NiXantphos: A deprotonatable ligand for room-temperature palladium-catalyzed cross-couplings of aryl chlorides

Article abstract of DOI:10.1021/ja411855d

Although the past 15 years have witnessed the development of sterically bulky and electron-rich alkylphosphine ligands for palladium-catalyzed cross-couplings with aryl chlorides, examples of palladium catalysts based on either triarylphosphine or bidentate phosphine ligands for efficient room temperature cross-coupling reactions with unactivated aryl chlorides are rare. Herein we report a palladium catalyst based on NiXantphos, a deprotonatable chelating aryldiphosphine ligand, to oxidatively add unactivated aryl chlorides at room temperature. Surprisingly, comparison of an extensive array of ligands revealed that under the basic reaction conditions the resultant heterobimetallic Pd-NiXantphos catalyst system outperformed all the other mono- and bidentate ligands in a deprotonative cross-coupling process (DCCP) with aryl chlorides. The DCCP with aryl chlorides affords a variety of triarylmethane products, a class of compounds with various applications and interesting biological activity. Additionally, the DCCP exhibits remarkable chemoselectivity in the presence of aryl chloride substrates bearing heteroaryl groups and sensitive functional groups that are known to undergo 1,2-addition, aldol reaction, and O-, N-, enolate-α-, and C(sp²)-H arylations. The advantages and importance of the Pd-NiXantphos catalyst system outlined herein make it a valuable contribution for applications in Pd-catalyzed arylation reactions with aryl chlorides.

Full text of DOI:10.1021/ja411855d

Article
pubs.acs.org/JACS
NiXantphos: A Deprotonatable Ligand for Room-Temperature
Palladium-Catalyzed Cross-Couplings of Aryl Chlorides
Jiadi Zhang,† Ana Bellomo,† Nisalak Trongsiriwat,† Tiezheng Jia,† Patrick J. Carroll,† Spencer D. Dreher,‡
Matthew T. Tudge,‡ Haolin Yin,† Jerome R. Robinson,† Eric J. Schelter,† and Patrick J. Walsh*,†
†Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
‡Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: Although the past 15 years have witnessed the
development of sterically bulky and electron-rich alkylphos-
phine ligands for palladium-catalyzed cross-couplings with aryl
chlorides, examples of palladium catalysts based on either
triarylphosphine or bidentate phosphine ligands for efficient room
temperature cross-coupling reactions with unactivated aryl chlo-
rides are rare. Herein we report a palladium catalyst based on
NiXantphos, a deprotonatable chelating aryldiphosphine ligand, to
oxidatively add unactivated aryl chlorides at room temperature.
Surprisingly, comparison of an extensive array of ligands re-
vealed that under the basic reaction conditions the resultant heterobimetallic Pd−NiXantphos catalyst system outperformed all
the other mono- and bidentate ligands in a deprotonative cross-coupling process (DCCP) with aryl chlorides. The DCCP with
aryl chlorides affords a variety of triarylmethane products, a class of compounds with various applications and interesting
biological activity. Additionally, the DCCP exhibits remarkable chemoselectivity in the presence of aryl chloride substrates
bearing heteroaryl groups and sensitive functional groups that are known to undergo 1,2-addition, aldol reaction, and O-, N-,
enolate-α-, and C(sp2)−H arylations. The advantages and importance of the Pd−NiXantphos catalyst system outlined herein
make it a valuable contribution for applications in Pd-catalyzed arylation reactions with aryl chlorides.
inability of chelating phosphines to oxidatively add aryl chlorides
at low temperature. The two reasonable pathways for oxidative
addition of aryl chlorides with bidentate phosphines are
dissociation of one of the phosphorus centers of a bidentate
chelating phosphine or direct oxidative addition without
dissociation of a phosphorus center, both of which are high in
energy.4e−g As a result, palladium complexes with chelating
bidentate ligands typically catalyze cross-couplings of unac-
tivated aryl chlorides only at elevated temperatures.5 In 1993, the
Milstein group reported the oxidative addition of aryl chlorides
1. INTRODUCTION
The past 15 years have witnessed the development of phosphine
ligands used for palladium-catalyzed cross-couplings with aryl
chlorides.1 Among them, sterically bulky and electron-rich
alkylphosphine ligands have proved particularly successful and
have been widely applied in synthesis.2 Simple triarylphosphine
ligands are generally ineffective for oxidative addition of
unactivated aryl chlorides to Pd(0), in part due to their reduced
electron-donating ability. Yet, aryl chlorides are arguably the
most useful substrates among aryl halides and pseudohalides,
because of their low cost and wide availability. To date, few
reports have documented the use of triarylphosphine ligands for
cross-couplings with unactivated aryl chlorides, most of which
require higher temperatures (≥60 °C), and typically give
moderate yields with narrow substrate scope.3a−i In 2005, the
Buchwald group reported that a sterically hindered monodentate
triarylphosphine ligand, 2-diphenylphosphino-2′,4′,6′-triisopro-
pylbiphenyl, promoted Suzuki−Miyaura couplings of aryl
chlorides at room temperature to 40 °C in excellent yields.3j
Mechanistic studies on oxidative addition of aryl chlorides to
Pd(0) bearing bulky electron-rich phosphine ligands have been
recently reported: the Hartwig group, as well as others, demon-
strated that oxidative addition of aryl chlorides to Pd(0) proceeds
through a monoligated palladium species, LPd(0) (L = monodentate
phosphine).4 This mechanistic picture is consistent with the
̂
̂
̂
to Pd(PP), which was generated from Pd(PP)2 [PP = a bidentate
phosphine, in this case, 1,3-bis(diisopropylphosphino)propane
(dippp)].6 Despite the bulky and strongly donating phosphorus
centers, the oxidative addition was conducted at 90 °C to achieve
complete conversion in 2 h. In 2003, a similar observation was
reported by the Hartwig group for the room temperature
̂
̂
oxidative addition of aryl tosylates to Pd(PP)2 (PP = PPFt-Bu
and CyPFt-Bu).7 However, we are not aware of examples of
palladium catalysts based on bidentate phosphine ligands for
efficient room temperature cross-coupling reactions with
unactivated aryl chlorides.
Received: November 20, 2013
© XXXX American Chemical Society
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Herein we report unprecedented reactivity employing a
deprotonatable chelating aryldiphosphine ligand, NiXantphos,8
for the room temperature palladium-catalyzed cross-coupling
reaction of unactivated aryl chlorides. Surprisingly, comparison
of an extensive array of ligands revealed that the heterobimetallic
(M−NiXantphos)Pd catalyst system (M = alkali metal)9 out-
performed all the other mono- and bidentate ligands in depro-
tonative cross-coupling reactions with aryl chlorides.
the structurally similar Xantphos begged the question: Why is
NiXantphos so active under these reaction conditions? We
hypothesized that the presence of a somewhat acidic N−H
moiety under the basic reaction conditions would result in
deprotonation and that the resultant heterobimetallic system
might exhibit cooperative reactivity. We then set out to determine
the validity of this hypothesis, starting with a deprotonation study.
2.2. Deprotonation of NiXantphos. 2.2.1. Solution
Studies. NiXantphos has a phenoxazine core, with a pKa around
22,13 and should be deprotonated by KN(SiMe3)2 under the
2. RESULTS AND DISCUSSION
1
reaction conditions in Scheme 1. The H and 31P{1H} NMR
2.1. Initial Studies with NiXantphos. We recently initiated
a program in the catalytic functionalization of weakly acidic sp3-
hybridized C−H bonds. We have categorized these reactions as
deprotonative cross-coupling processes (DCCP), because they
involve initial reversible deprotonation of the C−H by base
without the participation of the catalyst. The catalyst promotes
the subsequent functionalization of the deprotonated species.
Thus, DCCP is mechanistically distinct from C−H activation/
functionalization processes.
Substrates we reported to undergo DCCP include diaryl-
methanes, allyl benzenes, sulfoxides, sulfones, amides and η6-
arene complexes of toluene derivatives and benzylic amines.10−12
Diphenylmethane (pKa = 32.313) and diarylmethane derivatives
were arylated at room temperature with aryl bromides in the
presence of KN(SiMe3)2 and a palladium catalyst bearing van
Leeuwen’s NiXantphos ligand8 (eq 1, see Scheme 1 for the
spectra of NiXantphos were recorded in THF-d8 at room
temperature before and after combination with 1.5−6 equiv of
MN(SiMe3)2 (M = Li, K). After 1.5 equiv of MN(SiMe3)2 were
added, the 1H NMR spectrum of the resulting solution displayed
significant shifts in the phenoxazine hydrogens (Ha, Hb, and Hc,
Table 1). A distinct upfield shift, Δ, of −0.75 ppm of Ha was
Table 1. 1H and 31P{1H} NMR Studies of NiXantphos
a
Deprotonated by Base
entry
base (equiv)
none
Ha
Hb
Hc
PPh2
1
2
3
4
5
5.91
5.16
5.14
5.15
5.22
6.52
6.06
6.03
6.04
6.07
6.32
5.73
5.70
5.70
5.75
−18.99
−18.69
−18.69
−18.68
−18.45
KN(SiMe3)2 (1.5)
KN(SiMe3)2 (3)
KN(SiMe3)2 (6)
LiN(SiMe3)2 (1.5)
a
Reactions conducted on a 0.04 mmol scale with 1 equiv of
NiXantphos and 1.5−6 equiv of MN(SiMe3)2 (M = Li, K) in 0.75 mL
of THF-d8 in a J. Young NMR tube at room temperature, chemical shifts
reported in ppm, referenced to the proteo internal standard.
Scheme 1. Selected HTE Results of the Cross-Coupling of 1a
with 1-Bromo-4-tert-butylbenzene (AY= assay yield)
a
observed in the presence of 1.5 equiv of KN(SiMe3)2 (entry 2
vs 1). Similarly, Hc exhibited a smaller shift (Δ=−0.59 ppm) as
did Hb (Δ=−0.46 ppm). 1H NMR chemical shifts did not change
upon further addition of KN(SiMe3)2 to NiXantphos (entries 3
1
and 4 vs 2). Similar shifts were observed in the H NMR
spectrum of the phenoxazine hydrogens of NiXantphos in the
presence of 1.5 equiv of LiN(SiMe3)2 (entry 5). These
observations indicated that deprotonation was complete with
1.5 equiv of MN(SiMe3)2 (M = Li, K). Interestingly, only a very
small shift was observed in the 31P{1H} NMR spectra of the PPh2
moiety of NiXantphos after addition of MN(SiMe3)2 (Table 1),
suggesting (1) the countercation is not bound to the phosphorus
centers (also see Figure 1a), and (2) the anionic phenoxazine
backbone does not render the phosphorus centers significantly
more electron-rich (see section 2.2.2 for DFT calculations).
2.2.2. DFT Calculations with NiXantphos and Related
Bis(phosphines). In reported work, the electron-donating ability
of mono- and bidentate phosphine ligands has been assessed
using density functional theory (DFT). For example, Spokoyny
and Buchwald correlated computed partial charges of B9-
connected trivalent aryl and alkyl phosphinoboranes with the
electronic properties of their resulting carbonyl complexes.20
In order to probe the experimental observations for the Pd−
NiXantphos system, DFT calculations were performed to assess
the electronic structures of the ligands. Gas-phase geometry
optimizations were performed at the B3LYP level of theory with
the 6-31 G* basis set for all atoms using Gaussian ’09. Natural
a
HTE conducted on a 10 μmol scale at 0.1 M.
structure of NiXantphos).11a This method facilitates rapid access
to a wide variety of sterically and electronically diverse
triarylmethanes, a class of compounds with various applications
and interesting biological activity.14−18
Interestingly, when we examined various ligands for the
cross-coupling of diphenylmethane (1a) with 1-bromo-4-tert-
butylbenzene at room temperature using microscale high-
throughput experimentation (HTE, Scheme 1),19 the NiXant-
phos-based catalyst showed superior performance over dippp as
well as the other bidentate ligands sharing similar bite angles (see
Supporting Information [SI] for a complete list of ligands).8 The
NiXantphos-based catalyst also outperformed monodentate
alkylphosphine ligands. The dominance of NiXantphos over
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Table 2. DFT Calculated Natural Charges for Members of the
Xantphos Ligand Family and Relevant Bidentate Phosphines
comparable to those in the other four structurally similar ligands
(Table 2). In particular, only small ranges of natural charges, qP =
0.918 to 0.930 and qO = −0.499 to −0.517, were observed,
suggesting the electronic structure at the phosphorus and oxygen
atoms is largely unchanged upon deprotonation of NiXantphos.
The calculations also suggested the three alkyl-substituted
̂
bidentate phosphine ligands: PP, PPFt-Bu, and CyPFt-Bu, were
significantly more electron-rich than the Xantphos family of
ligands. Overall, the calculations disfavor the possibility that the
oxygen atom in the deprotonated NiXantphos is electron-rich,
suggesting it is not likely to play a critical role in the oxidative
addition of aryl chlorides (see section 2.3).
2.2.3. Structures of Deprotonated NiXantphos. We were
curious how deprotonation would impact the structure of the
NiXantphos ligand and how the main group metal would interact
with the ligand framework. Bala and co-workers reported the
crystal structure of neutral NiXantphos, where the phenoxazine
is essentially planar.21 We synthesized the metalated ligand,
K−NiXantphos by combination of 1 equiv of NiXantphos
with 1 equiv of KN(SiMe3)2 in Et2O at room temperature
under a nitrogen atmosphere. Upon addition of KN(SiMe3)2,
K−NiXantphos rapidly precipitated from Et2O as a yellow solid,
1
and was isolated by vacuum filtration. H and 31P{1H} NMR
Figure 1. (a) ORTEP diagram of [K(THF)3−NiXantphos]2 with 50%
probability thermal ellipsoids displayed. Hydrogen atoms omitted for
clarity. N1−K1 = 2.808(3) Å, N1−K1′ = 2.857(3) Å, P1···P2 distance =
4.245 Å. (b) ORTEP diagram of K(THF)(18-crown-6)−NiXantphos
with 50% probability thermal ellipsoids displayed. Hydrogen atoms
omitted for clarity. N1−K1 = 2.885(2) Å, P1···P2 distance = 4.301 Å.
spectra of the isolated K−NiXantphos in THF-d8 were identical
to those obtained in situ from combination of NiXantphos with
KN(SiMe3)2 in THF-d8 (Table 1, entry 3).
We obtained diffraction-quality single crystals of K−
NiXantphos in the absence and presence of 18-crown-6 for a
structural study. As illustrated in Figure 1, [K(THF)3−
NiXantphos]2 is a dimer in the solid state, and the deprotonated
phenoxazine ring exhibits a dihedral angle of 1.9° between the
two benzo groups, similar to that observed in neutral
NiXantphos. The reddish-orange crown ether adduct, K(THF)-
(18-crown-6)−NiXantphos, was found to be a monomer in the
solid state (Figure 1b). A change in geometry of the phenoxazine
ring was observed with deprotonation: a dihedral angle of
16.4° between the two benzo rings. The K−N distances were
bond orbital (NBO) analyses of the resulting structures afforded
comparisons of atomic natural charges (Table 2 and SI).
Computations for the five ligands: neutral NiXantphos, the
deprotonated NiXantphos anion, N-Bn NiXantphos, Xantphos,
̂
and DPEPhos, and three related bidentate phosphines, PP =
dippp, PPFt-Bu, and CyPFt-Bu, were performed. The results
suggested that both the phosphorus atoms and the oxygen atom
in the deprotonated NiXantphos anion exhibited natural charges
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2.808(3) Å and 2.857(3) Å in the dimer (Figure 1a), and
2.885(2) Å in the monomer (Figure 1 b).
bromobenzene to afford (Xantphos)Pd(C6H5)(Br).25b We used
the same procedure for the oxidative addition studies with
chlorobenzene (2b, 5 equiv) to in situ-generated (Xantphos)-
Pd(dba) and neutral (NiXantphos)Pd(dba) at 24 and 80 °C.
Under these conditions no oxidative addition products were
detected. These results suggested that Xantphos and neutral
NiXantphos were not effective ligands for oxidative addition of
aryl chlorides to palladium(0). We also mixed in situ-generated
(NiXantphos)Pd(dba) with 1 equiv of KN(SiMe3)2 and 5 equiv
of chlorobenzene (2b) at 24 °C, but the reaction gave multiple
products, as judged by 31P{1H} NMR spectroscopy, probably
because of interference with dba.
The Buchwald group demonstrated an oxidative addition of
chlorobenzene to an LPd(0) (L = a monodentate phosphine)
complex, which was in situ-generated by combination of their
first-generation chloride precatalyst with 1 equiv of base.27 Other
groups also reported on palladacycles used as precatalysts for
cross-coupling reactions with aryl chlorides.28 The Buchwald
group recently reported their third-generation precatalysts,
wherein a dimeric 2-aminobiphenylpalladium methanesulfonate
complex can be treated with a range of phosphine ligands
(including sterically bulky ligands and bidentate ligands) to
provide methanesulfonate precatalysts.29 To determine the
reactivity of our palladium catalyst system based on deproto-
nated NiXantphos in the absence of dba, we combined 1 equiv of
the methanesulfonate precatalyst 4 (see eq 2 for the structure)
2.2.4. Probing NiXantphos N-Arylation. The above studies
confirm that NiXantphos is deprotonated in the presence of
MN(SiMe3)2 (M = Li, K). Thus, under the DCCP reaction
conditions (Scheme 1) we were concerned that the deproto-
nated NiXantphos could be N-arylated via Buchwald−Hartwig
amination of aryl halides.22 To address this concern, we needed
to displace the NiXantphos-derived products from palladium
after the DCCP. For this purpose, an excess of 1,2-bis-
(diethylphosphino)ethane (depe), a more basic and stronger
binding phosphine, was examined for this ligand exchange/
NiXantphos recovery experiment. As shown in Scheme 2A,
Scheme 2. Ligand Exchange and Recovery of NiXantphos
palladium acetate was stirred with NiXantphos for 12 h at room
temperature, resulting in coordination of NiXantphos, as
determined by 31P{1H} NMR spectroscopy (see SI). Treatment
of the complex with 8 equiv depe followed by filtration over a pad
of silica and flash chromatography resulted in 88% recovered
NiXantphos (Scheme 2A). In order to determine whether
the deprotonated NiXantphos was N-arylated after the cross-
coupling reaction with aryl bromide, we performed the DCCP in
Scheme 2B and then carried out a ligand exchange/recovery
procedure. We recovered 80% of NiXantphos after flash chro-
matography (average of two runs). No N-arylated NiXantphos
was observed (Scheme 2B), suggesting the catalyst does not
undergo N-arylation.
2.3. Oxidative Addition with Aryl Chlorides. On the
basis of the studies in sections 2.1 and 2.2, NiXantphos was
deprotonated to generate the metalated ligand, K−NiXantphos,
but it was not N-arylated under the DCCP reaction conditions.
While the potassium atom was positioned away from the oxygen
and the phosphorus atoms in the solid-state structures, we
wondered if its presence could facilitate the activation of less
reactive aryl chlorides, either by cooperative reactivity with the
palladium9,23 or by an electrostatic effect caused by the presence
of the charged potassium and nitrogen atoms near the site of
oxidative addition.24 Such interactions could be envisioned to
facilitate oxidative additions with less reactive aryl chlorides. On
the basis of this supposition, we set out to study the oxidative
addition of chlorobenzene to our heterobimetallic catalyst
system.
with 3.5 equiv of LiN(SiMe3)2 and 5 equiv of chlorobenzene 2b
in THF at 24 °C (eq 2). We propose that the first equiv of
LiN(SiMe3)2 deprotonates the NH2 moiety to induce the
reductive elimination affording carbazole and (NiXantphos)-
Pd(0).27 The second and third equivalents of LiN(SiMe3)2
deprotonate carbazole (pKa = 19.9) and (NiXantphos)Pd(0)
(pKa ≈ 22).13 The room-temperature oxidative addition of
chlorobenzene reached about 75% conversion in 6 h and near
completion in 24 h, as judged by a singlet at 2.6 ppm in 31P{1H}
NMR spectrum for the oxidative addition product. The singlet is
due to the rapid exchange between cis- and trans-chelation modes
of the wide bite angle NiXantphos ligand (114°)8 in solution, as
also observed with (Xantphos)Pd(Ar)(Br).30 The oxidative
addition product, (Li−NiXantphos)Pd(Ph)(Cl), is generated
along with byproducts lithium mesylate and lithium carbazoleate,
rendering the isolation of the Pd-containing product challenging
(eq 2). Nevertheless, single crystals of the neutral (NiXantphos)-
Pd(Ph)(Cl) were obtained by vapor diffusion of pentane into a
concentrated THF solution of the reaction mixture (Figure 2).
The solid-state structure shows a slightly distorted square planar
geometry with trans phosphorus atoms. This trans-chelating
mode of NiXantphos is similar to that of Xantphos: Xantphos
is trans-chelating in all reported solid-state structures of
(Xantphos)Pd(Ar)(halide) complexes to date.30 A larger
dihedral angle between the two benzo groups of the phenoxazine
ring system was observed in (NiXantphos)Pd(Ph)(Cl): 27.8° vs
1.9° in Figure 1a and 16.4° in Figure 1b.
The oxidative addition of aryl bromides to (Xantphos)-
Pd(dba) (dba = dibenzylideneacetone) has been previously
studied.25 In these studies, combination of 1 equiv of Pd(dba)2
(or 0.5 equiv of Pd2dba3) with 1 equiv of Xantphos generated
(Xantphos)Pd(dba) in situ.26 In the presence of 4-bromobenzo-
nitrile, this intermediate reacted at room temperature to afford
(Xantphos)Pd(4-C6H4CN)(Br) in 80% yield.25a Higher temper-
ature was required (80 °C) for reaction with less reactive
The same reactivity was also observed when KN(SiMe3)2
was used in place of LiN(SiMe3)2 in the oxidative addition of
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Scheme 3. Selected Results of the Cross-Coupling of 1a
a
with 2a
a
Conducted on a 10 μmol scale at 0.1 M.
Figure 2. ORTEP diagram of (NiXantphos)Pd(Ph)(Cl) with 50%
probability thermal ellipsoids displayed. Hydrogen atoms omitted for
clarity. Pd1−P1 = 2.3168(9) Å, Pd1−P2 = 2.3083(8) Å, Pd1−C37 =
2.048(2) Å, Pd1−Cl1 = 2.4348(8) Å, P1···P2 distance =4.454 Å,
Pd1···O1 distance = 2.686 Å, C37−Pd1−Cl1 angle = 178.70°,
P1−Pd1−P2 angle = 148.76°.
addition of aryl chlorides, we synthesized and tested N-benzyl-
NiXantphos, which cannot undergo deprotonation.8
In agreement with our hypothesis, excellent HPLC assay
yield (AY) of the product 3aa was observed using 10 mol %
Pd−NiXantphos. In contrast, catalysts generated from N-Bn-
NiXantphos showed <2% conversion and Xantphos did not
generate detectable amounts of products (Scheme 3). Other
ligands known to participate in coupling reactions with aryl
chlorides showed little or no reactivity in this cross-coupling.
Considering the structural similarity of NiXantphos, N-Bn-
NiXantphos, and Xantphos, as well as the fact that NiXantphos
was deprotonated by KN(SiMe3)2 under the DCCP reaction
conditions, the data in Scheme 3 support the hypothesis that K−
NiXantphos forms the active palladium catalyst to “turn on” the
cross-couplings with aryl chloride 2a at room temperature, while
the neutral N-Bn-NiXantphos and Xantphos do not (Figure 3).
chlorobenzene: the reaction neared completion after 24 h, as
judged by a singlet at 2.8 ppm in 31P{1H} NMR spectrum. The
results of these experiments are counterintuitive given that
oxidative addition of aryl chlorides has been shown to pro-
ceed via a PdL1 pathway. Bidentate ligands typically require
significantly higher temperatures because they react via the less
favorable PdL2 pathway. Thus, the observation that a bidentate
triarylphosphine derivative can activate aryl chlorides at room
temperature is unexpected and highlights the novel character-
istics of this heterobimetallic catalyst system under the basic
DCCP conditions. The oxidative addition studies lay the foun-
dation for aryl chlorides to undergo room temperature cross-
coupling reactions catalyzed by Pd−NiXantphos.
By directly employing K−NiXantphos as a ligand, at-
tempts to synthesize the corresponding palladium compounds
(K−NiXantphos)Pd(dba), (K−NiXantphos)PdCl2 and (K−
NiXantphos)Pd(OAc)2 were unsuccessful. Upon mixing
1 equiv of K−NiXantphos with the corresponding palladium
sources [0.5 equiv of Pd2dba3, 1 equiv of (norbornadiene)PdCl2,
or 1 equiv of Pd(OAc)2] we observed multiple products
as judged by 31P{1H} NMR spectroscopy. It is possible that
K−NiXantphos could undergo rapid transmetalation with Pd(II)
or react with dba. Furthermore, combination of 0.5 equiv of
Pd2dba3 with 2 equiv of neutral NiXantphos in THF (or toluene)
resulted in precipitation of a greenish yellow solid. The identity
of the precipitate was confirmed as Pd(NiXantphos)2 by HRMS
analysis. Unfortunately, Pd(NiXantphos)2 was insoluble in
common organic solvents. A similar synthetic route was reported
for Pd(Xantphos)2 by the Buchwald group, and its poor solubility
was also noted.26
2.4. Development of DCCP with Aryl Chlorides. On the
basis of the preliminary studies in section 2.3, we carried out a
ligand comparison experiment employing 1-tert-butyl-4-chlor-
obenzene (2a) as the cross-coupling partner under reaction
conditions related to our previous DCCP of aryl bromides
(Scheme 3). The comparison was performed on a 10 μmol scale.
To probe our hypothesis that the deprotonation of NiXantphos
is responsible for the exceptional reactivity in the oxidative
Figure 3. Proposed “turn on” form of palladium(0) bearing a
deprotonated NiXantphos and the “turn off” form of palladium(0)
bearing a neutral N-Bn-NiXantphos or Xantphos for the DCCP with
aryl chlorides.
2.5. Optimization of DCCP with Diphenylmethane and
Aryl Chloride 2a. The results in Scheme 3 provided an excellent
starting point for the C−C bond formation from diphenyl-
methane and aryl chloride 2a at room temperature. A 91% assay
yield (HPLC) was obtained at 10 mol % catalyst loading on
microscale. This microscale reaction was successfully translated
to laboratory scale (0.1 mmol) under the same conditions
(Table 3, entry 1, 87% assay yield). In further agreement with the
data in Scheme 3, Pd−Xantphos catalyst system did not render
any product 3aa under the same conditions either at 24 or 80 °C.
Considering 10 mol % catalyst loading was relatively high, further
optimization on laboratory scale was desired for the room
temperature DCCP.
We next examined five additional ethereal solvents [DME,
2-MeTHF, THF, dioxane, and MTBE (methyl tert-butyl ether)]
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Table 3. Optimization of Pd−NiXantphos Catalyzed DCCP
Table 4. Scope of Aryl Chlorides in Pd−NiXantphos-
a
a
of 1a with 2a
Catalyzed DCCP with 1a
Pd
(mol %)
concentration
(M)
b
entry
1a:2a
solvent
yield (%)
1
2
3
4
S
6
7
8
1.2:1.0
1.2:1.0
1.2:1.0
1.2:1.0
1.2:1.0
1.2:1.0
1.2:1.0
1.2:1.0
1.2:1.0
1.0:2.0
1.0:2.0
10
10
10
10
10
10
5
CPME
DME
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.2
87
61
78
2-MeTHF
THF
>95
dioxane
MTBE
THF
25
10
79
5
THF
58
c
9
5
THF
76
d
10
11
5
THF
>95 (99)
d
2.5
THF
(81)
a
Reactions conducted on a 0.1 mmol scale using 1a, 2a, and 3 equiv of
b
KN(SiMe3)2 at 24 °C. Yield determined by 1H NMR spectroscopy of
the crude reaction mixture. 5 mol % the methanesulfonate precatalyst
4 was used in place of Pd(OAc)2/NiXantphos. Isolated yield after
c
d
chromatographic purification.
in the presence of 1.2 equiv of diphenylmethane (1a), 1 equiv of
1-tert-butyl-4-chlorobenzene (2a), and 3 equiv of KN(SiMe3)2 at
0.1 M and 24 °C (entries 2−6). Dioxane and MTBE (entries 5
and 6) afforded <25% yield of product 3aa due to solubility issues
of the reactants at 24 °C. The lead result was obtained when THF
was used as solvent, where the triarylmethane 3aa was generated
in >95% yield (entry 4). Reduction of the catalyst loading
from 10 to 5 mol % while increasing the reaction concentration
from 0.1 to 0.2 M in THF resulted in only a minor loss in yield
(entries 7 and 8 vs 4). Under otherwise identical conditions,
a similar yield (76%, entry 9) was obtained using 5 mol %
of the methanesulfonate precatalyst 4 in place of Pd(OAc)2/
NiXantphos (entry 9 vs 8). Considering the commercial
availability of both Pd(OAc)2 and NiXantphos, we continued
with the Pd(OAc)2/NiXantphos catalyst system for further
optimization. Switching the limiting reagent from aryl chloride
2a to diphenylmethane 1a resulted in >95% yield of the
triarylmethane product 3aa with 5 mol % catalyst loading in THF
at 0.2 M at 24 °C (entry 10). Compound 3aa was ultimately
isolated in 99% yield after flash chromatography. Further
reducing the catalyst loading to 2.5 mol % rendered 3aa in
81% isolated yield (entry 11). These optimized conditions were
carried forward in the next phase, which focused on the
determination of the scope of aryl chlorides in Pd−NiXantphos-
catalyzed DCCP.
a
Reactions conducted on a 0.1 mmol scale using 1.2 equiv of 1a,
3 equiv of KN(SiMe3)2, and 1 equiv of 2 (conditions A) or 1 equiv of
1a, 3 equiv of KN(SiMe3)2, and 2 equiv of 2 (conditions B) using 2.5−
10 mol % Pd(OAc)2 and NiXantphos (Pd:L = 1:2) in THF at 0.2 M at
b
24 °C. Isolated yield after chromatographic purification. 1a:KN-
(SiMe3)2:2 = 4:2:1. CPME was used as solvent. 80 °C. 1a:KN-
(SiMe3)2:2 = 1:3:3. 2-MeTHF was used as solvent. 1a:KN(SiMe3)2:
2 = 1.2:4:1. 1a:KN(SiMe3)2:2 = 3:4:1. 1a:KN(SiMe3)2:2 = 1:5:2.
c
d
e
f
g
h
i
combination from (1) the two ratios of reagents [diphenyl-
methane (1a):KN(SiMe3)2:aryl chloride (2) = 1.2:3:1 (con-
ditions A) and 1:3:2 (conditions B)] and (2) the three ethereal
solvents (THF, CPME, and 2-MeTHF) at 2.5−10 mol % catalyst
loading successfully delivered the desired DCCP products in
56−99% yields (average yield: 86% for 11 aryl chlorides, 2a−2k).
Both 4-tert-butylphenyl and phenyl chloride furnished 3aa and
3ab in 81% and 96% yield, respectively, at 2.5 mol % palladium
loading. Methyl (2c), N,N-dimethylamino (2d), and trifluor-
omethyl (2e) groups at the meta position were all well-tolerated
(3ac−3ae in 82−94% yields). Excellent yields were obtained
using aryl chlorides bearing both electron-withdrawing CF3
and 4-F groups (2e, 2f, 2g) and electron-donating 4-OMe and
4-(N-pyrrolyl) groups (2h, 2i). The sterically more hindered
1-chloronaphthalene and 2-chloroanisole (2j and 2k) also
participated in DCCP to produce the desired products. These
substrates, however, required higher temperature (80 °C) to give
66% (3aj) and 56% (3ak) yield, respectively.
2.6. Scope of Aryl Chlorides in DCCP with Diphenyl-
methane. In previous reports, we demonstrated that a
large range of sterically and electronically diverse hetero- and
nonheteroaryl-containing diarylmethane derivatives readily
undergo DCCP with aryl bromides to afford an array of tri-
arylmethane products.11 In the current study, the scope of
Pd−NiXantphos catalyzed DCCP using a variety of aryl
chlorides with a model diarylmethane substrate (1a) is presented
in Table 4.
In general, fair to excellent reactivity was exhibited by aryl
chlorides bearing various substituents (2a−2k). At least one
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Article
We next tested aryl chloride substrates bearing sensitive
functional groups and heteroaryl groups (2l−2t). As shown in
Table 4, remarkable chemoselectivity was demonstrated with aryl
chlorides containing cyano, keto, acetyl, phenol, phenothiazine,
acetamide, and 1H-indole moieties, all of which underwent
DCCP delivering the corresponding functionalized triaryl-
methane products without observation of byproducts (3al−
3at). Nitriles and ketones are well-known to undergo 1,2-
addition reactions with reactive organometallics, while 4′-
chloroacetophenone can participate in competitive aldol31 and
α-arylation32 reactions under the basic reaction conditions (pKa
of acetophenone: 24.713). Yet the triarylmethane products (3al,
3am, 3an) were produced in 59−94% yields. Challenging classes
of substrates bearing acidic O−H and N−H bonds (2o−2t)
were next examined. Phenols are known to undergo O− and
C(sp2)−H arylation,33 while 1H-indoles (and anilines) have
been reported to react via N-arylation (Buchwald−Hartwig
coupling)22,34 and C-2- and C-3-arylation35 in the presence of
palladium catalysts and bases. Our method exhibits orthogonal
chemoselectivity with DCCP taking place exclusively at the
benzylic C(sp3)−H of diphenylmethane (1a) and the C(sp2)−Cl
of aryl chlorides 2o−2t. These functional groups and heteroaryl
groups present opportunities to further functionalize the tri-
arylmethane products. Note that for each equivalent of aryl chlo-
ride bearing acidic protons (2n−2t), an extra equivalent of
KN(SiMe3)2 was employed. For substrates giving less than 80%
byproduct. Since 2q has a phenothiazine core, which is
structurally similar to the phenoxazine core in NiXantphos,
this result supports our earlier conclusion based on the ligand
exchange/recovery experiments that NiXantphos was not
N-arylated during the reaction.
2.7. Scope of Diarylmethanes in DCCP. The scope of the
DCCP with respect to diarylmethanes was next explored with
aryl chlorides (2a, 2b) (Table 5).
Table 5. Scope of Diarylmethanes in Pd−NiXantphos-
a
Catalyzed DCCP
1
yield (2n, 2p, 2r−2t), H NMR of the reaction mixture after
workup showed only remaining starting materials and product.
No byproduct formation was observed. Attempts to push these
reactions to completion, however, were unsuccessful. Unfortu-
nately, 3-chloropyridine and 2- and 3-chlorothiophene failed to
give the DCCP products in reasonable yield (<10%).
After demonstrating that aryl chloride substrates bearing
sensitive functional groups and heteroaryl groups (2l−2t) were
viable cross-coupling partners in Pd−NiXantphos-catalyzed
DCCP with diphenylmethane (1a), an unactivated alkenyl
chloride 2u was tested (eq 3). Vinyl chloride 2u participated in
a
Reactions conducted on a 0.1 mmol scale using 1 equiv of 1, 3 equiv
of KN(SiMe3)2, and 2 equiv of 2 with 2.5−5 mol % Pd(OAc)2 and
NiXantphos (Pd:L = 1:2) in THF at 0.2 M at 24 °C. Isolated yield
after chromatographic purification. LiN(SiMe3)2 was used as base
instead of KN(SiMe3)2.
b
Substrates bearing various substituents on the diarylmethane
exhibited excellent reactivity at 2.5−5 mol % catalyst loading at
room temperature. Alkyl (3bb), electron-donating (3cb), and
electron-withdrawing groups (3db) were all well-tolerated.
Heteroaryl-containing diarylmethane analogues proved to be
good substrates, with corresponding products isolated in 76−
99% isolated yields (3eb, 3fb, 3ga, 3ha). Note that, although
3-benzylpyridine required KN(SiMe3)2 as base to promote
DCCP (3fb), a weaker base, LiN(SiMe3)2, successfully pro-
moted DCCP with the more acidic 2- and 4-benzylpyridines
(pKa = 28.2 and 26.7, respectively)13 to deliver 3ga and 3ha in
good yields.
2.8. Identification of the Catalyst Resting State and
Countercation Effects. To determine the resting state of the
palladium catalyst in our DCCP reactions, we conducted
the catalytic reaction with diphenylmethane (1a), chlorobenzene
(2b), and KN(SiMe3)2 as base in the presence of 10 mol % of
the methanesulfonate precatalyst 4 in THF in a sealed J. Young
NMR tube at room temperature. The only species observed by
31P{1H} NMR spectroscopy over the course of the DCCP (12 h)
was Pd(K−NiXantphos)2, as judged by a singlet at −1.3 ppm
in 31P{1H} NMR spectrum. Using 10 mol % Pd(OAc)2 and
20 mol % NiXantphos gave the same dominant catalyst resting
state 10 min after addition of 1a, 2b, and KN(SiMe3)2 at room
temperature (see SI). The catalyst resting state suggests that
ligand dissociation and/or oxidative addition is turnover limiting.
DCCP to afford 3au in 99% yield at 2.5 mol % catalyst loading at
80 °C. Even at 1.25 mol % catalyst loading under identical con-
ditions, 3au was produced in 80% yield. These results indicate
the Pd−NiXantphos catalyst can oxidatively add unactivated
alkenyl chlorides. It is also interesting that the product did not
isomerize, suggesting that deprotonation of the product did not
occur.
As shown in Table 4, both the synthetic utility and the
remarkable chemoselectivity of the Pd−NiXantphos-catalyzed
C−C cross-coupling method with a large variety of aryl chlorides
have been demonstrated. Several aspects are noteworthy: (1) 3-
and 4-chlorophenols (2o, 2p) reacted with 1a to give the DCCP
products in 84% and 40% yield, respectively. Given that these
phenols are deprotonated by KN(SiMe3)2 to give phenoxides
under the reaction conditions, these results suggest that the Pd−
NiXantphos catalyst system is able to undergo oxidative addition
with very electron-rich C(sp2)−Cl bonds (such as those in
phenoxides). (2) 2-Chlorophenothiazine (2q) produced the
DCCP product in 86% yield without observation of N-arylation
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The Hartwig group has reported the identification of Pd(PP)2
Article
̂
linked together by bridging potassium−nitrogen interactions,
similar to those observed in the structure of K−NiXantphos
(Figure 1a). The P−Pd−P angle containing two phosphorus
atoms of the same K−NiXantphos ligand is 113.22(7)°.
The other P−Pd−P angles are 102.91(12)°, 106.78(7)°, and
113.54(12)°. The deprotonated phenoxazine ring exhibits a
dihedral angle of 23.1° between the two benzo groups of the
heterocyclic framework. In contrast to the solid-state polymeric
structure, the hydrodynamic radius (rH) of Pd(K−NiXantphos)2,
as measured by diffusion-ordered 1H NMR spectroscopy
(DOSY) in THF-d8, was consistent with a monomer (see SI).
̂
complexes (PP = a chelating diphosphine ligand such as BINAP
̂
and DPPF) as the dominant resting state in the Pd−PP catalyzed
amination of aryl bromides.7b The turnover-limiting step was
dissociation of BINAP from Pd(BINAP)2 when BINAP was used
as the ligand, while the combination of ligand dissociation and
irreversible oxidative addition were the turnover-limiting steps in
the catalytic process when DPPF was used as ligand.
Pd(K−NiXantphos)2 was independently prepared from
combination of 1 equiv of the methanesulfonate precatalyst
4 with 4.5 equiv of KN(SiMe3)2 and 1 equiv of NiXantphos
ligand in THF at 24 °C under a nitrogen atmosphere (eq 4). We
To compare the catalytic reactivity using different counter-
cations (Li, Na vs K), we carried out our DCCP reactions under
standard conditions with 2-benzylpyridine (1g) and 1-tert-butyl-
4-chlorobenzene (2a) using the following 3 bases: LiN(SiMe3)2,
NaN(SiMe3)2, and KN(SiMe3)2. We have previously demon-
strated that DCCP of diphenylmethane (1a) with aryl bromides
is readily promoted by KN(SiMe3)2, but the reaction fails when
NaN(SiMe3)2 or LiN(SiMe3)2 is used in the absence of additives.
In contrast, DCCP of the more acidic substrate 2-benzylpyridine
(1g) can be promoted by MN(SiMe3)2 (M = Li, Na, K).11b Assay
yields of the product 3ga at 2 h from the DCCP reactions
employing 3 bases MN(SiMe3)2 (M = Li, Na, K) are illustrated in
eq 5 (average of two runs). The impact of the countercation on
propose that the in situ-generated coordinatively unsatu-
rated (K−NiXantphos)Pd(0) reacts rapidly with 1 equiv of K−
NiXantphos. The formation of Pd(K−NiXantphos)2 was
complete in 10 min as judged by the disappearance of 4 and
appearance of a new singlet at −1.3 ppm in the 31P{1H} NMR
spectrum. Single-crystals of Pd(K−NiXantphos)2 were obtained
by crystallization from THF at 24 °C and found to be extremely
sensitive, and sample decomposition during mounting could not
be avoided (see SI). Although the quality of the structure
precludes detailed discussion of the metrics, it does serve to
establish the connectivity {see Figure 4 for a drawing of the
the catalytic reaction follows the trend: K ≈ Na > Li. At this
point, it is difficult to draw conclusions from these data because
the main group metal is involved in the deprotonation of the
substrate and catalyst and in each step of the catalytic cycle.
Finally, we wanted to determine if the oxidative addition
product was a competent intermediate in the catalytic reaction.
As mentioned in eq 2, isolation of (Li−NiXantphos)Pd(Ph)(Cl)
from the byproducts of its synthesis was challenging. Instead, we
synthesized a neutral oxidative addition species, (NiXantphos)-
Pd(4-C6H4CN)(Br) (5) in 88% yield, following the procedure
for the preparation of (Xantphos)Pd(4-C6H4CN)(Br).25a
Subjecting 5 mol % 5 to the catalytic reaction resulted in 86%
isolated yield of the DCCP product 3aa (eq 6), suggesting that
the oxidative addition species is a competent intermediate.
Figure 4. Drawing of the solid-state structure of polymeric Pd(K−
NiXantphos)2 illustrating the connectivity.
structure and Figure 5 for the structure of [PdK2(THF)4-
(NiXantphos)2]∞}. In the solid state Pd(K−NiXantphos)2
exhibits a polymeric structure in which the Pd(0) center adopts
a slightly distorted tetrahedral geometry. The PdL2 units are
3. SUMMARY AND OUTLOOK
On the basis of a large number of studies, it was widely accepted
that palladium complexes based on bidentate triarylphosphines
Figure 5. Structure of polymeric [PdK2(THF)4(NiXantphos)2]∞.
Coordinated THF molecules and phenyl groups from NiXanphos are
shown in wireframe, and hydrogen atoms are omitted for clarity.
H
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Journal of the American Chemical Society
Article
obtained on a Waters LC-TOF mass spectrometer (model LCT-XE
Premier) using chemical ionization (CI) or electrospray ionization
(ESI) in positive or negative mode, depending on the analyte. Melting
points were determined on a Unimelt Thomas-Hoover melting point
apparatus and are uncorrected.
would not oxidatively add unactivated aryl chlorides at room
temperature and could not, therefore, catalyze coupling
processes with aryl chloride substrates. In this report we have
disclosed an exception to this paradigm by demonstrating that
under basic reaction conditions the heterobimetallic Pd(M-
NiXantphos)-based catalyst system readily activates aryl
chlorides at room temperature and successfully promotes the
arylation of diphenylmethane derivatives.
The advantages of the Pd−NiXantphos catalyst system are (1)
mild conditions (room temperature) for cross-coupling reactions
with unactivated aryl chlorides, (2) greater air- and oxidative-
stability of NiXantphos relative to alkylphosphines (many of
which are of high sensitivity and/or pyrophoric), (3) superior
catalytic performance to all the other mono- and bidentate
ligands examined in this report, and (4) commercial availability
of palladium source and ligand.
A dramatic difference in the catalytic performance was ob-
served between NiXantphos (91% AY) and its structurally
similar analogues N-Bn-NiXantphos (1% AY) and Xantphos
(0% AY), supporting our hypothesis that the oxidative addition is
facilitated with NiXantphos because the heterobimetallic
Pd−ligand catalyst system exhibits greatly enhanced reactivity
due to the presence of the main group metal. The DCCP with
aryl chlorides affords a variety of triarylmethane products, a class
of compounds with applications and biological activity. Addi-
tionally, the DCCP exhibits remarkable chemoselectivity in the
presence of aryl chloride substrates bearing heteroaryl groups
and sensitive functional groups that are known to undergo 1,2-
addition, aldol reaction, O−, N−, enolate-α−, and C(sp2)−H
arylation reactions.
The advantages and importance of the Pd−NiXantphos
catalyst system outlined herein make it a valuable contribution
to applications in Pd-catalyzed arylation reactions with aryl chlo-
rides under mild conditions. Future work will focus on structural
modification of NiXantphos to increase its reactivity and effi-
ciency in catalytic processes.
4.2. General Procedure A. Pd-Catalyzed DCCP of Diaryl-
methanes with Aryl Chlorides. An oven-dried 10 mL reaction
vial equipped with a stir bar was charged with KN(SiMe3)2 (59.8 mg,
0.30 mmol, 3 equiv) under a nitrogen atmosphere. A solution (from a
stock solution) of Pd(OAc)2 (0.56 mg, 0.0025 mmol, 2.5 mol %) and
NiXantphos (2.76 mg, 0.0050 mmol, 5 mol %) in 0.5 mL of dry THF
was taken up by syringe and added to the reaction vial. After stirring for
5 min at 24 °C, diphenylmethane (16.7 μL, 0.1 mmol, 1 equiv) was
added to the reaction mixture followed by 1-tert-butyl-4-chlorobenzene
(33.4 μL, 0.2 mmol, 2 equiv). Note that the aryl chloride in a solid form
was added to the reaction vial prior to KN(SiMe3)2. The reaction
mixture was stirred for 12 h at 24 °C, quenched with three drops of H2O,
diluted with 3 mL of ethyl acetate, and filtered over a pad of MgSO4 and
silica. The pad was rinsed with additional ethyl acetate, and the solution
was concentrated in vacuo. The crude material was loaded onto a silica
gel column and purified by flash chromatography.
4.3. General Procedure B. Pd-Catalyzed DCCP Followed by
Ligand Exchange and Recovery of NiXantphos. The experiments
were set up inside a glovebox under a nitrogen atmosphere. An 8 mL reac-
tion vial equipped with a stir bar was charged with KN(SiMe3)2 (329 mg,
1.65 mmol, 3 equiv). A solution of Pd(OAc)2 (6.2 mg, 0.028 mmol,
5 mol %) and NiXantphos (30.0 mg, 0.054 mmol, 10 mol %) in 6 mL of
dry CPME was taken up by syringe and added to the reaction vial.
After stirring for 5 min at 24 °C, diphenylmethane (110 μL, 0.66 mmol,
1.2 equiv) was added to the reaction mixture followed by 1-bromo-4-
tert-butylbenzene (95 μL, 0.55 mmol, 1 equiv). The reaction mixture
was stirred for 12 h at 24 °C, before 1,2-bis(diethylphosphino)ethane
(depe, 103 μL, 0.44 mmol, depe:NiXantphos = 8:1) was added into the
reaction mixture. The reaction mixture was stirred for another 40 min at
24 °C. The reaction was quenched with H2O, diluted with ethyl acetate,
and filtered over a pad of silica. The pad was rinsed with additional ethyl
acetate, and the solution was concentrated in vacuo. The crude material
was loaded onto a silica gel column and purified by flash chro-
matography to afford the triarylmethane product 3aa (91% yield) and
NiXantphos (80% recovery).
4.4. General Procedure C. HTE for Pd-Catalyzed DCCP of
Diphenylmethane with 1-tert-Butyl-4-chlorobenzene. Experi-
ments were set up inside a glovebox under a nitrogen atmosphere. A 96-
well aluminum block containing 1 mL glass vials was predosed with
Pd(OAc)2 (1 μmol) and Ligand (Ligand was used in a 4:1 ratio relative
to Pd for monodentate ligands and 2:1 ratio for bidentate ligands) in
THF. The solvent was evacuated to dryness using a Genevac vacuum
centrifuge, and KN(SiMe3)2 (30 μmol) in THF was added to the ligand/
catalyst mixture. The solvent was removed on the Genevac, and a
parylene stir bar was then added to each reaction vial. 1-tert-Butyl-4-
chlorobenzene(10μmol/reaction), diphenylmethane(12 μmol/reaction)
and biphenyl (1 μmol/reaction) (used as an internal standard to mea-
sure HPLC yields) were then dosed together into each reaction vial as a
solution in CPME (100 μL, 0.1 M). The 96-well plate was then sealed
and stirred for 18 h at 24 °C. Upon opening the plate to air, 500 μL of
acetonitrile was pipetted into each vial. The plate was then covered again
and the vials stirred for 20 min to extract the product and to ensure good
homogenization. Into a separate 96-well LC block was added 700 μL of
acetonitrile, followed by 40 μL of the diluted reaction mixtures. The LC
block was then sealed with a silicon-rubber storage mat, and mounted on
an HPLC instrument for analysis.
4. EXPERIMENTAL SECTION
Representative procedures are described herein. Full experimental
details and characterization of all compounds are provided in the SI.
4.1. General Methods. All reactions were performed under
nitrogen using oven-dried glassware and standard Schlenk or vacuum
line techniques. Air- and moisture-sensitive solutions were handled
under nitrogen and transferred via syringe. THF was freshly distilled
from Na/benzophenone ketyl under nitrogen. Anhydrous CPME,
2-MeTHF, dioxane, and MTBE were purchased from Sigma-Aldrich
and used as solvent without further purification. Unless otherwise stated,
reagents were commercially available and used as purchased without
further purification. Chemicals were obtained from Sigma-Aldrich,
Acros, TCI America or Alfa Aesar, and solvents were purchased from
Fisher Scientific. The progress of the reactions was monitored by thin-
layer chromatography using Whatman Partisil K6F 250 μm precoated
60 Å silica gel plates and visualized by short-wavelength ultraviolet light
as well as by treatment with ceric ammonium molybdate (CAM) stain or
iodine. Silica gel (230−400 mesh, Silicycle) was used for flash chro-
1
matography. The H NMR and 13C{1H} NMR spectra were obtained
4.5. General Procedure D. Synthesis of K−NiXantphos.
Experiments were set up inside a glovebox under a nitrogen atmosphere.
To a 20 mL vial containing NiXantphos (110 mg, 0.2 mmol, 1 equiv)
dissolved in 10 mL of Et2O was slowly added a solution of KN(SiMe3)2
(40 mg, 0.2 mmol, 1 equiv) in 2 mL of Et2O, resulting in rapid
precipitation of a yellow solid. After stirring for 2 h, the slurry was filtered
through a fritted filter, and the solid was washed with 3 × 5 mL Et2O.
Drying the solid under reduced pressure yielded a yellow powder.
X-ray diffraction-quality single crystals were obtained by layering a
using a Bruker AM-500 Fourier-transform NMR spectrometer at 500
̈
and 125 MHz, respectively. Chemical shifts are reported in units of parts
per million (ppm) downfield from tetramethylsilane (TMS), and all cou-
pling constants are reported in hertz. The 31P{1H} NMR spectra were
obtained using a Bruker DMX-360 NMR spectrometer at 145.8 MHz,
̈
with chemical shifts reported with respect to calibration with an external
standard of phosphoric acid (0 ppm). The infrared spectra were
obtained with KBr plates using a PerkinElmer Spectrum 100 series FTIR
spectrometer. High-resolution mass spectrometry (HRMS) data were
I
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Journal of the American Chemical Society
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concentrated THF solution of K−NiXantphos with hexanes at −21 °C.
X-ray diffraction-quality single crystals of the reddish-orange crown
ether adduct, K(THF)(18-crown-6)−NiXantphos, were obtained
by vapor diffusion of pentane into a concentrated THF solution of
K−NiXantphos and 18-crown-6 (1:1) at −21 °C.
Rosemeier, S. M.; Beranek, M. T.; Nickse, S. B.; Stone, J. J.; Stockland, R.
A.; Baldwin, S. M.; Kastner, M. E. Organometallics 2003, 22, 523. Suzuki
coupling at ≥110 °C: (e) Kwong, F. Y.; Chan, K. S.; Yeung, C. H.; Chan,
A. S. C. Chem. Commun. 2004, 2336. Suzuki coupling at ≥50 °C and
Heck reaction at ≥110 °C: (f) Iwasawa, T.; Komano, T.; Tajima, A.;
Tokunaga, M.; Obora, Y.; Fujihara, T.; Tsuji, Y. Organometallics 2006,
25, 4665. Suzuki coupling at ≥75 °C (2 examples) and Heck reaction at
120 °C (1 example): (g) Iwasawa, T.; Kamei, T.; Watanabe, S.;
Nishiuchi, M.; Kawamura, Y. Tetrahedron Lett. 2008, 49, 7430. Suzuki
coupling at 60 °C: (h) Fujihara, T.; Yoshida, S.; Terao, J.; Tsuji, Y. Org.
Lett. 2009, 11, 2121. Suzuki coupling at ≥110 °C: (i) So, C. M.; Chow,
W. K.; Choy, P. Y.; Lau, C. P.; Kwong, F. Y. Chem.−Eur. J. 2010, 16,
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See references on computational studies of oxidative addition of aryl
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26, 550.
4.6. General Procedure E. Oxidative Addition of Chloroben-
zene to (M−NiXantphos)Pd(0). Experiments were set up inside a
glovebox under a nitrogen atmosphere. Precatalyst 4 (9.2 mg, 0.01 mmol,
1 equiv) was added to a J. Young NMR tube followed by chlorobenzene
(5.1 μL, 0.05 mmol, 5 equiv). LiN(SiMe3)2 (5.9 mg, 0.035 mmol,
3.5 equiv) was weighed in a vial, dissolved in THF (500 μL), and trans-
ferred to the NMR tube. The solution became reddish-orange imme-
diately. The progress of the reaction was monitored by 31P{1H} NMR
spectroscopy. X-ray diffraction-quality single crystals of the protonated
(NiXantphos)Pd(Ph)(Cl) were obtained by vapor diffusion of pentane
into a concentrated THF solution of the reaction mixture at −21 °C.
4.7. General Procedure F. Synthesis of Pd(K−NiXantphos)2.
Experiments were set up inside a glovebox under a nitrogen atmosphere.
NiXantphos (5.5 mg, 0.01 mmol, 1 equiv) and precatalyst 4 (9.2 mg,
0.01 mmol, 1 equiv) were added to a J. Young NMR tube. KN(SiMe3)2
(9.0 mg, 0.045 mmol, 4.5 equiv) was weighed in a vial, dissolved in
THF (500 μL), and transferred to the NMR tube. The solution be-
came reddish-orange immediately. The progress of the reaction was
monitored by 31P{1H} NMR spectroscopy. The formation of Pd(K−
NiXantphos)2 was complete in 10 min, as judged by disappearance of 4
and appearance of a new singlet at −1.3 ppm in 31P{1H} NMR spectrum.
The reaction mixture was set undisturbed for 12 h. X-ray diffraction-quality
single crystals of Pd[K(THF)2(NiXantphos)]2 were obtained under these
conditions. The crystalline product was then filtered and washed with 3 ×
10 mL Et2O. Drying under reduced pressure yielded the product as a yellow
crystalline solid. The product is highly sensitive to trace oxygen.
(5) Reference 1a and references therein.
(6) Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1665 Note that
the oxidative addition of 10-fold excess of PhCl to Pd(dippp)2 required
90 °C to go to completion in 2 h in dioxane. The temperature range of
the kinetic measurements was 30−70 °C.
(7) Aryl tosylates oxidatively add to Pd(chelate)2: (a) Roy, A. H.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704. Aryl bromides
oxidatively add to Pd(chelate)2: (b) Alcazar-Roman, L. M.; Hartwig, J.
F.; Rheingold, A. L.; Liable-Sands, L. M.; Guzei, I. A. J. Am. Chem. Soc.
2000, 122, 4618. (c) Amatore, C.; Broeker, G.; Jutand, A.; Khalil, F. J.
Am. Chem. Soc. 1997, 119, 5176. (d) Jutand, A.; Hii, K. K.; Thornton-
Pett, M.; Brown, J. M. Organometallics 1999, 18, 5367.
(8) van der Veen, L. A.; Keeven, P. H.; Schoemaker, G. C.; Reek, J. N.
H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Lutz, M.; Spek, A. L.
Organometallics 2000, 19, 872.
(9) Note that transition metal/main group metal bimetallic activation
mode of sp2 C−X bonds has rarely been reported. The Nakamura group
disclosed that in the reaction of a lithium diorganocuprate(I) with an
alkenyl bromide, the sp2 C−Br bond was activated by Cu(I) and Li(I)
synergistically. See: (a) Yoshikai, N.; Nakamura, E. J. Am. Chem. Soc.
2004, 126, 12264. (b) Yoshikai, N.; Iida, R.; Nakamura, E. Adv. Synth.
Catal. 2008, 350, 1063. The same group later reported that in nickel-
catalyzed cross-coupling reactions of aryl electrophiles and Grignard
reagents, the sp2 C−X bonds (X = F, Cl, carbamates, phosphates, etc.)
were activated via a nickel/magnesium bimetallic cooperative
mechanism. See: (c) Yoshikai, N.; Matsuda, H.; Nakamura, E. J. Am.
Chem. Soc. 2009, 131, 9590.
ASSOCIATED CONTENT
* Supporting Information
Procedures, full characterization of new compounds, and crys-
tallographic data for (NiXantphos)Pd(Ph)(Cl), [K(THF)3−
NiXantphos]2, K(THF)(18-crown-6)−NiXantphos, and
[PdK2(THF)4(NiXantphos)2]∞.This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
pwalsh@sas.upenn.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-1152488 and 0848460) and NIH
(NIGMS 104349) for partial support of this research. We would
also like to thank Dr. Jun Gu for assistance with the DOSY
measurements.
(10) (a) McGrew, G. I.; Temaismithi, J.; Carroll, P. J.; Walsh, P. J.
Angew. Chem., Int. Ed. 2010, 49, 5541. (b) McGrew, G. I.; Stanciu, C.;
Zhang, J.; Carroll, P. J.; Dreher, S. D.; Walsh, P. J. Angew. Chem., Int. Ed.
2012, 51, 11510. (c) Zhang, J.; Stanciu, C.; Wang, B.; Hussain, M. M.;
Da, C.-S.; Carroll, P. J.; Dreher, S. D.; Walsh, P. J. J. Am. Chem. Soc. 2011,
133, 20552.
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