Laboratory of Synthetic Chemistry. We are grateful to Prof.
Zhongyuan Zhou (PolyU) for X-ray analysis, Dr. Yun Wei
(Anhui Normal University) and Dr. Wesley Ting Kwok Chan
(PolyU) for X-ray refinement, Dr. Pui Kin So (University
Facilities in Life Science, PolyU) for HRMS analysis, and Ms.
Man Yee Ho for NMR analysis.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.0c00816.
1H, 13C, and 31P NMR, HRMS, and IR spectra and
characterization data of the coupling compounds and
crystal data and structure refinement details of
complexes 3 and 4 (PDF)
REFERENCES
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AUTHOR INFORMATION
■
Corresponding Author
Fuk Yee Kwong − Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic
University, Kowloon, Hong Kong SAR, China; State Key
Laboratory of Synthetic Chemistry and Department of
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