Preparation of a highly congested carbazoyl-derived p,n-type phosphine ligand for acetone monoarylations

Article abstract of DOI:10.1021/acs.organomet.6b00154

We report a newly developed carbazoyl-derived P,N-type phosphine ligand (L1) for the monoarylation of acetone with aryl chlorides. The proposed Pd(dba)₂/L1 catalyst exhibited remarkable catalytic reactivity toward highly electron rich and sterically congested aryl chlorides, with catalyst loading as low as 0.1 mol % of Pd along with excellent chemoselectivity. A reaction rate study of the system using electronically diverse aryl chlorides determined the mechanisms regarding the rate-limiting steps in this reaction. The oxidative addition adduct of Pd-PhenCar-Phos with p-chlorotoluene showed the participation of N-Pd coordination in the metal complex. The isolated palladium complex C1 could be utilized as a precatalyst in the transformation and achieved performance comparable to that of the in situ generated palladium species.

Full text of DOI:10.1021/acs.organomet.6b00154

Article
pubs.acs.org/Organometallics
Preparation of a Highly Congested Carbazoyl-Derived P,N-Type
Phosphine Ligand for Acetone Monoarylations
Wai Chung Fu, Zhongyuan Zhou, and Fuk Yee Kwong*
State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon, Hong Kong, People’s Republic of China
*
S Supporting Information
ABSTRACT: We report a newly developed carbazoyl-derived P,N-type phosphine
ligand (L1) for the monoarylation of acetone with aryl chlorides. The proposed
Pd(dba) /L1 catalyst exhibited remarkable catalytic reactivity toward highly electron
2
rich and sterically congested aryl chlorides, with catalyst loading as low as 0.1 mol %
of Pd along with excellent chemoselectivity. A reaction rate study of the system
using electronically diverse aryl chlorides determined the mechanisms regarding the
rate-limiting steps in this reaction. The oxidative addition adduct of Pd-PhenCar-
Phos with p-chlorotoluene showed the participation of N−Pd coordination in the
metal complex. The isolated palladium complex C1 could be utilized as a precatalyst
in the transformation and achieved performance comparable to that of the in situ
generated palladium species.
INTRODUCTION
Zheda-Phos and a ferrocenyl-based phosphine as effective
■
1c,d
ligands for this process (Figure 1).
However, it was
The transition-metal-catalyzed selective monoarylation of
1
discovered that the scope might suffer from electron-deficient
acetone has emerged as a powerful synthetic tool due to its
1a,h
arenes when aryl halides or sulfonates were used.
This is
simplicity and practicality in constructing important inter-
mediates in organic materials and pharmaceuticals. Never-
theless, a challenge originated from the multiple reactive acidic
protons, which render unselective multiple arylations. Since the
2
presumably due to ineffective reductive elimination (RE) or
transmetalation as a result of employing highly electron-rich
phosphorus donor ligands. Indeed, a decrease in electron
richness on the phosphorus donor would accelerate the rate of
3
4
5
pioneering work by Buchwald, Hartwig, and Miura in 1997,
the reaction scope of ketone arylations has been extensively
expanded to allow various electrophiles, catalysts, and reaction
1a,6p
C−C reductive elimination
and an increase in the steric
bulkiness of the ligand (i.e., either with the bulky phosphino
group or the bottom ring of the ligand in a remote fashion) can
facilitate the RE process. Recently, we designed an electroni-
cally appropriate indolylphosphine ligand which can effectively
promote the acetone monoarylation with electron-poor
6
parameters to be used. Lately, development has focused on the
design of ancillary ligands in the hope of pursuing enhanced
reactivity and, more importantly, mono selectivity toward this
arylation of methyl ketones.
1
,6
1g
arenes, even on a scale up to 100 mmol. Nevertheless, it
would be intriguing to determine whether the reductive
elimination of electron-deficient substrates could be promoted
when the two factors of electron-rich phosphorus donor and
highly sterically encumbered bottom ring are confined in one
single ligand. Whereas a few other phosphines also showed
effectiveness in this reaction, they tended to employ high
While reports on the monoarylation of ketones have been
limited, the group of Stradiotto demonstrated the first
monoarylation of acetone in 2011, employing a Pd catalyst
with the morpholine-based P,N-type ligand Mor-DalPhos
1
a
(
Figure 1). Afterward, Ma and Lang independently reported
1e,f
catalyst loadings. With our continuing interest in phosphine
1g,7
ligand design and monoarylation of methyl ketones,
we
herein disclose a newly developed P,N-type phosphine ligand
for acetone monoarylation. The new P,N-Pd catalyst was found
to be particularly effective against sterically hindered and
electron-rich substrates, and the P,N coordination to the Pd
center was also confirmed by X-ray crystallographic analysis.
Figure 1. P,N-type phosphine ligands used in the Pd-catalyzed
monoarylation of acetone and our proposed target ligand scaffold for
this study.
Special Issue: Organometallics in Asia
Received: February 25, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.6b00154
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Organometallics
Article
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Carbazolyl-Based
Phosphine Ligand L1. In 2011, we reported the carbazolyl-
based P,N phosphine ligand PhenCar-Phos for sterically
7b
hindered biaryl syntheses (Figure 1), in which we believe
the extended carbazolyl framework is the key for the difficult
2
2
C(sp )−C(sp ) bond-forming reductive elimination. Recently,
we further extended the aromatic carbazolyl framework to
7c
enable tetra-ortho-substituted biaryl syntheses. In this regard,
we envisioned that the PhenCar-Phos ligand skeleton would
hold great promise against the Ar−Pd−acetone enolate
reductive elimination after adequate modifications. On the
basis of this scaffold, we sought to incorporate steric
prominence on the carbazole moiety (Scheme 1). The
Scheme 1. Preparation of Carbazolyl-Based Phosphine
Ligand L1
Figure 2. ORTEP diagram of L1. All hydrogen atoms have been
omitted for clarity.
a
Table 1. Representative Entries for Reaction Optimization
entry amt of Pd (mol %)
L
base
time (h) yield (%)
1
2
3
4
5
6
7
8
9
1
1
0.5
L1
L2
L3
L4
L5
L6
L1
L2
L3
L1
L2
L1
L1
L1
K PO4
4
4
99
3
0.5
K PO4
3
99
preparation of L1 was accomplished by a ligand-free Cu-
catalyzed animation followed by nucleophilic phosphination.
The basic 3,6-di-tert-butyl-9H-carbazole was prepared in good
yield with a simple Friedel−Crafts reaction according to
0.5
K PO4
3
4
99
0.5
K PO4
3
4
trace
trace
trace
40
0.5
K PO4
3
4
8
0.5
K PO4
3
4
literature procedures. To further realize the amenability of this
0.1
K PO4
3
4
procedure, the Cu-catalyzed animation was attempted on a
multigram scale and 10.2 g of product was successfully
obtained. A single crystal of L1 suitable for X-ray diffraction
was grown by a liquid−liquid diffusion of ethanol into a
chloroform solution of L1 at −20 °C. The X-ray analysis of L1
0.1
K PO4
3
4
39
0.1
K PO4
3
4
18
0
1
0.05
0.05
0.05
0.05
0.05
K PO4
3
18
18
18
18
18
83
K PO4
3
42
2
12
Cs CO
2
3
73
confirmed an sp -N conformation in the carbazole structure
1
3
4
CsOH·H O
K PO4
3
trace
2
(
Figure 2).
b
1
84
Catalytic Studies of Pd(dba) /L1 Catalyst. With the
2
a
Reaction conditions unless specified otherwise: Pd(OAc) :ligand =
:2, p-chlorotoluene (0.5 mmol), base (1.25 mmol), acetone (1.7 mL,
.30 M); 90 °C for the indicated time under N . Calibrated GC-FID
yields are reported. Pd(dba) was used as the Pd source.
newly developed P,N ligand in hand, we next initiated the
reaction trials using electronically neutral p-chlorotoluene as the
benchmarking substrate. In addition to L1, a series of other
PhenCar-Phos ligands L2−L6, which are electronically and
sterically diverse at the phosphorus donor, were also evaluated.
At the beginning of ligand screening, we found that ligands
bearing PCy and P-i-Pr groups gave superior results over the
2
1
0
2
b
2
performance as Pd(OAc) (Table 1, entry 10 vs entry 14), yet it
provided more reproducible results.
2
2
2
other counterparts (Table 1, entries 1−3 vs entries 4−6).
Further evaluation of L1−L3 with lower catalyst loadings
revealed comparable performances, while L3 provided a slightly
lower product yield (Table 1, entries 7−9). L1 was found to
provide 83% product yield with lengthened reaction time, while
L2 was inferior in this respect (Table 1, entry 10 vs entry 11).
Carbonated base and strongly basic hydroxide were found to be
not suitable in this system (Table 1, entries 12 and 13). The use
Having the optimal reaction conditions in hand, we sought to
examine the scope of the system for the monoarylation of
acetone. Generally, only 0.2 mol % of Pd(dba) /L1 catalyst
2
allowed good-to-excellent product yields with electron-neutral
and -rich arenes (Scheme 2, compounds 1a−f). It is particularly
noteworthy that highly electron-rich and sterically hindered
substrates, such as 1h, were able to react and gave 99% product
yield with only 0.3 mol % of Pd; the same substrate required 1.5
mol % of catalyst in our previous report. Other sterically
of Pd(dba) as a metal source gave almost the same catalytic
2
B
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Scheme 2. Pd(dba) /L1-catalyzed Mono-α-Arylation of
Acetone with Aryl and Heteroaryl Chlorides
Scheme 3. Reaction Rate Study of Electronically Diverse
Aryl Chlorides in Acetone Monoarylation using the
2
a
Pd(dba) /L1 System
2
ingly, the reaction rate with electron-rich p-chloroanisole was
found to be much higher than that with electron-poor p-
chlorobenzotrifluoride. Notwithstanding the fact that the
extended carbazole framework of L1 was proven to greatly
improve the catalytic performance of PhenCar-Phos in acetone
monoarylations toward electron-rich substrates, the reaction
with electron-deficient arenes was not entirely applicable. This
result was consistent with a previous report regarding the use of
1a
1g
P,N ligand but not with ours, which next drew our attention
to the interaction between the PhenCar-Phos ligand and the
palladium metal center.
To gain an insight into the ligand−metal interaction during
the catalysis, we attempted to prepare and isolate the catalytic
intermediate of the Pd/PhenCar-Phos catalyst. The oxidative
addition adduct C1 was successfully prepared by direct
treatment of Pd(dba) /PhenCar-Phos with p-chlorotoluene in
2
tetrahydrofuran at 90 °C, giving an isolated yield of 70%
(
Scheme 4). A single crystal of C1 suitable for X-ray diffraction
a
Reaction conditions: Pd:L1 = 1:2, ArCl (0.5 mmol), K PO (1.25
3
4
was obtained by vapor diffusion of diethyl ether into a
dichloromethane solution containing C1. The crystallographic
analysis of C1 confirmed a κ -P,N coordination of PhenCar-
mmol), acetone (1.7 mL, 0.30 M); 90 °C for 18 h under N . Isolated
2
yields are reported. The catalyst loading is reported in parentheses as
mol % of Pd with respect to ArCl. Reaction times were not optimized
for each substrate.
2
Phos to the palladium while chloride bound trans to the
phosphorus donor. This coordination mode is consistent with
previous reports regarding the P,N-type ligand Mor-DalPhos.
As suggested by the molecular structure of C1 and reaction rate
study with electron-rich aryl chlorides, we believe that the high
steric hindrance of L1 did improve the catalytic rate by
facilitating the reductive elimination. However, the inferior
performance with electron-poor aryl chlorides should originate
from the extra electron richness or heightened basicity on the
palladium center provided by the ligand through N−Pd
coordination, in which it binds trans to the arene substrate.
This vastly heightened basicity ultimately led to the increased
reductive elimination rate with electron-rich arenes but to a
significant performance drop for electron-poor substrates. We
found that this phenomenon is likely in line with the results of
Zheda-Phos by Ma and co-workers, where lowering the
electron richness at the nitrogen atom or a secondary
competitive binding atom (oxygen of methoxy group in that
case) within the ligand could allow the transformation of
certain electron-deficient arenes such as p-keto or p-cyano aryl
chlorides.
hindered arenes were successfully converted to the desired
products in 86−99% yield (Scheme 2, entries 1f−j).
Functionalities such as esters, enolizable ketones, and a variety
of heterocycles were tolerated in our system, and up to 95%
isolated yield was given (Scheme 2, compounds 1j−s). Despite
the moderate product yield afforded for compound 1t, the
reaction with the highly electron-deficient p-chlorobenzotri-
fluoride 1u gave 22% yield. In addition to acetone, other alkyl
and aryl ketones were shown to be applicable substrates in our
reaction (see Scheme S1 in the Supporting Information).
Reaction Rate Study and Oxidative Addition Complex
of Pd/PhenCar-Phos Catalyst. Although our system was
found to be highly efficient toward electron-rich and sterically
hindered substrates, para-substituted electron-deficient arenes
were still problematic despite the reinforced steric hindrance
provided by L1. To shed light on the limitations and
mechanisms of the system, we studied the initial reaction rate
of electronically diverse aryl chlorides (Scheme 3). Interest-
1c
C
DOI: 10.1021/acs.organomet.6b00154
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Article
a
Scheme 4. Preparation of C1 and ORTEP Diagram of C1
congested aryl chlorides in acetone monoarylations, with
catalyst loadings as low as 0.1 mol % (the lowest catalyst
loading achieved so far) and exhibition of chemoselectivity. The
carbazolyl-based ligand L1 can be readily prepared by
straightforward synthetic procedures with easily accessible
materials and was amenable for multigram-scale synthesis.
The steric prominence of the carbazolyl framework of L1 was
found to greatly enhance the catalytic performance of PhenCar-
Phos in the acetone arylation process, yet the N−Pd
coordination may contribute negatively to the reaction with
electron-deficient arenes. We believe that these findings can
offer a further understanding of the ligand−metal interaction
and effect of bidentate P,N ligands and be considered as a
distinctive characteristic for future phosphine ligand design.
Other mechanistic and catalytic studies regarding the use of
PhenCar-Phos in not only ketone arylation but also a variety of
fundamentally different catalyses are now underway in our
laboratory.
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise noted, all reagents
were purchased from commercial suppliers and used 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 (4 mm × 10 mm).
Acetone was dried with activated 4 Å molecular sieves under N2
followed by vacuum distillation into a 100 mL Schlenk flask and was
stored for not more than 5 days. Cs CO , CsOH·H O, and K PO
a
All hydrogen atoms have been omitted for clarity. Reaction
conditions: Pd(dba)2 (1.0 mmol), PhenCar-Phos (1.2 mmol), p-
chlorotoluene (15.0 mmol) in THF at 90 °C for 6 h under N2.
Selected distances (Å): Pd1−P1 2.216(8), Pd1−N1 2.285(2), Pd1−
Cl1 2.342(8), Pd1−C31 1.990(3).
2
3
2
3
4
were purchased from Aldrich. Pd(OAc) and Pd(dba) were purchased
2
2
from Strem Chemical. Ligands L2−L6 were prepared according to
7
b
reported literature procedures. Commercially available aryl halides
were used as received. Thin-layer chromatography was performed on
Merck precoated silica gel 60 F254 plates. Silica gel (Merck, 70−230
Recently, palladium precatalysts have received considerable
attention due to their stability, ease of handling, and sometimes
9
and 230−400 mesh) was used for column chromatography. Melting
greater catalytic activity. We envisioned that the isolated
1
points were recorded on Bu
̈
chi B-545 melting point instrument. H
palladium complex C1 could also be employed as a precatalyst
for catalytic applications (Scheme 5). Without the addition of
NMR spectra were recorded on a Bruker (400 MHz) spectrometer.
Spectra were referenced internally to the residual proton resonance in
CDCl (δ 7.26 ppm), or with tetramethylsilane (TMS, δ 0.00 ppm) as
3
a
Scheme 5. Acetone Monoarylations using Precatalyst C1
the internal standard. Chemical shifts (δ) are reported in parts per
million (ppm) on the δ scale downfield from TMS. 13C NMR spectra
3
1
are referenced to CDCl (δ 77.00 ppm, the middle peak). P NMR
3
spectra are referenced to external 85% H PO . Coupling constants (J)
3
4
are reported in hertz (Hz). Mass spectra (EI-MS and ES-MS) were
recorded on a HP 5989B mass spectrometer. High-resolution mass
spectra (HRMS) were obtained on a Bruker APEX 47e FTICR mass
spectrometer (ESIMS). GC-MS analysis was conducted on a HP 5973
GCD system using an HP5MS column (30 m × 0.25 mm). The GC
yields described for the products were in accord with the authentic
samples/dodecane calibration standard from an HP 6890 GC-FID
system. All yields reported refer to isolated yields of compounds
estimated to be greater than 95% purity as determined by capillary gas
a
Reaction conditions for eq 1: C1 (0.5 mol %), p-chlorotoluene (0.5
mmol), K PO (1.25 mmol), acetone (1.7 mL, 0.30 M); 90 °C for 1 h
under N . The calibrated GC-FID yield is reported. Reaction
conditions for eq 2: C1 (0.05 mmol), K PO (1.25 mmol), acetone
3
4
2
1
3
4
chromatography (GC) or H NMR. Compounds described in the
1
13
(
1.7 mL, 0.30 M); 90 °C for 1.5 h under N . The calibrated GC-FID
literature were characterized by comparison of their H, and/or
C
2
yield is reported.
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 Carbazolyl-Based Phos-
phine Ligand L1. General Procedure for Synthesis of 9-(2-
Bromophenyl)-3,6-di-tert-butyl-9H-carbazole (P1). 3,6-Di-tert-butyl-
extra amounts of ligand, 0.5 mol % of C1 catalyzed the
monoarylation of acetone with p-chlorotoluene and afforded
8
5% yield in 1 h (eq 1). Direct reaction of C1 with acetone in
the presence of K PO gave the product in 73% yield (eq 2).
9H-carbazole (11.1 g, 40 mmol), CuI (7.62 g, 40 mmol), K CO (11.0
2 3
3
4
g, 80 mmol), and a Teflon-coated magnetic stir bar were placed in a
two-necked round-bottom flask (250 mL) equipped with a condenser
and fitted with a septum. The system was carefully evacuated and back-
filled with nitrogen (three cycles). 1,2-Dibromobenzene (9.65 mL, 80
mmol) and xylene (130 mL) were added by syringe via septum. The
septum was replaced with a stopper and the reaction mixture was
refluxed in a preheated oil bath (185 °C) for 3 days. After completion
of the reaction, the copper powder was filtered through Celite and the
This air-stable precatalyst C1 gave performance comparable to
that of the in situ generated palladium species (Scheme 5, eq 1,
vs Table 1, entry 2).
SUMMARY
■
In summary, we have developed a new catalyst (Pd(dba) /L1)
that is specifically efficient toward electron-rich and highly
2
D
DOI: 10.1021/acs.organomet.6b00154
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Article
xylene was removed by distillation under high vacuum. The crude
products were purified by flash column chromatography on silica gel
temperature. Ethyl acetate (∼3 mL), dodecane (114 μL, internal
standard), and water (∼2 mL) were added. The organic layer was
separated, and the aqueous layer was washed with ethyl acetate. The
filtrate was concentrated under reduced pressure. The crude products
were purified by flash column chromatography on silica gel (230−400
mesh) to afford the desired product.
(
230−400 mesh) to afford the product as a white solid (10.2 g, 59%):
1
H NMR (400 MHz, CDCl ) δ 1.54 (s, 18H), 7.06 (d, J = 8.6 Hz,
3
2
H), 7.39−7.43 (m, 1H), 7.47−7.54 (m, 4H), 7.90 (dd, J = 8.1, 0.9
13
Hz, 1H), 8.24 (s, 2H); C NMR (100 MHz, CDCl ) δ 32.4, 35.0,
3
1
1
09.8, 116.6, 123.5, 123.9, 124.0, 129.0, 130.1, 131.3, 134.4, 137.6,
39.7, 143.1; HRMS calcd for C H NBr 433.1400, found 433.1410.
General Procedure for Reaction Rate Study. K PO (1.25
3 4
mmol) was loaded into a Schlenk tube equipped with a Teflon-coated
magnetic stir bar and fitted with a septum. The tube was carefully
evacuated and back-filled with nitrogen for three cycles. Pd(dba)2
(0.005 mmol) and L1 (0.01 mmol) in 2.50 mL of acetone (0.2 mol %
26
28
General Procedure for Synthesis of 3,6-Di-tert-butyl-9-(2-
dicyclohexylphosphanyl)phenyl)-9H-carbazole (L1). The ligand
(
precursor (P1) obtained from the previous step (2.17 g, 5.0 mmol)
was dissolved in freshly distilled THF (25 mL) at room temperature
under a nitrogen atmosphere. The solution was cooled to −78 °C in a
dry ice/acetone bath. Titrated n-BuLi (5.5 mmol) was added dropwise
with a syringe, and the reaction mixture was stirred for 30 min at −78
Pd per 500 μL stock solution) were then prepared under N with
2
stirring until all solids were dissolved (usually within 1 min). The stock
solution (500 μL) was then immediately placed in the Schlenk tube by
syringe. The solution was stirred for 5 min at room temperature. p-
Chloroanisole (0.50 mmol) or p-chlorobenzotrifluororide (0.50
mmol) was added by syringe, and the solution was diluted with
acetone to 1.70 mL. The tube was stirred at room temperature for
another 5 min, and the septum was then replaced with a screw cap. An
array of Schlenk tubes that were prepared in parallel according to the
above procedure were placed in a preheated oil bath (90 °C) and
stirred for the time indicated. After completion of the reaction, the
reaction tube was immediately placed in an ice bath to quench the
reaction. Ethyl acetate (∼3 mL), dodecane (114 μL, internal
standard), and water (∼2 mL) were added. The organic layer was
subjected to GC analysis. The GC yield was previously calibrated by
an authentic sample/dodecane calibration curve.
°C. Chlorodiphenylphosphine (1.32 mL, 6.0 mmol) was then added
dropwise to the reaction mixture with a syringe. The reaction mixture
was warmed to room temperature and stirred for 12 h. The solvent
was then removed under reduced pressure. Methanol (10 mL) was
added to the residue, and the mixture was stirred at 1250 rpm for 10
min. The white solid product was successively filtered and washed with
cold methanol. The white solid was collected and dried over vacuum
to afford 3,6-di-tert-butyl-9-(2-(dicyclohexylphosphanyl)phenyl)-9H-
1
carbazole (2.26 g, 82%): H NMR (400 MHz, C D ) δ 0.98−1.17 (m,
6
6
8
7
8
H), 1.41 (s, 18H), 1.51−1.72 (m, 14H), 7.10−7.12 (m, 2H), 7.18−
.20 (m, 3H), 7.51 (dd, J = 8.6, 1.6 Hz, 2H), 7.57 (d, J = 7.6 Hz, 1H),
.38 (s, 2H); 13C NMR (100 MHz, C D ) δ 27.2, 28.1 (d, J = 23.4
6
6
Hz), 28.1 (d, J = 3.9 Hz), 30.6 (d, J = 11.0 Hz), 31.0 (d, J = 16.8 Hz),
Synthesis of Metal Complex C1. Pd(dba) (1.0 mmol) and
2
3
1
1
2.8, 34.9 (d, J = 16.9 Hz), 35.4, 111.4 (d, J = 2.5 Hz), 117.2, 124.0,
24.6, 130.9, 134.6 (d, J = 3.4 Hz), 138.8, 139.1, 142.3, 143.0, 145.4,
45.6; 31P NMR (162 MHz, C D ) δ −14.54; HRMS calcd for
PhenCar-Phos (1.2 mmol) were loaded into a Schlenk tube (250 mL)
equipped with a screw cap and Teflon-coated magnetic stir bar. The
tube was carefully evacuated and back-filled with nitrogen for three
cycles. p-Chlorotoluene (15.0 mmol) and subsequently THF (30 mL)
were added by syringe. The solution was stirred at room temperature
for 5 min. The tube was placed into a preheated oil bath (90 °C) and
stirred for 6 h. After completion of the reaction, the reaction tube was
warmed to room temperature. The unreacted palladium was filtered
through Celite, and the solvent was removed; diethyl ether was then
added to precipitate the product. The crude product was washed
successively with diethyl ether to eliminate the unreacted materials and
dibenzylideneacetone ligands. The solvent was removed under high
vacuum to give the desired product as a light yellow solid (470 mg,
70%). A single crystal of C1 suitable for X-ray diffraction was obtained
6
6
+
C H NPH 552.3759, found 552.3762.
38
50
General Procedure for Ligand and Reaction Condition
Screenings. Base (1.25 mmol) was loaded into a Schlenk tube
equipped with a Teflon-coated magnetic stir bar and fitted with a
septum. The tube was carefully evacuated and back-filled with nitrogen
for three cycles. The Pd source (0.02 mmol) and ligand (0.04 mmol)
in 4.00 mL of acetone (1.00 mol % of Pd per 1.00 mL of stock
solution) were then prepared under N with stirring until all solids
2
were dissolved (usually within 1 min). The corresponding volume of
the stock solution was then immediately added to the Schlenk tube by
syringe (in the case of 0.10 mol % of Pd, an additional 400 μL of
acetone was added). The solution was stirred for 5 min at room
temperature. p-Chlorotoluene (0.50 mmol) was added by syringe, and
the solution was diluted with acetone to 1.70 mL. The septum was
then replaced with a screw cap, and the solution was stirred at room
temperature for 5 min. The tube was placed into a preheated oil bath
by vapor diffusion of diethyl ether into a dichloromethane solution
1
containing C1: H NMR (400 MHz, CDCl ) δ 0.85−0.95 (m, 2H),
3
1.20−1.53 (m, 5H), 1.74−1.89 (m, 11H), 2.11−2.19 (m, 5H), 2.32−
2.37 (m, 2H), 6.31 (dd, J = 8.3, 3.1 Hz, 1H), 6.74 (d, J = 7.9 Hz, 2H),
6.99 (dd, J = 8.4, 1.8 Hz, 2H), 7.10 (d, J = 7.1 Hz, 2H), 7.30−7.41 (m,
5H), 7.46 (t, J = 7.4 Hz, 1H), 7.75 (t, J = 6.8 Hz, 1H), 8.01−8.03 (m,
(
90 °C) and stirred for the desired duration. After completion of the
2H); 13C NMR (100 MHz, CDCl ) δ 20.6, 25.8, 26.9 (d, J = 11.2 Hz),
reaction, the reaction tube was warmed to room temperature. Ethyl
3
acetate (∼3 mL), dodecane (114 μL, internal standard), and water
27.1 (d, J = 13.7 Hz), 28.1, 28.3 (d, J = 2.6 Hz), 33.6 (d, J = 27.4 Hz),
116.5, 120.8, 125.3, 127.3, 127.9 (d, J = 7.8 Hz), 128.3, 128.8 (d, J =
4.6 Hz), 130.9, 131.2 (d, J = 30.5 Hz), 131.5, 132.3, 133.4, 133.9 (d, J
(
∼2 mL) were added. The organic layer was subjected to GC analysis.
The GC yield was previously calibrated by an authentic sample/
dodecane calibration curve.
3
1
= 2.7 Hz), 136.0 (d, J = 3.7 Hz), 151.7, 154.2 (d, J = 14.5 Hz);
P
+
General Procedure for Mono-α-Arylation of Acetone with
Aryl Chlorides. Aryl chloride (if solid, 0.50 mmol) and K PO (1.25
NMR (162 MHz, CDCl ) δ 37.12; HRMS calcd for C H PNPd
3
37 41
3
4
638.2020, found 638.2023.
mmol) were loaded into a Schlenk tube equipped with a Teflon-coated
magnetic stir bar and fitted with a septum. The tube was carefully
evacuated and back-filled with nitrogen for three cycles. Pd(dba)2
General Procedure for Mono-α-Arylation of Acetone using
Precatalyst C1. K PO (1.25 mmol) and C1 (1.68 mg, 0.0025 mmol)
3
4
were loaded into a Schlenk tube equipped with a Teflon-coated
magnetic stir bar and fitted with a septum. The tube was carefully
evacuated and back-filled with nitrogen for three cycles. p-
Chlorotoluene (0.50 mmol) and subsequently acetone (1.70 mL)
were added by syringe. The contents of the tube were stirred at room
temperature for 5 min, and the septum was then replaced with a screw
cap. The tube was placed into a preheated oil bath (90 °C), and the
contents were stirred for 1 h. After completion of the reaction, the
reaction tube was immediately placed in an ice bath to quench the
reaction. Ethyl acetate (∼3 mL), dodecane (114 μL, internal
standard), and water (∼2 mL) were added. The organic layer was
subjected to GC analysis. The GC yield was previously calibrated by
an authentic sample/dodecane calibration curve.
(0.02 mmol) and L1 (0.04 mmol) in 4.00 mL of acetone (1.00 mol %
of Pd per 1.00 mL of stock solution) were then prepared under N2
with stirring until all solids were dissolved (usually within 1 min). The
corresponding volume of the stock solution was then immediately
added to the Schlenk tube by syringe (in the case of 0.20 mol % of Pd,
an additional 300 μL of acetone was added). The solution was stirred
for 5 min at room temperature. Aryl chloride (if liquid, 0.50 mmol)
was added by syringe, and the solution was diluted with acetone to
1.70 mL. The septum was then replaced with a screw cap, and the
solution was stirred at room temperature for 5 min. The tube was
placed into a preheated oil bath (90 °C) and stirred for 18 h. After
completion of the reaction, the reaction tube was warmed to room
E
DOI: 10.1021/acs.organomet.6b00154
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
General Procedure for Reaction of C1 and Acetone. K PO
1.25 mmol) and C1 (33.7 mg, 0.05 mmol) were loaded into a
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3
4
(
Schlenk tube equipped with a Teflon-coated magnetic stir bar and
fitted with a septum. The tube was carefully evacuated and back-filled
with nitrogen for three cycles. p-Chlorotoluene (0.50 mmol) and
subsequently acetone (1.70 mL) were added by syringe. The contents
of the tube were stirred at room temperature for 5 min, and the
septum was then replaced with a screw cap. The tube was placed into a
preheated oil bath (90 °C), and the contents were stirred for 1.5 h.
After completion of the reaction, the reaction tube was immediately
placed in an ice bath to quench the reaction. Ethyl acetate (∼3 mL),
dodecane (114 μL, internal standard), and water (∼2 mL) were added.
The organic layer was subjected to GC analysis. The GC yield was
previously calibrated by an authentic sample/dodecane calibration
curve.
(6) For selected reviews on Pd-catalyzed α-arylation of carbonyl
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3
262. For notable examples of Pd-catalyzed α-arylation of ketones,
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00154.
see: (f) Lundgren, R. J.; Stradiotto, M. Chem. - Eur. J. 2012, 18, 9758−
■
9
5
2
5
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*
S
X-ray crystallographic data (CIF)
X-ray crystallographic data (CIF)
Am. Chem. Soc. 2002, 124, 1261−1268. (l) Rutherford, J. L.; Rainka,
M. P.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 15168−15169.
(m) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
1
13
31
H, C, and P NMR spectra and characterization data
2
003, 125, 11818−11819. (n) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am.
of the compounds and crystal data and structure
refinement detailss of L1 and C1 (PDF)
All computed molecule Cartesian coordinates (XYZ)
Chem. Soc. 2008, 130, 195−200. (o) Adjabeng, G.; Brenstrum, T.;
Frampton, C. S.; Robertson, A. J.; Hillhouse, J.; McNulty, J.; Capretta,
A. J. Org. Chem. 2004, 69, 5082−5086. (p) Culkin, D. A.; Hartwig, J. F.
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AUTHOR INFORMATION
Corresponding Author
E-mail for F.Y.K.: fuk-yee.kwong@polyu.edu.hk.
■
*
1
1
7272−17276. (s) Biscoe, M. R.; Buchwald, S. L. Org. Lett. 2009, 11,
773−1775. (t) Crawford, S. M.; Alsabeh, P. G.; Stradiotto, M. Eur. J.
Notes
Org. Chem. 2012, 2012, 6042−6050. For recent progress in new Pd-
catalyzed direct α-arylation of carbonyl compounds, see: (u) Zheng,
B.; Jia, T.; Walsh, P. J. Adv. Synth. Catal. 2014, 356, 165−178. (v) Sha,
S.-C.; Zhang, J.; Walsh, P. J. Org. Lett. 2015, 17, 410−413. (w) Zheng,
B.; Jia, T.; Walsh, P. J. Org. Lett. 2013, 15, 4190−4193. (x) Vo, G. D.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 2127−2130.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Research Grants Council of Hong Kong (CRF:
C5023-14G), General Research Fund (PolyU 153008/14P),
and State Key Laboratory of Chirosciences for financial
support. We are grateful to Equipment Grant (PolyU11/
CRF/13E) for X-ray crystallographic analysis.
(7) For our recent notable works on indolyl and P,N phosphine
ligand design, see: (a) Chung, K. H.; So, C. M.; Wong, S. M.; Luk, C.
H.; Zhou, Z.; Lau, C. P.; Kwong, F. Y. Chem. Commun. 2012, 48,
1
5
2
967−1969. (b) To, S. C.; Kwong, F. Y. Chem. Commun. 2011, 47,
079−5081. (c) Fu, W. C.; Zhou, Z.; Kwong, F. Y. Org. Chem. Front.
016, 3, 273−276. (d) So, C. M.; Lau, C. P.; Kwong, F. Y. Angew.
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DOI: 10.1021/acs.organomet.6b00154
Organometallics XXXX, XXX, XXX−XXX