Rational ligand design for the arylation of hindered primary amines guided by reaction progress kinetic analysis

Article abstract of DOI:10.1021/ja512903g

We report the Pd-catalyzed arylation of very hindered α,α,α-trisubstituted primary amines. Kinetics-based mechanistic analysis and rational design have led to the development of two biarylphosphine ligands that allow the transformation to proceed with excellent efficiency. The process was effective in coupling a wide range of functionalized aryl and heteroaryl halides under mild conditions.

Full text of DOI:10.1021/ja512903g

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Article
Rational Ligand Design for the Arylation of Hindered Primary
Amines Guided by Reaction Progress Kinetic Analysis
Paula Ruiz-Castillo, Donna G Blackmond, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja512903g • Publication Date (Web): 04 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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Rational Ligand Design for the Arylation of Hindered Primary
Amines Guided by Reaction Progress Kinetic Analysis
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Paula Ruiz-Castillo†, Donna G. Blackmond‡ and Stephen L. Buchwald*,†
†Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United
States ‡ Department of Chemistry, Scripps Research Institute, La Jolla, California 92037, United States
ABSTRACT: We report the Pd-catalyzed arylation of very hindered α,α,α-trisubstituted primary amines. Kinetics-based
mechanistic analysis and rational design have led to the development of two biaryl phosphine ligands that allow the
transformation to proceed with excellent efficiency. The process was effective in coupling a wide range of functionalized
aryl and heteroaryl halides under mild conditions.
Introduction
primary amines have been reported. Amines 1 and 2 have been
previously cross-coupled with catalysts with either phosphines or N-
heterocyclic carbenes as supporting ligands.7a-e However, most of
these reactions require moderate catalyst loadings (1-5 mol%),
elevated temperatures (90-135 °C) and, most importantly, are
limited with regard to the substrate scope. In addition, there are no
examples using more hindered and challenging amine substrates
such as 3-5. The availability of a general method to obtain a broad
range of hindered anilines by a Pd-catalyzed C–N cross-coupling
process is desirable. Herein, we describe the development of two
related catalyst systems that demonstrate high activity for the
coupling of α,α,α-trisubstituted primary amines (1-5) with a variety of
(hetero)aryl halides. These complementary systems were developed
through an initial ligand screen followed by a rational ligand design
based on the results of the kinetic analysis of the reaction (Figure
1).
Organic molecules containing bulky alkyl groups have
shown great potential in drug discovery and medicinal chemistry.1a
Sterically-demanding alkyl substituents such as adamantyl or t-butyl
are often introduced into pharmaceuticals to enhance lipophilicity
and/or improve the drug’s metabolic stability by shielding adjacent
functional groups or reactive sites from enzymatic degradation.1b-f
Aminoadamantanes themselves have been examined and used as
antiviral drugs,1a,g-j however, aryl aminoadamantane derivatives and
other anilines based on hindered amines such as 3-5 (Figure 1)
remain largely unexplored, presumably due to difficulty in their
preparation.
Successful strategies that have previously been used to
synthesize these bulky anilines employ an electrophilic amination
approach. Amines 1 and 3 have been arylated through a titanium-
mediated coupling of the corresponding N-chloroamines with
Grignard reagents.2 Additionally, there are examples of transition-
metal free amination of arylboroxines and copper-catalyzed
amination of organozinc reagents using 3.3 Recently, Lalic
Initial Ligand Evaluation
In 2008 we reported BrettPhos (L1, Table 1), a biaryl
(dialkyl) phosphine ligand for the Pd-catalyzed arylation of primary
amines.8a BrettPhos-based catalyst systems often promote
amination reactions at low catalyst loadings and exhibit an
exceptionally broad scope for both the aryl halide and the primary
amine.8b
However,
when
we
evaluated
the
2-
aminobiphenylpalladium methanesulfonate precatalyst of L1 (P1),9
for the coupling of 3,5-dimethoxychlorobenzene (6) with t-octylamine
(3), the product (7) was formed in low yield (Table 1, entry 1). Given
the size of both L1 and 3, we felt that either amine binding (III,
Figure 1) or amine deprotonation (III to IV, Figure 1) could be
problematic.10 Therefore, we hypothesized that the use of a smaller
ligand would allow for more effective coordination to the Pd (II)
center and/or facilitate the approach of the base. Indeed, the yield
was significantly improved with the less sterically demanding11 and
less electron-rich PhBrettPhos, L2 (Table 1, entry 2). Furthermore,
the use of L3, which lacks methoxy groups on the phosphine-
containing arene ring, was even more effective (Table 1, entry 3).
The use of a ligand in which the distal arene of L3
Figure 1. The mechanism of Pd–catalyzed arylation of primary
amines and examples of bulky α,α,α–trisubstituted primary amines.
reported an elegant synthesis of hindered tertiary anilines through
the copper-catalyzed coupling of aryl boronic esters with O-benzoyl
hydroxylamines.4 While these methods are efficient, the electrophilic
amine must be separately prepared and many of the nucleophiles
that are employed are moisture-sensitive. A useful alternative is the
palladium-catalyzed C–N cross-coupling—an operationally simple
and widely used reaction in both industrial and academic settings.5a-i
Although advances in ligand design have overcome many
challenges,6 only a few examples of the N-arylation of hindered
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d
e
yield. 2% P4, 120 °C, 24 h. 1% P4, 100 °C, 12 h. fisolated
yield. (Ad= adamantyl)
Table 1. Ligand evaluation for the cross-coupling of 6
and
3a
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4
Reaction Kinetics Analysis
While the results with P4 were promising, relatively high
temperatures (100-120 °C) and catalyst loadings (1-3 mol %) were
required for the reaction to reach completion. In order to design an
improved catalyst system, we set out to qualitatively explore the
reaction rate dependence on each substrate using Reaction
Progress Kinetic Analysis (RPKA). As described by Blackmond,12a,b
RPKA is a simple, systematic method to obtain a complete picture of
a reaction’s kinetic profile from a limited number of experiments
performed under synthetically relevant conditions. This method has
been succesfully used in a number of laboratories,12c-f to elucidate
the reaction mechanism of various catalytic processes. The key
parameter utilized in RPKA is “excess”, which refers to the
difference between the initial concentrations of the two reactants (eq
(1)), and the kinetic information is obtained from reactions run under
“different excess” conditions.
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[excess] = [amine]0 – [aryl halide]0
(1)
We chose the model reaction between aryl chloride 6 and
amine 3 for our kinetic analysis using precatalyst P4. To broaden
the study, we also explored the reaction with the corresponding aryl
bromide 12. The reactions were monitored in situ by reaction
calorimetry along with GC analysis to support the calorimetry
results13 (see the Supporting Information). The reaction rate
progress over time profiles for both aryl halides are shown together
in Figure 2. It is immediately apparent that the shape of the curves is
different for each aryl halide, and that the reaction for ArBr is notably
faster than for ArCl. These observations suggest that the nature of
the aryl halide plays a key role in the kinetics of the reaction.14
Following the RPKA method, the data may be replotted as rate vs.
[substrate] to determine the rate orders of each substrate (only the
most informative graphs are shown for each case; all graphs are
included in the Supporting Information).
aAryl halide (0.5 mmol), amine (0.6 mmol), NaOt-Bu (0.6
mmol), 1,4-dioxane (0.5 mL). c
orrected GC yields
C
Figure 2. Temporal reaction rate profiles for the reaction of amine 3
(1.0 M) and ArCl 6 or ArBr 12 (concentrations defined by [excess]
given in legend, see eq (1)) catalyzed by P4 (0.02 M). Reaction at
had been modified by replacing the triisopropyl substituents with two
dimethylamino groups (L4) also gave the desired product in good
yield (Table 1, entry 4). The catalyst derived from the corresponding
dicyclohexylphosphino analog, CPhos (L5), gave no product,
suggesting that the relatively smaller and less electron-donating
phenyl groups on the phosphine atom are required to promote the
desired transformation.
The most effective precatalysts, P3 and P4, were further
evaluated in reactions between 3 and more complex aryl halides,
and the use of P4 initially gave the best results (Table 2).
0.04
ArBr, [excess] = 0 M
Table 2. Comparison between P3 and P4 and selected
examples of the initial reaction scope using P4a
0.03
ArBr, [excess] = 0.5 M
ArCl, [excess] = 0 M
0.02
0.01
0
ArCl, [excess] = 0.5 M
0
50
100
150
200
250
time (min)
70 °C in 1,4-dioxane.
aAryl halide (0.5 mmol), amine (0.6 mmol), NaOt-Bu (0.6
c
mmol), 1,4-dioxane (0.5 mL).b1% P, 80 °C, 90 min. GC
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Figure 3 shows the rate vs. [ArCl] plot for the two
“different excess” experiments shown in Figure 2 over the range of
[ArCl] common to both reactions. At any given value of [ArCl],
suggesting zero order kinetics in [amine]. Since oxidative addition of
aryl bromides is faster, the rate-determining step of the reaction has
shifted to a subsequent step in the catalytic cycle, which is
independent of both [ArBr] and [amine].18 Therefore, for the reaction
of aryl bromide 12 and amine 3 with precatalyst P4, reductive
elimination is most likely the rate-determining step.
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8
At approximately 40% conversion, the initial zero-order
regime shown in Figure 4 gives way to a slow linear decay in
reaction rate for the [excess] = 0 M reaction (equal amounts of aryl
bromide 12 and amine 3, see Supporting Information for full graph).
This behavior corresponds to initial saturation kinetics in [amine].12a
As the concentration of amine 3 decreases, amine binding to the Pd
(II) center becomes slower than reductive elimination and therefore,
rate-determining.
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0.008
[excess] = 0.5M
[amine] = 0.8 M
[excess] = 0 M
0.006
0.004
0.002
0
[amine] = 0.3 M
0.06
[excess] = 0 M
[ArBr] = 0.25 M
0
0.1
0.2
0.3
0.4
0.5
0.05
[excess] = 0.5 M
[ArCl] (M)
0.04
0.03
Figure 3. Reaction progress kinetic profiles for the reaction of ArCl 6
with amine plotted as rate vs. [ArCl] over the range of
concentrations common to the two reactions. Concentration of
amine 3 at the point in the reaction progress marked by the dashed
line is shown for each reaction.
3
0.02
[ArBr] = 0.75 M
0.01
0
the concentration of amine is different for the two kinetic profiles, as
illustrated by the dashed line (when [ArCl] = 0.3 M, [amine] = 0.8 M
and 0.3 M for the blue and red curves, respectively). Overlay of the
curves at different [amine] indicates that the rate is independent of
the concentration of amine for this range of concentrations. This
behavior was unexpected given the steric encumbrance of 3, which
we initially predicted to bind to the Pd (II) center with difficulty10 and
therefore be involved in the rate-determining step. However, the
linear decay of the curves indicates that the reaction has a positive
order in [ArCl] and that oxidative addition is (at least partially) rate-
determining.15 The fact that the reactions reached different
maximum rates when starting at different [ArCl] (Figure 2) provides
additional evidence for a positive order in aryl halide (since the
maximum rates do not differ by a factor of two, the order in ArCl is
fractional). The use of a ligand (L4) with phenyl groups as the
phosphine substituents could explain the relatively slow rate of
oxidative addition (computational evidence suggests that L2, has a
higher energy barrier than its alkyl analog L1 for this step).16
0.4
0.5
0.6
0.7
0.8
0.9
1
[amine] (M)
Figure 4. Reaction progress kinetic profiles for the reaction of ArBr
12 with amine 3 plotted as rate vs. [amine] over the range of
concentrations common to the two reactions. Concentration of ArBr
12 at the point in the reaction progress marked by the dashed line is
shown for each reaction.
The kinetic analysis of the reactions with two different aryl
halides suggests that to improve the catalyst system, oxidative
addition as well as reductive elimination need to be accelerated.
Modifying the ligand to make it both more electron-rich (faster
oxidative addition) and larger (faster reductive elimination) might
result in faster rates for each step.19 We reasoned that switching
from a biaryl (diaryl) phosphine-type ligand to the (dialkyl) phosphino
analog (Figure 5) would accomplish both requirements. However,
our initial ligand screen (Table 1) showed that CPhos (L5) gave no
product, suggesting this ligand was too large and/or too electron-
rich. We thus prepared ligands with one phenyl group and one alkyl
group (Figure 5). By incorporating one large alkyl group, we could
increase the electron density and size of the ligand, while keeping
the smaller aryl group should still allow amine binding and
deprotonation to proceed at a rapid rate.
Further probing of the reaction mechanism is possible by
exploring the behavior of aryl bromide 12. Since the rate of oxidative
addition is determined by the strength of the C–X bond,17 it was not
surprising that the reaction of 12 was ca. four times faster than that
of the aryl chloride 6 (t1/2 =10 min vs. 46 min for [ArX]0= 0.5 M). In
this case, plotting the data of the “different excess” experiments as
rate vs. [amine] for the concentrations common to the two reactions
provides insights about the aryl bromide reaction kinetics (Figure 4).
First, the overlay between the curves reveals identical rates at
different [ArBr] (as illustrated by the dashed line: when [amine] =
0.75 M, [ArBr] = 0.25 and 0.75 M for the blue and red curves,
respectively), indicating zero order kinetics in aryl halide, in contrast
to the ArCl case. This observation is confirmed by the fact that the
reactions achieve identical maximum rates (~0.03 M/min) for
different initial concentrations of aryl bromide (Figure 2). Second,
the rate appears to be relatively insensitive to the concentration of
amine. The nearly horizontal curves show the rate slightly
decreasing over the range of [amine] from 0.9 M to 0.5 M,
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rate of these reactions was ca. one order of magnitude greater than
those with precatalyst P4 (Figures 2 and 6)
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7
8
Figure 5. Ligand modifications at the phosphine atom
9
We synthesized two biaryl (alkyl)phenyl ligands in which
one of the phenyl groups on the phosphine of L4 is replaced with
either a cyclohexyl (L6) or a t-butyl group (L7) (Table 3, see the
Supporting Information for details of the preparation of the ligands).
The corresponding precatalysts P6 and P7 were prepared and
examined under identical conditions used in our previous ligand
assessment (Table 1). As hypothesized, the hybrid (alkyl)phenyl
phosphines L6 and L7 provided superior catalysts. A system based
on ligand L7 proved optimal, giving full conversion of 6 in less than
30 minutes at 70 °C (Table 3, entry 3).
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0.3
ArBr, [excess] = 0 M
0.25
0.2
0.15
0.1
0.05
0
ArBr, [excess] = 0.5 M
ArCl, [excess] = 0 M
ArCl, [excess] = 0.5 M
Table 3. Evaluation of P6 and P7 for the C–N cross-
coupling reaction between 6 and 3a
0
5
10
15
20
25
time (min)
Figure 6. Temporal reaction rate profiles for the reaction of amine 3
(1.0 M) and ArCl 6 or ArBr 12 (concentrations defined by [excess]
given in legend, see eq 1). Reaction at 70 °C for ArCl and 60 °C for
a
ArBr in 1,4-dioxane. Pd(L7): oxidative addition complex generated
in situ from (COD)Pd(CH2TMS)2, L7 and 12 (see the Supporting
Information for details).
Figure 7 shows the data from the “different excess”
experiments for aryl chloride 6 as rate vs. [ArCl] over the range of
[ArCl] common to both reactions. Although the reaction has a more
complex profile than with P4, the non-horizontal shape of the curves
and the different maximum rates (0.124 and 0.02 M/min for the blue
and the red curves, respectively), imply that there is a positive order
in aryl chloride, and thus that oxidative addition remains, at least
partially, the rate-determining step (the reaction has a fractional
order in [ArCl]). In contrast to the ArCl reactions with P4, the two
curves do not overlay, which could indicate a positive reaction order
in [amine] (the reactions have different rates at different amine
concentrations). However, the convex shape of the rate curves
(particularly explicit for the red curve) is typically a hallmark of
catalyst deactivation.22 The likelihood of rate dependence on [amine]
vs. catalyst deactivation can be deconvoluted with a quantitative
assessment. We can consider
aAryl halide (0.5 mmol), amine (0.6 mmol), NaOt-Bu (0.6
mmol), 1,4-dioxane (0.5 mL). bCorrected GC yields
To understand the difference between L4 and L7, we
investigated the kinetics of the reactions between aryl halides 6 and
12 and amine 3 using a catalyst based on L7 under the same
reaction conditions used for P4 (2% Pd, 70 °C). The use of ligand
L7 dramatically accelerated the rate of the reaction: t1/2 = 2.6 min
and 1.9 min for 6 and 12, respectively, whereas the half-lives with
P4 were 46 and 10 minutes for 6 and 12 ([ArX]0= 0.5 M; see
Supporting Information for details). To perform accurate calorimetric
kinetic studies of the improved system, we adjusted the reaction
conditions by reducing the catalyst loading (from 2 to 0.5 mol %)
and the temperature for the aryl bromide (from 70°C to 60 °C).20
More consistent results were observed at lower catalyst loadings
through in situ generation of an oxidative addition complex from
(COD)Pd(CH2TMS)2, ligand L7, and aryl halide than through the use
of precatalyst P7 as Pd source.21 In addition, it was found that better
results were obtained in the presence of an extra equivalent of L7
(with respect to the palladium catalyst), which was extended to the
general reaction conditions (Table 4).
The temporal rate profiles for these experiments are
shown in Figure 6. Even with the sharply reduced catalyst
concentration (and reduced temperature for the ArBr substrate), the
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a persistent steady-state kinetics behavior to allow further RPKA
0.15
0.1
0.05
0
analysis. However, since both “different excess” reactions with aryl
bromide 12 reach the same maximum rate independent of their
initial concentration, it can be inferred that the reaction is likely zero
order in ArBr as with precatalyst P4.23
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2
3
4
5
6
7
8
[excess] = 0 M
[excess] = 0.5 M
[amine] = 1.0 M
r = 0.124 M/min
[amine] = 0.5 M
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12
13
14
15
0
0.2
0.4
0.6
[ArCl] (M)
Figure 7. Reaction progress kinetic profiles for the reactions of ArCl
6 with amine 3 plotted as rate vs. [ArCl] over the range of
concentrations common to the two reactions. Concentration of
amine 3 at the point in the reaction progress marked by the dashed
line is shown for each reaction.
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relative rates of the two reactions at any given concentration of ArCl
and amine, with “x” and “y” as the reaction orders in [ArCl] and
[amine] respectively, and kobs as the observed rate constant, which
contains the catalyst concentration (eq (2)). Choosing [ArCl] = 0.5
M, we see from Figure 7 that [amine] = 1.0 M for the blue curve (the
beginning of the reaction) and 0.5 M for the reaction in red (50 %
conversion), and that their relative rates differ by a factor of 5 (eq
(3)). If kobs is identical for the two runs, “y”, is calculated to be
greater than two (eq (4a)), which is not mechanistically reasonable.
If the reaction is in fact zero order in [amine] (y = 0), eq (4b)
indicates that kobs for the red curve has been deactivated by a factor
of five at 50% conversion. Although this mathematical argument can
not entirely exclude rate dependence on [amine], catalyst
deactivation is a more likely explanation based on the shape of the
curves and the fact that different maximum rates are obtained for
different [ArCl].
Figure 8. X-ray structures of oxidative addition complexes 13 and
14, and relevant bond lengths. Thermal ellipsoids plotted at 50%
probability, hydrogen atoms are omitted for clarity.
X-Ray Structures of Oxidative Addition Complexes
Bearing L4 and L7
(2)
To gain a deeper insight into the differences between L4
and L7, we prepared oxidative addition complexes [L4ꢀPd(4-
CNPh)Br] (13) and [L7ꢀPd(4-CNPh)Br] (14),24 as air-stable yellow
solids and analyzed them by single crystal X-ray crystallography
(Figure 8). Similar to what has been previously observed with biaryl
(dialkyl) phosphine ligands, the complexes possess a slightly
distorted square planar geometry at Pd. As it has been observed
with L5,25 the dimethyl amino substituents were not coplanar with
the aryl ring to which they are attached, indicating that no
conjugation of the nitrogen lone pairs with the aromatic π-system is
occurring. Thus, the dimethylamino groups should be considered as
overall electron withdrawing by induction rather than electron
donating. This could assist the binding of bulky and electron-rich
amines by rendering the Pd center more electrophilic.16,26
(3)
(4a)
(4b)
Lastly, the data for the cross-coupling between aryl
bromide 12 and amine 3 with a catalyst based on L7, shown in
Figure 6, reveal the fastest reactions run in this work (even at 60
°C). The curves show an uncommon shape in which the rates reach
their maximum at ca. 25-35 % conversion, which suggests a delay
in the catalyst entering the catalytic cycle. In addition, as in the
reaction with aryl chloride 6, unusual behavior is observed at the
end of the reactions: the curves decay displaying a convex shape
(see Supporting Information for full graph), presumably due to
catalyst decomposition. Thus, it seems that the catalyst based on L7
has a transient nature in such a fast reaction, and does not establish
The most important distinction between 13 and 14 is the
C41–Pd–Br angle (θ), which decreased from 86.5° to 83.2°. We
infer that this geometric difference also applies to the amido
complexes (IV, Figure 1), bringing the two groups to be connected
closer in 14 than in 13 and therefore facilitating reductive
elimination.19
Reaction Scope
We next set out to examine the substrate scope of the
reaction with P7. We were able to reduce catalyst loadings from 1-
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2% P4 to 0.5 mol % P7 and the temperature from 100-120 °C to 80
°C for many substrates (Table 4). More challenging substrates
required 1 mol % Pd and 100 °C (e.g., with 30 or 33). A variety of
electron-deficient, electron-rich, and heteroaryl chlorides and
bromides were successfully coupled using this catalyst system.
Esters and nitriles (32, 34) were tolerated under the reaction
conditions, although free N–H heterocycles and enolizable ketones
were not compatible. Protic substrates such as phenols, carboxylic
acids and amides were also successfully coupled by using two
equivalents of base (23, 25, and 29). As previously reported,
nitrogen-containing five-membered heterocycles are challenging,
albeit important, substrates.8b,27 The reaction with 1-methyl-4-
bromopyrazole formed several byproducts in addition to the desired
product. However, replacing the methyl group with a trityl protecting
group led to the clean formation of 31.
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Reactions using ortho-substituted substrates and/or
tritylamine 5, were sluggish with P7 and the use of P4 provided
better results in these cases (Table 5). This system allowed for the
preparation of extremely hindered secondary anilines as 2,6-
disubstituted aryl halides (35) and substrates bearing large ortho
substituents (36) were successfully coupled in high yields.
Additionally, certain heteroaryl halides such as 5-chloro-[2,1,3]-
benzothiadiazole and 4-methyl-3-bromothiophene gave better
results using P4 (40, 42; 10-15% yields were obtained using P7).
For activated 2-halopyridines and pyrazine (41, 44, 45) the
corresponding ArOt-Bu byproduct was also observed28 but was
easily separated from the desired compound. Weaker inorganic
bases (Cs2CO3, K3PO4 or K2CO3) that could circumvent this issue
were found to be ineffective in promoting the desired transformation.
Nonetheless, a wide variety of substrates, including aryl halides
containing base-sensitive functional groups, were coupled with
deliberate choice of the supporting ligand (L7 or L4)
Table 4. Substrate scope using preatalyst P7a,b
aAryl halide (1 mmol), amine (1.2 mmol), NaOt-Bu (1.2 mmol), 1,4-
b
dioxane (1 mL). Isolated yields (average of two runs). c 0.5% P7,
0.5% L7, 80 °C. d1% P7, 1% L7, 80 °C. e1% P7, 1% L7, 100 °C. f2%
P7, 2% L7, 110 °C. g 3% P7, 3% L7, 100 °C
Table 5. Substrate scope using precatalyst P4a,b
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represent the official views of the National Institutes of Health. P.R-
C acknowledges “la Caixa” Fellowship for a predoctorate fellowship.
1
2
3
Notes
MIT has or has filed patents on ligands/precatalysts that are
described in the paper from which SLB and former/current
coworkers receive royalty payments.
4
5
6
ACKNOWLEDGMENTS
7
8
9
We thank Dr. Peter Müller (MIT) for X-ray structural analysis.
We thank Nootaree Niljianskul for providing L4 and Dr.
Naoyuki Hoshiya for helpful discussions and preliminary
studies. We thank Nicholas C. Bruno (MIT), Phillip J. Milner
(MIT), Dr. Aaron C. Sather (MIT) and Dr. Michael Pirnot for
assistance in the preparation of this manuscript.
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d
Conclusions
In summary, we have developed a general method for the
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a range of
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phosphine ligand that greatly accelerated the reaction with both aryl
halides. L7 is the first example of a hybrid (alkyl)aryl ligand that
provides superior results as compared to its analogues with identical
alkyl or aryl phosphorous substituents,19d offering another tunable
site for better control of catalyst activity. We anticipate that this
methodology will find applications in both academic and
pharmaceutical settings, and we expect the new class of biaryl
phosphine ligands reported here to influence our future design of
ligands.29
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ASSOCIATED CONTENT
Experimental procedures, experimental and spectroscopic
data for the new compounds, kinetic graphs and X-ray
crystallographic (CIF) data. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: sbuchwal@mit.edu
Funding Sources
Research reported in this publication was supported by the National
Institutes of Health under Award Number GM58160. The content is
solely the responsibility of the authors and does not necessarily
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8
(17) The reactivity trend towards oxidative addition follows
the order ArI > ArBr≈ArOTf > ArCl, (a) Crabtree, R. H., “The
Organometallic Chemistry of the Transition Metals”, John Wiley
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(18) Addition of different equivalents of base had no effect on
the reaction. However, it was observed that the base was not
totally soluble in the reaction solvent, therefore the possibility of
deprotonation being the rate-determining step can not be
completely disregarded.
(19) (a) Spessard, G. O.; Meissler, G. L. “Organometallic
Chemistry” Oxford University Press, 2nd Edition, 2010, New
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(20) In order to obtain accurate calorimetry data, the reaction
time should be at least 15-20 minutes.
(21) These conditions are comparable to the reaction set up
with precatalyst P4, in which the respective oxidative addition
complex was the palladium source as well, thus excluding
precatalyst activation from the calorimetry profile.
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(13) Due to the limited solubility of precatalyst P4, amine 3
was injected in to the reaction vial to initiate the reaction. The
reaction mixture was prepared with addition of P4, aryl halide 6,
base, and solvent. Before 3 was added, precatalyst P4 was
activated in the presence of the base and converted into the
respective oxidative addition complex, which enabled
precatalyst activation to be excluded from the calorimetry
profile.
(22) Blackmond D. G.; Schultz T.; Mathew, J. S.; Loew, C.;
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(23) Although the scenario in which the amine deprotonation
step is rate-determining could not be completely disregarded,
the great acceleration caused by the more hindered ligand, L7
suggests that the rate-determining step is in fact reductive
elimination.
(24) 4-bromobenzonitrile was used to prepare oxidative
addition complexes due to poor crystallinity of oxidative addition
complexes of aryl halides 6 or 12
(25) Yang, Y.; Niedermann, K.; Han, C.; Buchwald, S. L. Org.
Lett. 2014, 16, 4638.
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observed. It is unclear if its formation in certain cases occurs
a SNAr mechanism or through a cross-coupling
through
pathway.
Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 8141
.
(15) Attempts to observe the resting state of the catalyst by
31P NMR were unsuccessful; the hypothesis that oxidative
addition is the rate-determining step is the most consistent with
the available data.
(16) Calculated reaction barriers for the oxidative addition of
PhCl with LPd: L1: ꢀG≠= 10.8 kcal/mol; L2: ꢀG≠= 16.5 kcal/mol.
(29) Gladysz, J. A.; Bedford, R. B.; Fujita, M.; Gabbai, F. P.;
Goldberg, K. I.; Holland, P. L.; Kiplinger, J. L.; Krische, M. J.;
Louie, J.; Lu, C. C.; Norton, J. R.; Petrukhina, M. A.; Ren, T.;
Stahl, S. S.; Tilley, T. D.; Webster, C. E.; White, M. C.;
Whiteker, G. T. Organometallics 2014, 33, 1505.
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R
R
NH2
Pd L
OMs
R'
R'
0.5 - 2% P4 or P7
Ar
+
Ar-X
N
H
R''
NaOt-Bu,
80-120 °C
1,4-dioxane
H2N
R''
9
P
(L = L4 or L7)
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Ph
Ph
Ph
Reaction Progress
Kinetic Analysis
(RPKA):
P
P
t-Bu
NMe2
Me2N
NMe2
Me2N
design of a
more effecient ligand
PhCPhos
L4
(t-Bu)PhCPhos
L7
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