Synthesis and Study of a Dialkylbiaryl Phosphine Ligand; Lessons for Rational Ligand Design

Article abstract of DOI:10.1021/acs.organomet.9b00153

The rational design and synthesis of a novel dialkylbiarylphosphine ligand, 2′-(dimethylphosphine)-2,6-dimethoxy-1,1′-biphenyl (MeSPhos), for palladium-catalyzed C-N cross-coupling reactions is described. Based on previous results, it was hypothesized that a ligand with electronic properties similar to (2-biphenyl)dimethylphosphine (MeJPhos) but with greater steric bulk would allow the cross-coupling of previously inaccessible deactivated aryl chlorides. As predicted, MeSPhos exhibited similar electronic properties to MeJPhos. However, MeSPhos surprisingly showed a significantly smaller steric profile than MeJPhos. In comparison to the widely used CySPhos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl), MeSPhos promoted the oxidative addition of highly deactived aryl chlorides for which CySPhos was ineffective, but significantly decreased the rate of reductive elimination. The kinetics of cross-coupling reactions showed that the altered steric and electronic parameters of MeSPhos had a significant impact on the rate of cross-coupling, and the decreased steric bulk had a profound deleterious impact on the catalyst stability. With regard to this latter point, only the most activated aryl chlorides reacted at a sufficient rate to overcome the rate of catalyst decomposition. These results indicate that the relationship between the electron-donating ability of the phosphine ligand and the rate of oxidative addition is complex, and they also illustrate that increasing substitution on the biphenyl structure does not necessarily increase the steric bulk of the ligand.

Full text of DOI:10.1021/acs.organomet.9b00153

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pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Synthesis and Study of a Dialkylbiaryl Phosphine Ligand; Lessons
for Rational Ligand Design
Dillon J. Bryant, Lev N. Zakharov, and David R. Tyler*
Department of Chemistry and Biochemistry, University of Oregon, 1253 University of Oregon, Eugene, Oregon 97403, United
States
S
* Supporting Information
ABSTRACT: The rational design and synthesis of a novel
dialkylbiarylphosphine ligand, 2′-(dimethylphosphine)-2,6-
dimethoxy-1,1′-biphenyl (MeSPhos), for palladium-catalyzed
C−N cross-coupling reactions is described. Based on previous
results, it was hypothesized that a ligand with electronic
properties similar to (2-biphenyl)dimethylphosphine (MeJPhos) but with greater steric bulk would allow the cross-coupling of
previously inaccessible deactivated aryl chlorides. As predicted, MeSPhos exhibited similar electronic properties to MeJPhos.
However, MeSPhos surprisingly showed a significantly smaller steric profile than MeJPhos. In comparison to the widely used
CySPhos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl), MeSPhos promoted the oxidative addition of highly deactived
aryl chlorides for which CySPhos was ineffective, but significantly decreased the rate of reductive elimination. The kinetics of
cross-coupling reactions showed that the altered steric and electronic parameters of MeSPhos had a significant impact on the
rate of cross-coupling, and the decreased steric bulk had a profound deleterious impact on the catalyst stability. With regard to
this latter point, only the most activated aryl chlorides reacted at a sufficient rate to overcome the rate of catalyst decomposition.
These results indicate that the relationship between the electron-donating ability of the phosphine ligand and the rate of
oxidative addition is complex, and they also illustrate that increasing substitution on the biphenyl structure does not necessarily
increase the steric bulk of the ligand.
A successful ligand must have two key properties to expedite
the possible rate-limiting steps in the catalytic mechanism
(Figure 3): (1) it must donate sufficient electron density to the
palladium center in the catalyst to facilitate rapid oxidative
addition of the substrate, and (2) it must be sufficiently
sterically bulky to facilitate reductive elimination of the
arylamine.7 Past work by Hartwig and co-workers has shown
that for Pd0L2 species the mechanism of oxidative addition
depends only on the identity of the aryl halide and is
unaffected by the steric bulk of the ligand.8 It is not clear,
however, if this pattern holds for the Pd0L1 species that are
generated by Buchwald-type precatalysts.9 An additional
feature of the later-generation dialkylbiaryl phosphine ligands
is the para-substitution on the nonphosphine containing ring;
this substitution allows a Pd-OR interaction which stabilizes
oxidative addition complexes.10 In addition, the ligand must
sufficiently shield the Pd center to prevent metallic aggregation
and decomposition.11
INTRODUCTION
■
Carbon−nitrogen bond-forming reactions are of keen interest
for applications in medicine and biotechnology.1 Despite the
ubiquity of C−N bonds in biologically relevant molecules, the
synthetic toolkit for achieving these transformations is limited.2
Among the C−N bond-forming reactions, the Buchwald-
Hartwig cross-coupling has become a preeminent tool for the
formation of aryl C−N bonds (Figure 1).3,4
Figure 1. General form of a Buchwald-Hartwig C−N cross-coupling
reaction.
Despite the development of multiple phosphine ligands
(Figure 2) for these cross-coupling transformations, significant
challenges remain. For instance, many pharmaceutical targets
include sterically hindered amines or would involve the cross-
coupling of heteroaryl chloridestwo notoriously difficult
classes of cross-coupling partners.1,5,6 Likewise, highly
deactived aryl chlorides present significant difficulties as
starting materials because they are significantly less active
than their bromide and triflate counterparts, frequently
requiring strenuous conditions that may not be compatible
with highly functionalized molecules.6
Although palladium catalyzed C−N bond-forming reactions
were initially developed using phosphine ligands, recent work
has shown that other types of ligands are also effective partners
for these transformations, predominantly N-heterocyclic
carbene (NHC) ligands and more rarely exotic ligands such
as ylides.12−14 Beller-type ligands, based on a dialkylphosphi-
noimidazole scaffold, have also proven to be highly effective
Received: March 7, 2019
© XXXX American Chemical Society
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Figure 2. Common phosphine ligands used in aryl amination reactions.
of deactivated aryl chlorides. Using structure−activity relation-
ships and reactivity data from our previous studies,18,19 we
hypothesized that MeSPhos (2′-(dimethylphosphine)-2,6-
dimethoxy-1,1′-biphenyl) would be capable of cross-coupling
highly deactived aryl chlorides based on two factors: (1) The
σ-donating ability of the RJPhos ligands follow the trend
tBuJPhos < EtJPhos < iPrJPhos < CyJPhos ≪ MeJPhos.19 It is
reasonable to predict a similar trend with the RSPhos ligands.
If so, the strong electron-donating ability of the MeSPhos
ligand should promote oxidative addition. (2) Methoxy
substitution on the biphenyl scaffold will increase the steric
bulk of the ligand, thereby promoting reductive elimination
and increasing catalyst stability. We report herein the synthesis
of MeSPhos, a rationally designed ligand intended to promote
both oxidative addition and reductive elimination, either of
which could be the rate-limiting step in the catalytic cycle. In
addition, we report the results of using the MeSPhos ligand in
C−N cross-coupling reactions.
Figure 3. Proposed cycle for Pd-catalyzed C−N cross-coupling
RESULTS AND DISCUSSION
■
reactions.
Synthesis of MeSPhos (4). MeSPhos was synthesized in
four steps from commercially available reagents (Figure 4).
1,3-Dimethoxybenzene was treated sequentially with n-
butyllithium and 1,2-dibromobenzene to yield 2′-bromo-2,6-
dimethoxybiphenyl (1) in good yields (70−80%). Subsequent
treatment with n-butyllithium and diethyl chlorophosphate
yielded phosphonate 2 in good yield (70−80%). The reaction
of 2 with methylmagnesium bromide and sodium triflate,
ligands, particularly for the synthesis of important pharma-
ceutical targets.15,16 In addition, the use of bidentate phosphine
ligands frequently has several advantages such as lower catalyst
loadings and improved turnover numbers.17
With these properties in mind, we sought to rationally
design a phosphine ligand capable of catalyzing the amination
Figure 4. Synthesis of MeSPhos (4) from commercially available precursors.
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reported recently by our group,20 yielded the phosphine oxide
3. Reduction of the phosphine oxide with diisobutylaluminum
hydride (DIBAL-H), using a method reported by us,21 yielded
MeSPhos (4) in 26% overall yield.
Electronic Characterization of MeSPhos. To quantify
the electronic properties of the MeSPhos ligand, the
Cr(CO)5PR3 complexes in Table 1 were synthesized and
tBuJPhos), indicating that, as hypothesized, electronic effects
are dominated by the substituents at phosphorus and relatively
unaffected by substitutions on the biphenyl scaffold.
Δk1 = Δσ + 2Δπ
(1)
Δk2 = Δσ + Δπ
(2)
Steric Characterization of MeSPhos. The steric profile
of MeSPhos was studied by synthesizing (Figure 5) and
crystallizing (Figure 6) the trans-Pd(MeSPhos)2Cl2 complex
and then comparing the structure to the known X-ray
structures of the trans-Pd(PR3)2Cl2 complexes, where PR3 is
CySPhos, CyJPhos, and MeJPhos. The steric data are
summarized in Table 3. From these data, several interesting
conclusions can be drawn. As shown in prior work, the
palladium−phosphine distance is a proxy for front-strain
induced by the ligand.18 As expected, CyJPhos exhibits
significantly higher front strain than MeJPhos (longer Pd−P
bond length: 2.380 Å vs 2.319 Å, respectively). However,
replacement of the cyclohexyl groups on the SPhos scaffold
with methyl groups changes the Pd−P bond length only
slightly (2.349 Å for cyclohexyl and 2.342 Å for methyl), a
difference far less than the difference between MeJPhos and
CyJPhos (2.319 and 2.380 Å, respectively). This suggests that
in the SPhos scaffold front strain is governed heavily by
substitution on the biphenyl ring and only slightly by
substitution at phosphorus. This counterintuitive conclusion
likely arises from a simple observation of the crystal structures:
in the unsubstituted ligands (MeJPhos and CyJPhos), the
nonphosphorus containing phenyl ring is oriented toward the
palladium, while in the methoxy-substituted ligands (MeSPhos
and CySPhos), the nonphosphorus-containing phenyl ring is
oriented away from the palladium. This phenomenon is related
to the biphenyl torsional angle, a factor that will be discussed
in more depth in the following paragraphs. This ligand−
palladium interaction would best be described as back-strain;
however, it shows how these measures of steric bulk often
affect one another and are deeply interrelated.
The percent buried volume (Table 3) is a measure of the
overall steric profile that incorporates front strain but also
considers all steric contributions of atoms within a 3.5 Å
sphere centered at palladium. This parameter was calculated
using SambVca 2, an online tool developed by Falivene et al.25
Two important points come out of the percent buried volume
calculations: (1) As chemical intuition would predict, CySPhos
is slightly larger than CyJPhos (32.7% versus 32.1%,
respectively), but the difference is relatively small. This point
is important because it hints that substitution on the biaryl
scaffold has only a modest impact on the steric bulk of the
ligand. (2) As also expected, MeJPhos is smaller than CyJPhos
(30.5% versus 32.1%, respectively) but the difference is only
5%. In contrast, the difference between MeSPhos, 26.7%
buried volume, and CySPhos, 32.7% buried volume, is 18%,
significantly larger than would be anticipated based on the
Table 1. Band Frequencies and Force Constants of the
Cr(CO)5PR3 Complexes
Phosphine tBuJPhos18 MeJPhos18 MeSPhos CySPhos CyJPhos18
a
ν1(A1)
ν2(B1)
ν3(E)
ki
k1
k2
2072.1
2062.5
1937.1
1.0127
15.828
17.178
2059.6
2003.2
1937.5
0.52276
15.507
16.205
2060.9
1979.2
1937.27
0.33134
15.377
15.819
2073
2058
1937
0.97526
15.153
17.104
2072.1
2056.7
1937.1
0.96446
15.796
17.082
a
ki is the force constant for CO−CO interactions, k1 is the stretching
force constant for the CO trans to the phosphine, and k2 is the
stretching force constant for the CO group cis to the phosphine.18 All
force constants in mdyn/Å. All frequencies in cm−1.
their infrared spectra analyzed. The CO absorbance bands of
the complexes were identified based on prior studies (Table
1),18 and the relative vibrational force constants were
calculated from the appropriate frequencies.22 The force
constants are summarized in Table 1. From these results, the
σ-basicities and π-acidities of MeSPhos and CySPhos relative
t
to BuJPhos were calculated using the Graham treatment (eqs
1 and 2).22−24
As shown in Table 2, the Δπ and Δσ values of MeSPhos are
modestly changed relative to the values for MeJPhos (Δπ:
Table 2. Relative σ Donation and π Acceptance of the
a
t
Cr(CO)5PR3 Complexes Relative to BuJPhos
Phosphine tBuJPhos MeJPhos MeSPhos
CySPhos
CyJPhos
Δ ki
Δ k2
Δ σ
Δ π
Δ σ(%)
Δ π(%)
0
0
0
0
0
0
0.3203
0.974
1.63
−0.653
9.31
0.4511
1.356
−2.268
0.909
12.98
−5.06
0.6751
0.0749
−0.525
0.6002
−0.0339
0.0382
0.0321
0.0965
−0.1609
0.0644
0.00920
−0.00359
−3.64
a
k1 and k2 in mdyne/Å. See the SI for details on how these parameters
were calculated.
−3.64% vs −5.06%; Δσ: 9.31% vs 12.98%; all values
t
normalized relative to BuJPhos). These results indicate that
the methyl groups’ electronic properties are largely retained
despite alteration of the biphenyl scaffold. Similarly, there is
almost no difference in the electronic properties between
CySPhos and CyJPhos (Δπ: 0.0382% vs −0.00359%; Δσ:
−0.0339% vs 0.00920%; all values normalized relative to
Figure 5. Synthesis of trans-(MeSPhos)2PdCl2.
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Figure 6. ORTEP crystal structure of PdCl2(MeSPhos)2. Thermal ellipsoids are drawn at 50% probability. Hydrogens have been omitted for
clarity.
(9.97 for CySPhos and 18.34 for MeSPhos), strongly
suggesting that substitution at phosphorus profoundly alters
the sterics of phosphines coordinating to metal centers.
However, it is noteworthy that CyJPhos and CySPhos also
have significantly different S4′ values (16.91 and 9.97,
respectively), which indicates that the coordination geometry
at phosphorus is also affected by the substitution on the
biphenyl scaffold. The point here is that substitution at
phosphorus and substitution on the biphenyl scaffold can both
affect the S4′ value, which has a direct impact on the steric
demand of the ligand.
Taken together, these steric results illustrate an important
point: the steric properties of a ligand cannot be adequately
described by any single parameter because back-strain, front-
strain, and overall volume often trend together but do not
necessarily depend on one another. Given these results, our
hypothesis that MeSPhos will exhibit a greater steric strain
than MeJPhos was incorrect; in fact, MeSPhos has the smallest
overall steric profile (percent buried volume = 26.7%), despite
having the second shortest Pd−P bond length (2.342 Å).
Thus, our second hypothesis proposed in the Introduction,
that methoxy substitution on the biphenyl scaffold will increase
steric bulk, is not supported by these data.
Reactivity of MeSPhos in Pd-Catalyzed C−N Cross-
Coupling Aminations. C−N cross-couplings involving
MeSPhos and Pd0 salts were studied. Unfortunately, the only
aryl chloride substrate for which catalytic amination reactivity
could be reproducibly demonstrated was p-chlorobenzonitrile,
a highly activated aryl chloride (Figure 7). Analysis of the failed
reactions showed that in most cases, the majority of the aryl
chloride simply failed to react; however, in some cases we
observed a small amount of the dehalogenated product, a
known product of catalyst decomposition and failed reductive
elimination.5 In a single case, we observed catalytic conversion
of the aryl chloride to the dehalogenated product in
approximately 20% yield (Figure 8).29,30 (See section 1 of
the Supporting Information for the full list of substrates
studied and the reaction conditions.) It was hypothesized that
the low reactivity was due to failed generation of the
Table 3. Summary of Steric Data Comparing MeSPhos to
the Previously Reported MeJPhos and the Commercially
Available CyJPhos and CySPhos
a
Parameter
CyJPhos27 CySPhos28 MeSPhos MeJPhos18
Pd−P bond length (Å)
Percent buried volume
(including hydrogens)
(%)
2.380
32.1
2.349
32.7
2.342
26.7
2.319
30.5
Symmetric deformation
16.91
9.97
18.34
27.96
coordinate, S4′
a
All data are from the trans-Pd(PR3)2Cl2 complexes with the
exception of CyJPhos, which was obtained from the trans-Pd(PR)3Br2
complex.
small difference in MeJPhos and CyJPhos (Table 3). Careful
examination of the crystal structure provides a possible
explanation for why the difference between MeSPhos and
CySPhos is so large; specifically, CySPhos exhibits a biphenyl
torsional angle of 89.90°, whereas MeSPhos exhibits a biphenyl
torsional angle of 82.93°. (For comparison, the biphenyl
torsional angles in MeJPhos and CyJPhos are 59.24° and
61.82°, respectively. See Figure S1 in the Supporting
Information for a graphic representation of the biphenyl
torsional angles and how they were calculated.) These data
suggest that for the SPhos scaffold, the overall steric bulk is
dictated primarily by substitution at phosphorus and only
secondarily by substitution on the biphenyl ringlikely
because the methoxy-containing ring is oriented away from
the palladium, and only a sparing number of hydrogen atoms
are within the 3.5 Å sphere considered by the percent buried
volume calculation.
The last steric parameter discussed is the symmetric
deformation coordinate, S4′,26 which describes the distortion
at phosphorus in a metal complex from tetrahedral geometry
(high S4′, low steric demand) to trigonal pyramidal geometry
(near-zero or negative S4′, high steric demand). For a graphic
explaining the S4′, see Figure S2 in the Supporting
Information. As expected, cyclohexyl substitution at phospho-
rus leads to a significantly lower S4′ than methyl substitution
1
Figure 7. Cross-coupling of p-chlorobenzonitrile with morpholine. Yield is based on duplicate runs and estimated based on H NMR spectra.
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Figure 8. Catalytic dehalogenation of 4-(4-chlorophenyl)morpholine was observed as a major side product during the corresponding C−N cross-
1
coupling reaction. Yield is estimated based on H NMR spectra and recovered mass.
Figure 9. Synthesis of the generation 4 (G4) precatalyst from the free phosphine.
catalytically active species (Figure 3), which is a well-known
challenge in Pd cross-coupling reactions.29,31,32 In an attempt
to increase the generation of a more active catalytic species,
precatalyst 5 (Figure 9) was synthesized based on Buchwald’s
N-substituted aminobiphenyl palladium system (Figures 9 and
10).9,33
evidence for the formation of the oxidative addition complex
(Figure 11 and section 5 in the Supporting Information). Prior
studies showed that significant downfield shifts occur in the 31
P
NMR spectra when oxidative addition occurs.10,34 For
example, the free CySPhos ligand resonates at −8.6 ppm in
the 31P NMR spectrum, whereas the oxidative addition
complex with chlorobenzene has resonances at ca. 35 ppm
(Δppm = 44).28,34 For MeSPhos, the free ligand resonates at
−54 ppm, and the resonance attributed to the oxidative
addition product is at −8.5 ppm (Δppm = 46 ppm). In
addition, 13C/1H NMR HMBC and 1-dimensional NOSEY
experiments showed through-space interactions of the Me-
SPhos with protons on griseofulvin, indicating that the
MeSPhos and griseofulvin are within approximately 6 Å (see
section 5 of the Supporting Information for details). This
NMR evidence and the evidence for a palladium bound
phosphine are interpreted as strong evidence that MeSPhos
supports the rapid oxidative addition of highly deactivated aryl
chlorides, but the resulting complex is relatively unstable,
decomposing in less than 4 h at room temperature. Thus, the
second hypothesis in the previous paragraph, that MeSPhos
was incapable of oxidatively adding deactivated aryl chlorides,
is refuted by these data. In contrast, using NOESY experi-
ments, we found no evidence that CySPhos promoted the
oxidative addition of griseofulvin (Figures S50−S52). These
results imply that the electron-donating ability of the
phosphine may have an effect on the ability of its palladium
complexes to undergo oxidative addition.
Figure 10. ORTEP crystal structure of MeSPhos Pd G4, 5. Thermal
ellipsoids are drawn at 50% probability. Hydrogens have been omitted
for clarity.
Unfortunately, precatalyst 5 exhibited nearly identical
reactivity to the free phosphine/Pd0 catalyst system. (See
section 1 of the Supporting Information for details and full
reaction screenings.) In light of these results, two possibilities
were considered: (1) MeSPhos was forming an active catalytic
species, but the active catalytic species decomposed relatively
quickly so that only highly activated aryl chlorides could be
successfully aminated; or (2) MeSPhos was incapable of
oxidatively adding deactivated aryl chlorides.
Attempted Isolation of the Oxidative-Addition
Complex with Griseofulvin. To differentiate between the
hypotheses presented in the previous paragraph, griseofulvin,
an extremely deactivated aryl chloride, was selected as the
substrate. The synthesis and crystallization of the MeSPhos·Pd·
griseofulvin oxidative addition complex was repeatedly
attempted, but no stable product was obtained. (As shown
in Figure 3, the amine has no role in the oxidative addition
step. Therefore, no amine was included in these reactions.)
However, 1H, 13C, and 31P NMR spectroscopy provided strong
Kinetics and Reactivity Studies. Based on the hypoth-
eses presented in the Introduction,5 we expected the excellent
electron-donating ability of MeSPhos to promote oxidative
addition at a far faster rate than the comparable CySPhos,
which is less electron-donating. However, plots of concen-
tration vs time (Figures S22−S25) for the oxidative addition
reactions using these ligands do not support this hypothesis
(see SI section 8).35 More specifically, the data in SI section 8
show the following: (1) Either MeSPhos promotes oxidative
addition more slowly than CySPhos, or the oxidative addition
product undergoes rapid decomposition (CySPhos rapidly
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Figure 11. Stepwise cross-coupling of griseofulvin with 3-fluoro-N-methylaniline using the MeSPhos Pd G4 precatalyst.
Figure 12. 31P {1H} NMR spectrum of the reaction between CySPhos and Pd(dba)2 in dioxane. The broad singlet at ca. 38 ppm is likely the
Pd(CySPhos)2,37 and we hypothesize that the peak at ca. 44 is the Pd(CySPhos) complex.
forms a stable oxidative addition product); (2) under standard
cross-coupling conditions involving Pd0 salts and precatalysts,
multiple catalytically active species are present, as discussed
next.36
complex,37 while the peak at ca. 44 ppm is likely the
Pd(CySPhos) complex.38 These data imply that under
standard cross-coupling conditions, both PdL1 and PdL2
complexes are present. Moreover, the peak that is tentatively
assigned as the Pd(CySPhos) complex is also observed during
kinetic monitoring of the oxidative addition of p-chloroanisole
to CySPhos-supported palladium complexes. In addition, the
amount of free ligand also increases. These observations
support the hypothesis that oxidative addition of p-
chloroanisole undergoes oxidative addition to two distinct
species. These kinetic data, presented in the SI (section 8),
provide little useful information regarding reaction rates.
With regard to reductive elimination, it has been suggested
that increasing the electron-donating ability of the phosphine
will retard reductive elimination by electronically stabilizing
An additional complication in the interpretation of the
kinetics data was the presence of multiple catalytically active
species. Prior work established that multiple catalytically active
species form in the oxidative addition of aryl bromides, but
only a single species is active for aryl chlorides. To probe the
presence of multiple catalytically active species, we studied the
reaction of Pd(dba)2 and MeSPhos or CySPhos in the absence
of an aryl chloride using 31P NMR spectroscopy. For both
MeSPhos and CySPhos, the spectra show two distinct peaks: a
broad singlet and a sharp singlet (Figures 12 and 13). For
CySPhos, the peak at ca. 38 ppm is likely the Pd(CySPhos)2
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Figure 13. 31P {1H} NMR spectrum of the reaction between MeSPhos and Pd(dba)2 in dioxane. The broad singlet at ca. −4 ppm and sharp singlet
at ca. −9 are hypothesized to be PdL1 and PdL2 species; however, definitive assignments have not been made.
Figure 14. Palladium-catalyzed amination of p-chlorobenzonitrile with N-methylaniline was chosen as a model reaction to study the rate of cross-
coupling. In this instance, the precatalyst was used to avoid problems with delayed catalyst activation. N-Methylaniline was chosen as the amine
because it is conveniently monitored by NMR and is comparable in cross-coupling properties to morpholine. [ArCl] = 0.25 M, [Amine] = 0.30 M,
[Base] = 0.35 M.
the amine-bound oxidative addition complex.5 However, past
studies on analogous palladium-catalyzed etherification reac-
tions by Hartwig and co-workers suggest that the rate of
reductive elimination is determined primarily by the ligand’s
steric bulk and only slightly by the ligand’s electronic
properties.39 For the reactions in this study, it was not
possible to attribute the difference in reductive elimination
rates to differences in the sterics or the electronics of the
ligands because of the significant difference between MeSPhos
and CySPhos in both sterics and electronics (MeSPhos is an
approximately 12% stronger σ donor compared to CySPhos;
MeSPhos is 12% smaller than CySPhos). For example,
consider the rates of two cross-coupling reactions (Figure 14,
SI section 8). The cross-coupling reaction between p-
chlorobenzonitrile and n-methylaniline at 90 °C using
MeSPhos reached approximately 50% completion in 150 min
(kobs = 3 × 10−3 s−1), after which no additional product
formed.40 In contrast, CySPhos reached completion in
approximately 10 s (kobs estimated as 4 × 100 s−1). Whether
the slower rate for the MeSPhos system is caused by the
increased electron-donating ability of this ligand or by its
smaller size cannot be determined. These results suggest that it
is necessary to tune a ligand for three equally important
factors: (1) electron-rich phosphorus to promote oxidative
addition; (2) sterically congested phosphorus to promote
reductive elimination; and (3) sterically bulky ligand backbone
to prevent metallic aggregation. These requirements greatly
complicate the process of rational ligand design for this type of
catalysis because the most electron-rich phosphine substituents
are in general the sterically smallest,18 implying that there may
be a catalytic sweet spot. Furthermore, these requirements
suggest that the task of oxidatively adding highly deactived aryl
chlorides may remain out of reach until novel phosphines can
be designed that are both sterically large and electron rich.
Formation and Decomposition of the Oxidative
Addition Complex. As shown in Figures 11 and 15,
treatment of a solution of the precatalyst and griseofulvin
with sodium t-butoxide led to complete and nearly immediate
(∼10 min) activation of the precatalyst and formation of the
oxidative addition complex. Addition of the sodium t-butoxide
caused a color change to red then deep black. The 31P NMR
spectrum displayed a single major peak, which was unique
compared to the spectrum obtained from activating the
precatalyst with sodium t-butoxide in the absence of any aryl
chloride. Subsequent treatment of the reaction mixture with 3-
fluoro-N-methylaniline led to the rapid precipitation of a black
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Figure 15. 31P {1H} NMR spectrum of the stepwise cross-coupling of griseofulvin with 3-fluoro-N-methylaniline using MeSPhos Pd G4 precatalyst.
Spectrum A shows the formation of the oxidative addition complex with griseofulvin (ca. −11 ppm). Spectrum B, enormously magnified compared
to spectrum A, is the reaction solution immediately after addition of 3-fluoro-n-methylaniline. The precatalyst appears at −8 ppm and is absent in
both spectra. The minor peaks (+28.5, +6, +2, and −14 ppm, respectively) are unidentified decomposition products.
solid that was completely insoluble in all organic and aqueous
solvents tested (over 30 in all). The 31P NMR spectrum
showed that the dominant peak at ca. −11 ppm, assigned as
the oxidative addition complex, disappeared nearly completely.
It is well established that palladium catalysts typically
decompose by the formation of palladium aggregates
(colloquially referred to as palladium black).11,41,42 Likewise,
it has been proposed that the shielding degree, a particular
measure of steric bulk, can predict the stability of mononuclear
organometallic complexes.43 In the case of common
dialkylbiaryl phosphine ligands, the ligand supplies adequate
steric protection so as to largely prevent metallic aggregation;
however, with MeSPhos we postulate that there is insufficient
steric bulk to shield the metal center, and thus aggregation of
palladium readily occurs. This suggestion is well supported by
the steric data reported above, which shows that MeSPhos is
unusually small. In consequence, the decomposition of
MeSPhos-supported Pd complexes is unusually facile.
Chemical intuition suggests that an additional factor
contributes to the instability of the oxidative addition
complexes in the MeSPhos system. When MeSPhos is used
as a ligand, the oxidative addition product is more electron
dense than the analogous complexes with CySPhos due to the
greater σ-donating ability of the MeSPhos ligand. The
increased electron density in the case of the MeSPhos system
may promote metallic aggregation leading to catalyst
decomposition. Finally, the data suggest that the electron
density of the aryl halide also likely impacts the stability of the
oxidative addition complex. In particular, because p-chlor-
obenzonitrile was the sole successful substrate, it is suggested
that electron withdrawing halides increase the stability of the
oxidative addition complex, giving the reductive elimination
reaction a chance to compete with the decomposition reaction.
To summarize this section, two factors, low steric bulk and
electron-rich oxidative addition complexes, likely contribute to
the decomposition of the MeSPhos·Pd oxidative addition
complexes on a time scale comparable to reductive elimination.
SUMMARY AND CONCLUSIONS
■
The rational design and synthesis of a dialkylbiaryl phosphine
ligand, MeSPhos, was reported. We hypothesized that this
ligand would combine the high σ-donating ability of the related
MeJPhos ligand with the high steric bulk of the previously
reported and thoroughly utilized CySPhos. MeSPhos was
found to be an exceptional electron-donating phosphine which
promoted the oxidative addition of aryl chlorides that are not
reactive using typical ligands. However, no positive relationship
between electron-donating ability and the rates of oxidative
addition could be established. In fact, initial data suggests that
there may be an inverse relationship. The altered steric and
electronic properties of MeSPhos compared to CySPhos had
an equally significant impact on the rate of reductive
elimination, and the small steric size caused a substantial
decrease in the overall stability of the active catalytic species.
The instability of the active catalyst explains the low yield in
the sole successful C−N cross-coupling reaction as well as the
inability of MeSPhos-supported palladium to cross-couple
deactivated aryl chlorides with amines; the decomposition
reaction rate is far faster than the cross-coupling reaction rate
for all but the most activated substrates. These results illustrate
H
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(2.4158 g, 8.32 mmol) was added to the solvent by syringe. An
addition funnel was attached to one neck and a rubber septum to the
other neck. The addition funnel was charged with 30 mL dry degassed
tetrahydrofuran and diisobutylaluminum hydride (4.1515 g, 29.17
mmol) was transferred by cannula to the addition funnel. The flask
was cooled to 0 °C and the diisobutylaluminum hydride added
dropwise with strong stirring. The flask was stirred at 0 °C for 15 min
before the ice bath was removed and the addition funnel quick-
switched for a reflux condenser attached to a recirculator set at 5 °C.
The reaction was heated to reflux for 4 h. After 4 h, the flask was
cooled to room temperature. The reaction mixture was transferred by
cannula to a 500 mL Schlenk flask. A solution of sodium tribasic
phosphate 12-hydrate (32 g, 84 mmol) in 350 mL distilled, sparged
water was added by cannula slowly while cooling the reaction mixture
to 0 °C with strong stirring. The resulting homogeneous mixture was
allowed to stir at room temperature for 4 h. Degassed pentane, 20 mL,
was added by syringe and the flask thoroughly mixed by vigorous
shaking. The layers were allowed to separate without stirring and the
organic layer extracted using a syringe before being transferred to a
250 mL Schlenk flask. This extraction technique was repeated 4 times.
Dichloromethane was then added to the crude reaction mixture and
the extraction procedure repeated three times. From both the hexane
extracts and the dichloromethane extracts, the solvent was removed
under high vacuum with gentle heating to yield a white solid. Both
fractions were transferred to a glovebox maintained at less than 2 ppm
oxygen. The hexane extract was taken up in approximately 5 mL
diethyl ether and forced through a pipet packed with basic alumina.
An additional 5 mL of diethyl ether was pushed through the column
and both fractions combined, and the solvent removed to yield a
white solid (1.8296 g, 72%). The phosphine can be further purified by
recrystallization with hexane if necessary. The dichloromethane
extracts were found to contain nearly exclusively phosphine oxide
(3) which is easily purified by taking up into isopropanol and pushing
through silica to yield the pure phosphine oxide, which can be reused
for subsequent reductions. 1H NMR (500 MHz, CDCl3) δ 7.65−7.60
(m, 1H), 7.50−7.41 (m, 2H), 7.30−7.25 (m, 1H), 7.25−7.20 (m,
1H), 6.67 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.3 Hz, 1H), 3.72 (s, 3H),
1.16 (dd, J = 35.0, 3.4 Hz, 7H). 31P {1H} NMR (202 MHz, CDCl3) δ
−51.69. 13C NMR (126 MHz, benzene-d6) δ 158.46, 142.68 (d, J =
15.4 Hz), 140.54 (d, J = 30.1 Hz), 131.50 (d, J = 5.3 Hz), 129.19,
129.00 (d, J = 1.4 Hz), 128.18, 127.52, 104.05, 67.15, 55.21, 14.74 (d,
J = 15.4 Hz).
In Situ Synthesis of (MeSPhos)Cr(CO)5. In a nitrogen filled
glovebox, a 20 mL scintillation vial was charged with chromium
hexacarbonyl (21.8 mg, 99.1 μmol) Caution: toxic! and MeSPhos
(28.0 mg, 102 μmol). Dry, degassed tetrahydrofuran (10 mL) was
added. A small portion was transferred by syringe into a CaF2 cell and
the cell was removed from the glovebox. Before irradiation, an IR
spectrum was acquired. The sample was then irradiated using a high-
pressure mercury arc lamp and the spectra immediately recorded. The
sample was observed to turn pale yellow after approximately 5 min of
irradiation. Irradiation times required for definitive assignment may
depend on the intensity of irradiation; however, in our experience
irradiation times of 10, 30, 90, 180, and 600 s (total times) were
sufficient to observe conversion of the chromium hexacarbonyl into
the monosubstituted species and subsequent conversion to the trans-
disubstituted species. From each spectrum, the cell filled with only
THF was subtracted and the baseline corrected.
In Situ Synthesis of (CySPhos)Cr(CO)5. The above procedure
was used; however, CySPhos was used in lieu of MeSPhos, and the
UV intensity of the mercury arc lamp was reduced by placing a
borosilicate glass beaker in front of the IR cell.
Synthesis of trans-(MeSPhos)2Pd(Cl)2. In a nitrogen filled
glovebox, a 25 mL round-bottom flask was charged with PdCl2 (59.1
mg, 0.333 mmol) and MeSPhos (181.9 mg, 0.663 mmol). Dry,
degassed dichloromethane (8 mL) was added with a Teflon coated
stir bar. The heterogeneous mixture was stirred vigorously for 24 h,
after which it was a homogeneous pale yellow solution. The solution
was filtered through Celite, washed with 2 mL dichloromethane, and
the solvent removed under reduced pressure to yield a yellow powder.
two key points: (1) The electron density of the phosphine
influences the ability to oxidatively add challenging aryl
chlorides, but changing the electron density has a complex
effect on the rate thereof; and (2) although the commercially
available CySPhos ligand cannot promote the oxidative
addition of highly deactived aryl chlorides, it possesses steric
and electronic parameters optimal to promoting both the
oxidative addition and reductive elimination steps in the
catalytic cycle.
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise noted, all reactions
were run in oven-dried glassware under an inert atmosphere of
nitrogen utilizing standard Schlenk techniques or in a drybox
maintained at less than 2 ppm of O2. Diethyl ether and
tetrahydrofuran (THF) were dried using a DriSolv system using
CuO and molecular sieves under argon. Other solvents were purified
according to literature procedures and distilled under nitrogen.44
Amines were purchased from TCI and purified by passing through a
column of activated and dry alumina before storage under nitrogen in
a drybox. All other reagents were used as received. Thin layer
chromatography (TLC) was visualized with long-wavelength ultra-
violet light and phosphomolybdic acid. NMR spectra were recorded
on a 500 MHz INOVA-500, a 500 MHz Avance-500 Bruker, or a 600
MHz Avance-600 Bruker spectrometer and reported relative to the
internal solvent signal for proton and carbon spectra, or relative to the
external standard (85% H3PO4 in D2O) for phosphorus. All spectra
were collected at 25 °C unless otherwise noted. The results are
reported as chemical shift (δ, ppm), multiplicity, coupling constant
(Hz), and relative integration. Infrared spectra were recorded using a
Nicolet Magna-550 Fourier transform infrared spectrophotometer
using an air-free fluorite prism solution cell with a 0.1 mm cell
thickness.
Synthesis of 2′-(Dimethyl phosphine oxide)-2,6-dimethoxy
1,1′-biphenyl (3). An oven-dried 100 mL Schlenk round-bottom
flask was charged with 2 (1.6 g, 4.567 mmol), 50 mL dry degassed
tetrahydrofuran, and sodium triflate (2.357 g, 13.701 mmol). A water-
cooled reflux condenser was attached and the reaction mixture was
cooled to 0 °C. A recirculator was attached to the reflux condenser
and set to 0 °C, the temperature of which was confirmed before
continuing. A freshly titrated 0.63 M solution of methyl magnesium
bromide in diethyl ether (18.1 mL, 11.417 mmol) was slowly added
dropwise down the reflux condenser in such a way that the drops were
precooled and dripped off the lip of the condenser. The reaction
mixture was stirred under nitrogen for 20 min at room temperature
before being heated to reflux. After 2 h of refluxing, the reaction
mixture was cooled to room temperature. The reaction was
subsequently quenched by pouring it into a separatory funnel charged
with 100 mL 0.5 M sulfuric acid in water. The layers were quickly
separated. (Note this must be done quickly to prevent polymerization
of the tetrahydrofuran.) The aqueous layer was washed 5 times with
25 mL dichloromethane. The combined organic layers were dried
over sodium sulfate. The mixture was filtered and solvent removed
under reduced pressure to yield a yellow oil. A short (ca. 7 cm) plug
of silica in a 30 mm flash chromatography column was loaded with
ethyl acetate. The oil was wet loaded in ethyl acetate and washed with
100 mL ethyl acetate and subsequently with 100 mL isopropanol. The
solvent was removed from the isopropanol fraction under reduced
pressure and the oil dried under high vacuum to yield a hydroscopic
colorless glass, yield = 0.9423 g, 71%. 1H NMR (500 MHz, CDCl3) δ
8.29 (dd, J = 12.6, 7.2 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.55−7.47
(m, 1H), 7.36 (t, J = 8.5 Hz, 1H), 7.16−7.09 (m, 1H), 6.62 (d, J = 8.4
Hz, 1H), 3.68 (s, 5H), 1.32 (d, J = 13.4 Hz, 5H). 31P {1H} NMR (202
MHz, CDCl3) δ 34.67. 13C NMR (126 MHz, CDCl3) δ 157.95,
136.47 (d, J = 10.4 Hz), 134.54, 133.77, 132.97 (d, J = 7.4 Hz),
131.66 (d, J = 10.5 Hz), 131.52 (d, J = 2.4 Hz), 118.33 (d, J = 3.4
Hz), 103.78, 55.48, 17.70 (d, J = 70.6 Hz).
Synthesis of MeSPhos (4). A 100 mL two-neck Schlenk flask was
charged with 8 mL dry degassed tetrahydrofuran and a stir bar. 3
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Article
The powder was triturated 3 times with 1 mL diethyl ether to yield
the title compound as a light yellow solid. Crystals suitable for X-ray
crystallography were grown by vapor diffusion using THF/Pentane.
Yield = 136.6 mg (57%). 1H NMR (500 MHz, benzene-d6) δ 8.44 (q,
J = 6.9 Hz, 1H), 7.21−7.07 (m, 5H), 6.36 (d, J = 8.2 Hz, 2H), 3.29 (s,
6H), 1.52 (t, J = 3.6 Hz, 6H). 31P {1H} NMR (202 MHz, benzene-d6)
δ −4.11. 13C NMR (126 MHz, benzene-d6) δ 158.69, 139.06, 135.47
(t, J = 8.2 Hz), 133.93, 132.87 (t, J = 3.5 Hz), 129.81 (d, J = 34.7 Hz),
127.01 (d, J = 5.7 Hz), 119.28, 103.83, 100.37, 55.07, 13.27 (t, J =
15.4 Hz). (Note that in CDCl3 this compound is in equilibrium with a
dimer, resulting in two peaks at −3.2 and 9.50 ppm.)
Synthesis of Chloro(2-dimethylphosphino-2′,6′-dimethoxy-
1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (5).
In a nitrogen filled glovebox, a 20 mL scintillation vial was charged
with (2′-methylamino-1,1′-biphenyl-2-yl)methanesulfonatopalladium-
(II) dimer (559.6 mg, 0.7291 mmol) and MeSPhos (4) (400 mg,
1.458 mmol). Dry, degassed dichloromethane (17 mL) was added
with a Teflon coated stir bar. The black solution was allowed to stir
under nitrogen for 1.5 h. The solvent was then removed with the use
of a rotary evaporator, cold pentane was added, and the
heterogeneous mixture filtered using a glass frit. The solids were
washed sequentially with 10 mL diethyl ether, then methyl tert-butyl
ether. The purified precatalyst was collected by washing the frit with
100 mL dichloromethane and removing the solvent under high
vacuum. Crystals suitable for X-ray crystallography were grown by
vapor diffusion using CDCl3/diethyl ether. 1H NMR (500 MHz,
CDCl3) δ 8.02 (dd, J = 13.2, 7.8 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H),
7.52−7.42 (m, 2H), 7.37 (t, J = 8.4 Hz, 1H), 7.31 (d, J = 6.8 Hz, 1H),
7.22−7.17 (m, 1H), 7.11 (s, 0H), 7.04 (s, 1H), 6.77 (s, 1H), 6.65 (t, J
= 9.2 Hz, 2H), 3.72 (s, 6H), 1.32 (d, J = 11.1 Hz, 3H), 1.05 (d, J = 9.8
Hz, 3H). 31P {1H} NMR (202 MHz, CDCl3) δ 8.17. 13C NMR (151
MHz, methylene chloride-d2) δ 158.54, 158.19, 145.29 (d, J = 4.4
Hz), 142.85 (d, J = 3.3 Hz), 141.60, 140.01 (d, J = 6.8 Hz), 138.74,
137.54 (d, J = 13.6 Hz), 134.87 (d, J = 15.5 Hz), 133.34 (d, J = 7.3
Hz), 132.22, 131.92, 131.04 (d, J = 2.7 Hz), 130.48, 129.26, 128.53,
127.75 (d, J = 11.4 Hz), 127.39 (d, J = 4.7 Hz), 127.03 (d, J = 9.4
Hz), 125.74, 122.61 (d, J = 2.7 Hz), 118.21 (d, J = 4.0 Hz), 104.36 (d,
J = 26.5 Hz), 67.59, 55.98 (d, J = 20.3 Hz), 40.35 (d, J = 2.5 Hz),
39.94, 15.29 (d, J = 34.5 Hz), 13.89 (d, J = 29.8 Hz).
General Procedure for MeSPhos-Catalyzed Aminations. In a
nitrogen filled glovebox, an unregulated pressure vessel was charged
with the appropriate aryl chloride (1 equiv, 1 mmol), dioxane (4 mL),
the appropriate amine (1.2 mmol), and sodium tert-pentoxide (1.4
mmol). The precatalyst (0.04 mmol, 4% loading) was added as a
stock solution in dioxane. A Teflon coated stir bar was added, and the
vessel sealed and removed from the glovebox. The vessel was heated
to 90 °C in an oil bath behind a blast resistant shield for 20 h with
strong stirring, during which time an extremely dark red color
developed. The vessel was removed from the oil, diluted with diethyl
ether, and filtered through a pad of Celite. Reaction outcome was
determined by comparison of the proton NMR spectrum to
previously published results. Crude reactions were further analyzed
by GC-MS and 15N/1H HMBC. Yields are estimated based on
recovered mass and corrected for purity as determined by GCMS/1H
NMR.
standard, tetraethyl-1,2-ethanebisphosphonate in C6D6 was added.
Palladium(dba)2 (7.2 mg, 12.5 μmol) was added as a solution in
dioxane (400 μL). The tube was then quickly removed from the
glovebox and inserted into the instrument.
Stoichiometric Cross-Coupling of Griseofulvin and 3-
Fluoro-N-methylaniline. In a nitrogen filled glovebox a 1 dram
vial was charged with MeSPhos Pd G4 precatalyst 5 (21 mg, 31.86
μmmol), griseofulvin (9.5 mg, 26.9 μmol), and 600 μL of d8-
tetrahydrofuran. Sodium tert-pentoxide (4.9 mg, 41 μmol) was added
resulting in an immediate change to a copper color. The reaction
mixture was taken up into a syringe and filtered with a 0.2 μm syringe
filter directly into a J-Young adapted NMR tube. The tube was sealed
and removed from the glovebox and an NMR spectrum collected. The
reaction was returned to the glovebox and 3-fluoro n-methylaniline
(7.5 mg, 69.99 μmol) was added by syringe. An additional amount
(1.8 mg, 16.34 μmol) of sodium tert-pentoxide was added and the
reaction sealed and removed from the glovebox. Addition of the
amine resulted in an immediate color change to black along with
precipitation of a black solid. An NMR spectrum was subsequently
obtained.
Kinetics of Cross-Coupling Reaction. In a nitrogen filled
glovebox, a 20 mL scintillation vial was charged with a Teflon coated
stir bar and charged with p-chlorobenzonitrile (137.57 mg, 1.0 mmol),
hexamethylbenzene internal standard (28 mg, 0.17 mmol), N-
methylaniline (129 μL 1.2 mmol), and the appropriate precatalyst
(0.022 mmol). Dioxane (2 mL) was then added. A solution of sodium
tert-pentoxide (154.2 mg, 1.4 mmol) was prepared in 2.0 mL dioxane.
The reaction mixture was heated to 90 °C in an oil bath, and the
sodium tert-pentoxide added by syringe. Aliquots (400 μL) were
taken by syringe and quenched by addition to 2 mL methanol. The
solvent was then removed under reduced pressure with gentle heating
and dried on high vacuum. (Note: the starting material may be volatile
depending on pressure and temperature, and so integrals of starting
material may be inaccurate if a consistent solvent removal protocol is not
followed. The product is not volatile and not subject to the same
variability.) The time in all experiments is the time when the base was
1
added. See SI for details on quantitative H NMR.
X-ray Crystallography. Diffraction intensities for precatalyst 5
and PdCl2(MeSPhos)2 were collected at 173 K, respectively, on a
Bruker Apex2 CCD diffractometer using Cu Kα radiation, λ =
1.54178 Å. Space groups were determined based on systematic
absences (PdCl2(MeSPhos)2) and intensity statistics (5). Absorption
corrections were applied by SADABS.45 Structures were solved by
direct methods and Fourier techniques and refined on F2 using full
matrix least-squares procedures. All non-H atoms were refined with
anisotropic thermal parameters. H atoms in all structures were refined
in calculated positions in a rigid group model. Solvent molecules Et2O
in precatalyst 5 fill out empty space around an inversion center and
are highly disordered. This solvent molecule was treated by
SQUEEZE;46 corrections of the X-ray data by SQUEEZE is 28
electron/cell. The crystal structure of PdCl2(MeSPhos)2 seems to
have orthorhombic pseudosymmetry based on symmetry of the
central heavy atoms fragment, but the structure was solved and
refined in a monoclinic crystallographic system. All calculations were
performed by the Bruker SHELXL-2014 package.47
The X-ray crystallographic data for molecule
5 and
In Situ Formation of Oxidative Addition Complexes for
Kinetic Analysis. To a J-Young adapted NMR tube in a nitrogen
filled glovebox was added the appropriate phosphine (2.0 equiv, 25
μmol). The aryl chloride, p-chloroanisole (32 μL, 250 μmol), was
added by syringe. Dioxane (68 μL) was added by syringe. A sealed
capillary tube containing the internal standard, tetraethyl-1,2-
ethanebisphosphonate in C6D6 was added. Palladium(dba)2 (7.2
mg, 12.5 μmol) was added as a solution in dioxane (400 μL). The
tube was then quickly removed from the glovebox and inserted into
the instrument. The time in all experiments is the time from
palladium addition. See SI for details on quantitative 31P NMR.
In Situ Formation of Active Catalysts Using Pd(dba)2. To a J-
Young adapted NMR tube in a nitrogen filled glovebox was added the
appropriate phosphine (2.0 equiv, 0.25 μmol). Dioxane (68 μL) was
added by syringe. A sealed capillary tube containing the internal
PdCl2(MeSPhos)2 have been deposited at the Cambridge Crystallo-
graphic Data Centre (CCDC) under deposition numbers CCDC
1895567 and CCDC 1895568, respectively. These data can be
obtained free of charge from the CCDC (www.ccdc.cam.ac.uk/data_
request/cif).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00153.
■
S
Additional discussion of general considerations, addi-
tional syntheses, and commentary on procedures,
J
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infrared and NMR spectra and detailed kinetics plots
Article
Heterocyclic Carbene (NHC) Palladacycle Complexes. Org. Lett.
2003, 5 (9), 1479−1482.
(13) Zhang, Y.; Cesar, V.; Storch, G.; Lugan, N.; Lavigne, G.
(PDF)
́
Skeleton Decoration of NHCs by Amino Groups and Its Sequential
Booster Effect on the Palladium-Catalyzed Buchwald−Hartwig
Amination. Angew. Chem., Int. Ed. 2014, 53 (25), 6482−6486.
(14) Weber, P.; Scherpf, T.; Rodstein, I.; Lichte, D.; Scharf, L. T.;
Gooßen, L. J.; Gessner, V. H. A Highly Active Ylide-Functionalized
Phosphine for Palladium-Catalyzed Aminations of Aryl Chlorides.
Angew. Chem., Int. Ed. 2019, 58 (10), 3203−3207.
(15) Harkal, S.; Rataboul, F.; Zapf, A.; Fuhrmann, C.; Riermeier, T.;
Monsees, A.; Beller, M. Dialkylphosphinoimidazoles as New Ligands
for Palladium-Catalyzed Coupling Reactions of Aryl Chlorides. Adv.
Synth. Catal. 2004, 346 (13−15), 1742−1748.
(16) Schwarz, N.; Pews-Davtyan, A.; Michalik, D.; Tillack, A.;
̈
Kruger, K.; Torrens, A.; Diaz, J. L.; Beller, M. Palladium-Catalyzed
Accession Codes
CCDC 1895567−1895568 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dtyler@uoregon.edu.
ORCID
Amination and Sulfonylation of 5-Bromo-3-[2-(Diethylamino)-
Ethoxy]Indoles to Potential 5-HT6 Receptor Ligands. Eur. J. Org.
Chem. 2008, 2008 (32), 5425−5435.
David R. Tyler: 0000-0002-5032-7533
Notes
The authors declare no competing financial interest.
(17) Driver, M. S.; Hartwig, J. F. A Second-Generation Catalyst for
Aryl Halide Amination: Mixed Secondary Amines from Aryl Halides
and Primary Amines Catalyzed by (DPPF)PdCl2. J. Am. Chem. Soc.
1996, 118 (30), 7217−7218.
ACKNOWLEDGMENTS
■
(18) Kendall, A. J.; Zakharov, L. N.; Tyler, D. R. Steric and
Electronic Influences of Buchwald-Type Alkyl-JohnPhos Ligands.
Inorg. Chem. 2016, 55 (6), 3079−3090.
Acknowledgment is made to the NSF (CHE-1503550) for the
support of this research.
(19) Kendall, A. Synthesis, Study, and Catalysis of the New Dimethyl-
Phosphine Ligands; University of Oregon: Eugene, OR, 2016.
(20) Kendall, A. J.; Salazar, C. A.; Martino, P. F.; Tyler, D. R. Direct
Conversion of Phosphonates to Phosphine Oxides: An Improved
Synthetic Route to Phosphines Including the First Synthesis of
Methyl JohnPhos. Organometallics 2014, 33 (21), 6171−6178.
(21) Rinehart, N. I.; Kendall, A. J.; Tyler, D. R. A Universally
Applicable Methodology for the Gram-Scale Synthesis of Primary,
Secondary, and Tertiary Phosphines. Organometallics 2018, 37 (2),
182−190.
(22) Cotton, F. A.; Kraihanzel, C. S. Vibrational Spectra and
Bonding in Metal Carbonyls. I. Infrared Spectra of Phosphine-
Substituted Group VI Carbonyls in the CO Stretching Region. J. Am.
Chem. Soc. 1962, 84 (23), 4432−4438.
(23) Atkins, P.; Overton, T. Shriver and Atkins’ Inorganic Chemistry;
OUP Oxford, 2010.
REFERENCES
■
(1) Torborg, C.; Beller, M. Recent Applications of Palladium-
Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical,
and Fine Chemical Industries. Adv. Synth. Catal. 2009, 351 (18),
3027−3043.
(2) Bariwal, J.; van der Eycken, E. C−N Bond Forming Cross-
Coupling Reactions: An Overview. Chem. Soc. Rev. 2013, 42 (24),
9283−9303.
(3) Guram, A. S.; Renells, R. A.; Buchwald, S. L. A Simple Catalytic
Method for the Conversion of Aryl Bromides to Arylamines - Guram -
1995 - Angewandte Chemie International Edition in English - Wiley
Online Library. Angew. Chem., Int. Ed. Engl. 1995, 34 (12), 1348−
1350.
(4) Louie, J.; Hartwig, J. F. Palladium-Catalyzed Synthesis of
Arylamines from Aryl Halides. Mechanistic Studies Lead to Coupling
in the Absence of Tin Reagents. Tetrahedron Lett. 1995, 36 (21),
3609−3612.
(5) Surry, D. S.; Buchwald, S. L. Dialkylbiaryl Phosphines in Pd-
Catalyzed Amination: A User’s Guide. Chem. Sci. 2011, 2 (1), 27−50.
(6) Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-
Catalyzed C−N Cross-Coupling Reactions. Chem. Rev. 2016, 116
(19), 12564−12649.
(7) Christmann, U.; Vilar, R. Monoligated Palladium Species as
Catalysts in Cross-Coupling Reactions. Angew. Chem., Int. Ed. 2005,
44 (3), 366−374.
(8) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. Effect of
Ligand Steric Properties and Halide Identity on the Mechanism for
Oxidative Addition of Haloarenes to Trialkylphosphine Pd(0)
Complexes. J. Am. Chem. Soc. 2009, 131 (23), 8141−8154.
(9) Bruno, N. C.; Niljianskul, N.; Buchwald, S. L. N-Substituted 2-
Aminobiphenylpalladium Methanesulfonate Precatalysts and Their
Use in C−C and C−N Cross-Couplings. J. Org. Chem. 2014, 79 (9),
4161−4166.
(10) Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Structural Insights
into Active Catalyst Structures and Oxidative Addition to (Biaryl)-
Phosphine−Palladium Complexes via Density Functional Theory and
Experimental Studies. Organometallics 2007, 26 (9), 2183−2192.
(11) Iwasawa, T.; Tokunaga, M.; Obora, Y.; Tsuji, Y. Homogeneous
Palladium Catalyst Suppressing Pd Black Formation in Air Oxidation
of Alcohols. J. Am. Chem. Soc. 2004, 126 (21), 6554−6555.
(12) Viciu, M. S.; Kelly, R. A.; Stevens, E. D.; Naud, F.; Studer, M.;
Nolan, S. P. Synthesis, Characterization, and Catalytic Activity of N-
(24) Graham, W. A. G. Approach to the Separation of Inductive and
Mesomeric Effects in Complexes of the Types LMn(CO)5 and
LMo(CO)5 - Inorganic Chemistry (ACS Publications. Inorg. Chem.
1968, 7 (2), 315−321.
(25) Falivene, L.; Credendino, R.; Poater, A.; Petta, A.; Serra, L.;
Oliva, R.; Scarano, V.; Cavallo, L. SambVca 2. A Web Tool for
Analyzing Catalytic Pockets with Topographic Steric Maps. Organo-
metallics 2016, 35 (13), 2286−2293.
́
́
(26) Starosta, R.; Bazanow, B.; Barszczewski, W. Chalcogenides of
the Aminomethylphosphines Derived from 1-Methylpiperazine, 1-
Ethylpiperazine and Morpholine: NMR, DFT and Structural Studies
for Determination of Electronic and Steric Properties of the
Phosphines. Dalton Trans. 2010, 39 (32), 7547−7555.
(27) Xu, C.; Li, Y.-F.; Wang, Z.-Q.; Cen, F.-F.; Zhang, Y.-Q.
Dibromidobis[2-(Dicyclohexylphosphanyl)biphenyl-ΚP]Palladium-
(II). Acta Crystallogr., Sect. E: Struct. Rep. Online 2008, 64 (10),
m1349−m1349.
(28) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
Catalysts for Suzuki−Miyaura Coupling Processes: Scope and Studies
of the Effect of Ligand Structure. J. Am. Chem. Soc. 2005, 127 (13),
4685−4696.
(29) Kashin, A. S.; Ananikov, V. P. Catalytic C−C and C−
Heteroatom Bond Formation Reactions: In Situ Generated or
Preformed Catalysts? Complicated Mechanistic Picture Behind
Well-Known Experimental Procedures. J. Org. Chem. 2013, 78 (22),
11117−11125.
K
DOI: 10.1021/acs.organomet.9b00153
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(30) Viciu, M. S.; Grasa, G. A.; Nolan, S. P. Catalytic
Dehalogenation of Aryl Halides Mediated by a Palladium/
Imidazolium Salt System. Organometallics 2001, 20 (16), 3607−3612.
(31) de Vries, J. G. A Unifying Mechanism for All High-
Temperature Heck Reactions. The Role of Palladium Colloids and
Anionic Species. Dalton Trans. 2006, No. 3, 421−429.
(32) Ananikov, V. P.; Beletskaya, I. P. Toward the Ideal Catalyst:
From Atomic Centers to a “Cocktail” of Catalysts. Organometallics
2012, 31 (5), 1595−1604.
(33) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. Insights into
the Origin of High Activity and Stability of Catalysts Derived from
Bulky, Electron-Rich Monophosphinobiaryl Ligands in the Pd-
Catalyzed C−N Bond Formation. J. Am. Chem. Soc. 2003, 125
(46), 13978−13980.
(34) Brazier, J. B.; Newton, M. A.; Barreiro, E. M.; Adrio, L. A.;
Naya, L.; Hii, K. K. (Mimi). Solvent-Dependent Nuclearity,
Geometry and Catalytic Activity of [(SPhos)Pd(Ph)Cl]2. Dalton
Trans. 2017, 46 (22), 7223−7231.
(35) Definitive conclusions about the relative rates of the two
reactions could not be drawn because practical technical difficulties
prevented us from acquiring data during the first 30 minutes of the
reaction. Numerous attempts to work around this technical difficulty
proved fruitless..
(36) We attempted to use the generation four precatalysts for
oxidative addition kinetics, but the data was not suitable for
publication due to irreproducibility. The initial data did, however,
suggest two mechanisms were occurring..
(37) Reid, S. M.; Boyle, R. C.; Mague, J. T.; Fink, M. J. A
Dicoordinate Palladium(0) Complex with an Unusual Intramolecular
η-Arene Coordination. J. Am. Chem. Soc. 2003, 125 (26), 7816−7817.
(38) There is no evidence that the Pd0(PR3)2(n2-dba) complex (PR3
= MeSPhos or CySPhos) forms in any detectable amount.18,48
.
(39) Mann, G.; Shelby, Q.; Roy, A. H.; Hartwig, J. F. Electronic and
Steric Effects on the Reductive Elimination of Diaryl Ethers from
Palladium(II). Organometallics 2003, 22 (13), 2775−2789.
(40) The amination of p-chlorobenzonitrile with N-methylaniline at
90 °C was chosen because it was the sole reaction for which MeSPhos
successfully promoted cross-coupling..
(41) van Leeuwen, P. W. N. M. Decomposition Pathways of
Homogeneous Catalysts. Appl. Catal., A 2001, 212 (1), 61−81.
(42) Tromp, M.; Sietsma, J. R. A.; van Bokhoven, J. A.; van
Strijdonck, G. P. F.; van Haaren, R. J.; van der Eerden, A. M. J.; van
Leeuwen, P. W. N. M.; Koningsberger, D. C. Deactivation Processes
of Homogeneous Pd Catalysts Using in Situ Time Resolved
Spectroscopic Techniques. Chem. Commun. 2003, 0 (1), 128−129.
(43) Zakharov, L. N.; Saf’yanov, Yu. N.; Domrachev, G. A. A Role of
Non-Bonding Interactions in the Chemistry of Organometalic
Compounds. Inorg. Chim. Acta 1989, 160 (1), 77−82.
(44) Armarego, W. L. F.; Chai, C. Purification of Laboratory
Chemicals - 6th ed., 6th ed.; Elsevier, 2009.
(45) Sheldrick, G. M. G. M. Bruker/Siemens Area Detector Absorption
Correction Program, SADABS; Bruker AXS Inc: Madison, Wisconsin,
USA, 1998.
(46) van der Sluis, P.; Spek, A. L. BYPASS: An Effective Method for
the Refinement of Crystal Structures Containing Disordered Solvent
Regions. Acta Crystallogr., Sect. A: Found. Crystallogr. 1990, 46 (3),
194−201.
(47) Sheldrick, G. M. Crystal Structure Refinement with SHELXL.
Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71 (1), 3−8.
(48) Majchrzak, M.; Kostera, S.; Kubicki, M.; Kownacki, I. Synthesis
of New Styrylarenes via Suzuki−Miyaura Coupling Catalysed by
Highly Active, Well-Defined Palladium Catalysts. Dalton Trans. 2013,
42 (44), 15535−15539.
L
DOI: 10.1021/acs.organomet.9b00153
Organometallics XXXX, XXX, XXX−XXX