Aryl Amination Using Soluble Weak Base Enabled by a Water-Assisted Mechanism

Article abstract of DOI:10.1021/jacs.0c09275

The amination of aryl halides has become one of the most commonly practiced C-N bond-forming reactions in pharmaceutical and laboratory syntheses. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C-N coupling using Et3N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H2O generates, after proton loss, a coordinatively unsaturated Pd-OH species that can bind amine substrate triggering intramolecular N-H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et3N. The use of a simple, commercially available ligand, PAd3, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.

Full text of DOI:10.1021/jacs.0c09275

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Article
Aryl Amination Using Soluble Weak Base Enabled by a Water-
Assisted Mechanism
Sii Hong Lau, Peng Yu, Liye Chen, Christina B. Madsen-Duggan, Michael J. Williams,
and Brad P. Carrow*
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ABSTRACT: The amination of aryl halides has become one of the
most commonly practiced C−N bond-forming reactions in
pharmaceutical and laboratory syntheses. The widespread use of
strong or poorly soluble inorganic bases for amine activation
nevertheless complicates the compatibility of this important
reaction class with sensitive substrates as well as applications in
flow and automated synthesis, to name a few. We report a
palladium-catalyzed C−N coupling using Et3N as a weak, soluble
base, which allows a broad substrate scope that includes bromo-
and chloro(hetero)arenes, primary anilines, secondary amines, and
amide type nucleophiles together with tolerance for a range of
base-sensitive functional groups. Mechanistic data have established
a unique pathway for these reactions in which water serves multiple
beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H2O generates, after proton
loss, a coordinatively unsaturated Pd−OH species that can bind amine substrate triggering intramolecular N−H heterolysis. This
water-assisted pathway operates efficiently with even weak terminal bases, such as Et3N. The use of a simple, commercially available
ligand, PAd3, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible
for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-
coupling reactions with sensitive substrates and functionality.
development of new methods that operate efficiently with weak,
soluble, and inexpensive bases could circumvent all of these
issues and broaden the applicability of C−N coupling in
industrial applications.
INTRODUCTION
■
Carbon−nitrogen cross-coupling reactions using palladium and
related late transition metal catalysts are some of the most widely
utilized methods for the synthesis of pharmaceuticals, agro-
chemicals, organic electronic materials, and fine chemicals.1
Over that past two decades, numerous innovations in the
ligand(s) and precatalyst structure of palladium complexes have
been made that have expanded the diversity of organic
electrophile and amine nucleophile classes applicable to this
transformation.2 On the other hand, the bases used for
Buchwald−Hartwig amination have evolved to a lesser extent;
modern C−N coupling methods still rely heavily on ionic bases,
such as sodium tert-butoxide or lithium hexamethyldisilazide
(LiHMDS).3 Such strong ionic bases impose compatibility
issues with functional groups susceptible to nucleophilic attack,
such as carboxylic acids, esters, nitriles, nitro groups, and
carbonyl groups with enolizable sites, to name a few.4 Amination
reactions conducted on scale in organic solvents using common
inorganic bases, such as hydroxide and carbonate and phosphate
salts, also frequently incur reproducibility issues.5 High-
throughput experimentation (HTE)6 and continuous flow
chemistry7 face similar issues where base insolubility can present
either an inconvenience or major hurdle, respectively.8 The
The difficulty of transitioning C−N coupling toward the use
of weak, soluble bases can be attributed, at least in part, to a
mechanistic challenge using conventional Pd catalysts, such as
those ligated by BINAP as a prototypical example. A combined
computational and experimental mechanistic study by Norrby
found that soluble neutral bases such as the phosphazene tert-
butylimino-tri(pyrrolidino)phosphorene (t-BuP1(pyrr)), Bar-
ton’s guanidine base 2-tert-butyl-1,1,3,3-tetramethylguanidine
(BTMG), or the amidines 7-methyl-1,5,7-triazabicyclo[4.4.0]-
dec-5-ene (MTBD) and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) perform poorly relative to NaOtBu as a prototypical
strong ionic base (Scheme 1a).9 This striking difference was
Received: August 28, 2020
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demonstrated to provide a sufficient driving force to utilize
weak bases, such as DABCO.
Scheme 1. Base Effects in Pd-Catalyzed C−N Coupling
Importantly in the (AlPhos)Pd-catalyzed reactions, a ligand-
enabled mechanism change from a typical neutral to an ionic
pathway for N−H cleavage was identified, which facilitates the
efficient turnover with a weak base (Scheme 1b).11a Dissociation
of a triflate anion and coordination of amine leads to
acidification of the bound substrate to such an extent that the
cationic intermediate is susceptible to external N−H deproto-
nation by even moderate bases, like DBU. Furthermore, the
turnover-limiting step of these reactions was found to be
dissociation of DBU from an off-cycle intermediate coordinated
by this base, which highlights another challenge facing weak base
amination reactions involving Lewis basic (strongly coordinat-
ing) reagents. The extension of the applicable weak base further
to tertiary amines remains highly desirable in this area due to
their low cost, tunable properties, stability,17 and low basicity in
comparison to other soluble bases such as amidines, guanidines,
or phosphazenes. To this end, a Ni-catalyzed amination of aryl
triflates with anilines and triethylamine as base was recently
reported by Buchwald and co-workers.18 An ionic catalytic
pathway is also believed to operate in this system for which aryl
bromides and chlorides are more challenging substrates,
possibly due to stronger halide coordination to the transition
metal that inhibits ionization and amine binding. An outstanding
need thus remains for the identification of new catalysts that can
promote weak base coupling with widely available halo(hetero)-
arene electrophiles, as opposed to specialty aryl triflates, with a
variety of amine nucleophile classes using an “ideal” soluble
weak base, such as Et3N.19
Our group previously reported a coordinatively unsaturated
organopalladium complex, Pd(PAd3)(ArF)Br 1 (ArF = 4-
FC6H4), which functions as an on-cycle catalyst for Suzuki-
Miyaura coupling with organoboronic acids prone to fast base-
catalyzed protodeboronation (PDB).20 A key aspect of this
development was achieving efficient catalytic turnover using the
combination of H2O and a weak, soluble amine base (Et3N).
Stoichiometric mechanistic experiments implicated the ioniza-
tion of Pd(PAd3)(ArF)X (X = Br, Cl) complexes to cationic
species [Pd(PAd3)(ArF)(S)]+ (S = water, solvent),21 which
undergo facile deprotonation of the acidified aqua ligand even by
mild bases (Scheme 1c).22 It is thus possible to access
coordinatively unsaturated Pd-hydoxo intermediates (III,
Scheme 1c) that feature both Lewis acidic (open coordination
site) and Lewis/Brønsted basic properties in the absence of
stoichiometric ionic bases (i.e., hydroxide or alkoxides).23
Because palladium hydroxo and alkoxo complexes have been
implicated in numerous other catalytic processes but are
classically accessed by reactions involving stoichiometric strong
bases (e.g., NaOH, NaOtBu),24 it may be possible to leverage the
water-assisted pathway we uncovered to promote a range of
catalytic transformations under conditions milder than what was
possible using traditional catalysts.
The Brønsted basicity of species such as III should also be
reactive toward the activation of strong element−hydrogen
bonds, such as in the amine activation step (N−H heterolysis) of
Buchwald−Hartwig amination.25 While such species can be
generated from stoichiometric reactions of Pd(II)−halide
complexes with hydroxide,26 the intermediacy of palladium
hydroxo complexes in N−H bond activation has to our
knowledge not been unambiguously established in a catalytic
setting.27 We hypothesized that the coordination of amine to the
catalyst open site should strongly acidify the N−H bond, and the
correlated to the preference of the system to maintain neutral
reaction pathways in nonpolar organic solvents because
ionization of the neutral metal halide complexes is too
energetically unfavorable. Ionic bases are more reactive in the
neutral manifold, either by deprotonating a neutral amine-
coordinated Pd intermediate or through salt metathesis to
generate a basic Pd-alkoxo intermediate that can deprotonate an
amine substrate.10 Furthermore, amine bases such as DBU were
implicated in catalyst inhibition by competitively binding Pd to
form off-cycle intermediates.11
Several studies have recently demonstrated that newer
generation Pd complexes featuring hindered phosphines can
catalyze C−N coupling reactions with soluble bases. The
phosphazene superbase P2Et enabled homogeneous aminations
suitable for HTE screening on micro- or nanomole scales.12
However, phosphazene bases are prohibitively expensive for
large scale applications. Buchwald developed a well-defined Pd
precatalyst coordinated by the hindered terphenyl phosphine
AlPhos, which catalyzes amination reactions of aryl triflates or
some halides with unhindered primary amines and amides using
DBU as base.13 Palladium catalysts featuring other phosphine
ligands, such as Xantphos, DPEphos, and Josiphos, have also
emerged for DBU-promoted C−N coupling.14,5 Additionally,
photoredox15 or electrochemical16 conditions have been
B
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cis-hydroxo ligand would then be poised for intramolecular
deprotonation to extrude water and generate the penultimate
Pd-amido catalytic intermediate. Here, we report a method for
aryl amination of bromo- and chloro(hetero)arenes using the
on-cycle catalyst 1 and Et3N as a soluble weak base. Water is an
essential component for these reactions, and mechanistic data
implicate three complementary roles by which water can
facilitate the overall catalytic process: (i) acceleration of an
inner sphere heterolysis of the substrate N−H bond, (ii) driving
an unfavorable ionization of neutral palladium halide species by
sequestering halide into an aqueous phase, and (iii) shunting
catalyst away from an inhibited, base-coordinated state.
coupling, even compared to a recently developed weak base
method using AlPhos-coordinated Pd catalysts.11a Importantly,
reactions conducted with more water performed better
regardless of the choice of base.
Additional optimization confirmed water loading as a crucial
dimension for achieving high reaction conversions (Figure 2), as
RESULTS AND DISCUSSION
■
High-throughput experimentation (HTE) techniques were used
to assess the multidimensional influence of solvent, amine base,
and water on a model reaction between 4-chlorobiphenyl and 4-
nitroaniline catalyzed by complex 1 (1 mol %) to form amine
2.28 Representative results of this three-dimensional screening
are visualized in the heat plot shown in Figure 1 (see Tables S1
Figure 2. Optimization of water assistance during weak base
Buchwald−Hartwig amination. Yield determined by 19F NMR versus
CF3C6H5 as internal standard. aVersus toluene volume.
determined by the formation of 3 by 19F NMR spectroscopy
during reactions of 1-bromo-4-fluorobenzene with aniline.
Together with an increase in reaction temperature from 60 to
80 °C, the adjustment of the solvent/water ratio to at least 2:3
gave markedly improved yields after 6 h. It is worth noting that
we believe the better performance of toluene in this model
reaction versus the HTE screen may reflect a solubility artifact
during catalyst dosing (compare Tables S1 and S2). In
subsequent methodology studies (Tables S3−S5), a 1:4 mixture
of toluene and water was ultimately selected as the most versatile
mixture across different haloarene and amine combinations. We
also found that the substitution of 1 for the admixture of PAd3
with a commercially available (Buchwald-G3) precatalyst gave a
comparable performance in the formation of 2 from 4-
chlorobiphenyl (see Tables 1 and S6).
A variety of chloro- and bromo(hetero)arene electrophiles
and nucleophiles were tested to explore the scope of a method
featuring this (Ad3P)Pd-catalyzed, water-assisted reaction
pathway (Table 1). For primary aryl amines, products generated
from an electron-poor nucleophile (4), which are more
challenging versus simple amines,15,29 and hindered aniline
(5) occurred in 92% and 72% isolated yield, respectively,
suggesting good tolerance to variations in aniline electronic and
steric properties. Preliminary screening suggested primary alkyl
amines (see Table S7) are challenging for this catalyst, as has
been noted before using catalysts with a single monophosphine
ligand.3g,30 Chemoselective oxidative addition favoring bromide
over triflate or chloride is confirmed by the formation of 6, 12,
13, 18, and 27 in 61−87% isolated yields. An internal
competition reaction with 4-BrC6H4OTf was also highly
selective for C−Br activation giving S1 in 90% isolated yield
(see the Supporting Information). This orthogonality makes
bond constructions at different C−X bonds viable and also
complements previous C−N coupling methods favoring the
activation of aryl triflates. Heteroaryl chlorides, such as those
containing thiophene (7) and pyrimidine (8) motifs, were
compatible substrates under the reaction conditions. Reactions
using heterocyclic amines such as 5-aminoindole (9) and 3-
amino-2-methoxypyridine (10) underwent arylation in high
yield (84% and 91%, respectively).
Figure 1. Heat plot for the survey of soluble amine bases under
Buchwald−Hartwig amination conditions with water cosolvent. ArF =
4-FC6H4. aVersus organic solvent volume.
and S2 for tabular data). The solvent dimension did not indicate
a clear contrast in conversion as a function of solvent polarity.
Both polar (a)protic (e.g., t-amyl alcohol, DMF) and relatively
nonpolar (e.g., toluene, DME, 2-methyl tetrahydrofuran)
solvents were associated with significant conversion. On the
DMSO
other hand, Et3N (pKaH
= 9) gave the best average
conversion versus other tertiary amines (e.g., diisopropylethyl-
amine, N-methyl morpholine) in the base dimension. Counter-
intuitively, stronger bases (pKaDMSO) such as MTBD (15), DBU
(14), or tetramethylguanidine (13) were generally inferior to
Et3N, which contrasts the base trends typically observed in C−N
Secondary anilines that underwent arylation in good to
excellent yields (79−98%) include carbazole (12), phenothia-
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a
Table 1. Substrate Scope of Water-Assisted Amination Using Triethylamine as a Soluble Weak Base
a
Standard conditions: Aryl halide (0.2 M), amine (1.5 equiv), Et3N (2 equiv), and catalyst 1 (1 mol %) were stirred in a toluene/H2O (1:4)
mixture at 80 °C (X = Br) or 100 °C (X = Cl) in a sealed vial over 24 h. Isolated yields are shown unless noted otherwise; parentheses denote
b
c
yields determined by 19F NMR vs CF3C6H5 as internal standard or calibrated UPLC analysis. 6 h. Catalyst generated in situ; see Table S6 for
d
e
f
g
h
i
j
details. Neat water. 48 h. 16 h. 3 mol % 1. 2 mol % 1, 48 h. 36 h. t-AmOH/H2O (1:3), 85 °C for 12 h. ArF = 4-FC6H4. PMP = 4-MeOC6H4.
zine (13), indoline (14), and N-methylaniline (15). Aliphatic
secondary amines are also competent nucleophiles to generate
16−18 in 61−89% isolated yields, the latter of which involved
the drug amoxapine as the nucleophile. As a point of
comparison, secondary amines were shown to be poor substrates
in previous C−N coupling strategies with organic base,
presumably due to steric clash with the extremely hindered
ligands used.14,18 The amide nucleophile 2-azetidinone or the
protected ammonia equivalent t-butyl carbamate generated 19
and 20 in 89% and 97% yields, respectively. Hydrazine
derivatives that are useful functional handles for heterocycle
synthesis,1a such as 1-Boc-1-methylhydrazide or benzophenone
hydrazone, were also suitable nucleophiles for this method
generating 21 and 22 in 69% and 80% isolated yields,
respectively. These results highlight versatility of this water-
assisted method across a spectrum of nucleophile classes that
sample a broad range of size and N−H pKa. A survey of several
alternative catalysts established for C−N coupling across a panel
D
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of three substrate combinations (Figure S2) indicates 1 gives
superior performance.
Drug-like electrophiles were also explored to gauge the
tolerance of the catalyst and water-assisted method to more
complex functionality. The reaction of 4-fluoroaniline with the
compounds X2, X3, X4, X6, or X8 generated amination products
23−27 in 76−98% isolated yields.31 The high yields in these
reactions indicate the synthetic utility of a weak base strategy
compared to established catalytic or stoichiometric C−N
coupling of these substrates using strong bases.12d,32
Importantly, we envisioned this weak base method should
engender improved compatibility toward base-sensitive func-
tionality. Ketone and ester functional groups with enolizable
sites were well-tolerated, as exemplified by the moderate to good
yields obtained for the formation of products 7 (45%), 19
(89%), 25 (94%), 26 (98%), 28 (90%), and 31 (58%). The
formation of 17 and 18 in 89% and 61% yield, respectively,
demonstrates tolerance of nitrile and nitro groups. Functional-
ization of the commercial drugs indomethacin, fenofibrate, and
haloperidol in 51%, 90%, and 58% isolated yields, respectively,
further highlight both the compatibility of this weak base
amination method with chloroarenes as well as with protic
functional groups (e.g., carboxylic acid in 29 and alcohol in 31).
Several amination reactions were also conducted in neat water
(e.g., 4, 6, and 14), which demonstrate that catalyst 1 can
operate under single solvent conditions that could be advanta-
geous for green chemistry33,34 or biorthogonal35 applications
and might hint that the beneficial role(s) of water may extend
beyond just the sequestration of halide away from an organic
solvent phase where catalyst resides.36
The amination of the chloroarene fenofibrate was selected to
evaluate the scalability of the method. The preliminary reactions
(Table S9) on the half-gram scale at 98 °C indicated comparably
high conversions for the reactions in toluene, anisole, cyclo-
propyl methyl ether, or t-amyl alcohol as solvent. At a lower
temperature (80 °C), t-AmOH was superior giving 94%
conversion within 21 h. A further increase of the reaction in t-
AmOH to a 20 mmol scale gave an excellent solution yield
(97%) of 30 within 12 h at 85 °C yielding 7.0 g (80%) of
analytically pure (>99%) product after crystallization. Kinetic
profiling of the reaction (Figure S4) indicated 100% conversion
was actually achieved within 45 min at 1 mol % catalyst loading.
The effectiveness of the combination of a (Ad3P)Pd catalyst
and water in enabling catalytic turnover of bromo- and
chloroarenes raised several mechanistic questions. For instance,
it was not clear a priori if a similar or distinct catalytic mechanism
might be operative compared to what has been proposed using
an (AlPhos)Pd catalyst and DBU under anhydrous conditions
(Scheme 1b).11a,13 A switch in mechanism could potentially
account for the improved reactivity toward bromo- and
chloroarene electrophiles in this method versus aryl triflates as
well as the lack of base inhibition observed previously.
Experiments were thus conducted to interrogate the role(s)
water plays in the catalytic mechanism, such as the initially
hypothesized potential for on-cycle Pd intermediates to be
generated from coordinated water.
Figure 3. Stoichiometric O−H heterolysis reactions initiated from (a)
neutral or (b) cationic aryl-palladium complexes using water and Et3N.
aNo conversion was observed in the absence of added H2O or Et3N. ArF
= 4-FC6H4.
resonance virtually coupled to phosphorus (δH = −2.19 ppm,
J(31P−1H) = 3.2 Hz) corresponding to a μ-OH ligand and an
anti disposition of PAd3 ligands. Importantly, the time frame for
this stoichiometric reaction is far less than that required for the
respective catalytic aminations in Table 1 even at a much lower
temperature, which suggests the formation of Pd hydroxo
species from water and Et3N is a kinetically viable step during
catalysis. On the other hand, the addition of water or Et3N
individually to 1 led to no detectable changes in the 31P NMR
spectra.
Deprotonation of a strongly acidified aqua ligand by Et3N in a
cationic Pd species would be expected to be facile and
presumably renders the preceding fast yet unfavorable
equilibrium hydrolysis step irreversible. An analogous cationic
pathway for B-to-Pd transmetalation was postulated in our
previous study of weak base Suzuki-Miyaura coupling.21 To
further probe if such a process could be operative in the present
amination reactions, a discrete cationic species [Pd(PAd3)-
(ArF)(THF)]+BF4 (33) was prepared at low temperature
−
according to a reported procedure.21 Treatment of 33 with Et3N
at −35 °C in THF for 1 min generated a new species (vide infra)
that cleanly converted to Pd hydroxo complex 32 within 1 min at
0 °C upon the addition of water (Figure 3b). This faster reaction
is consistent with a cationic aqua complex being a competent
intermediate in the conversion of the palladium halide complex
1 to the palladium hydroxo complex 32, considering that the
exchange of the labile solvento ligand in 33 for water should
occur readily. Furthermore, water could also play a role in
driving the reaction forward by sequestering the resulting
ammonium salts. Finally, the presumed basicity of the hydroxo
ligand was confirmed by the immediate reversion of 32 back to
33 upon treatment with HBF4 etherate in THF at −25 °C
(Figure S11).
While palladium hydroxo complexes have been proposed as
intermediates in numerous cross-coupling reactions, their
formation is generally believed to require anion exchange
processes using stoichiometric ionic bases. The hydrolysis of
halide ligands in a nonpolar organic solvent represents a unique
and much milder pathway to access these versatile intermedi-
ates, yet such ionization processes have been proposed to be
energetically prohibitive.9 This issue has been mitigated by
The observation of the reaction of neutral complex 1 with
water and Et3N in toluene by 31P NMR spectroscopy indicated
clean formation of a new palladium complex after 1 min (Figure
3a). On the basis of the comparison to an independently
prepared sample, this new species was assigned as the μ-hydroxo
complex 32. A dimeric solution structure for 32 is suggested by
1
the observation in the H NMR spectrum of a single upfield
E
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moving away from halide electrophiles to those with weaker
leaving groups (e.g., triflate) or by the addition of halide
abstracting reagents (i.e., Ag+, Tl+), such as in methods that
access the cationic pathway for the Mizoroki-Heck reaction.37
Our data suggest that an appropriate coordinatively unsaturated
metal intermediate, such as the T-shaped (Ad3P)Pd(II) species
in this work, can in fact undergo facile ionization through
hydrolysis even in toluene, which allows deprotonation of the
resultant acidified aqua ligand in the cationic complex using very
mild bases. To our knowledge, such a process represents a novel
pathway for a key catalytic step of Buchwald−Hartwig
amination reactions that activates the substrate amine, which
engenders advantages in the electrophile scope to include more
strongly coordinating anions (e.g., Br, Cl) without the need for
halide scavengers.
determined for the independent reactions of ArFBr with aniline
in toluene/H2O or aniline-d2 in toluene/D2O (Figure 4). The
absence of a primary KIE in these reactions is inconsistent with
turnover-limiting N−H heterolysis regardless of potential
reversibility in amine substrate coordination.
Figure 4. Determination of kinetic isotope effect from independent
catalytic amination reactions of aniline or aniline-d2.
A catalytic cycle is proposed for (Ad3P)Pd-catalyzed aryl
amination of aryl halides in Scheme 2, which incorporates a
The kinetic and isotope effect data above seem to implicate
C−N reductive elimination as the likely turnover-limiting step of
catalysis. However, analysis of the initial rates for reactions using
a series of para-substituted anilines (Figure 5) suggests C−N
Scheme 2. Proposed Catalytic Cycle for (Ad3P)Pd-Catalyzed,
Water-Assisted Amination
Figure 5. Hammett plot for catalytic amination of 4-BrC6H4F with a
para-substituted aniline under the optimized conditions of Table 1 as
determined by the method of initial rates.
bond formation (step v) is not rate-determining. The slope of
this Hammett plot (ρ = +0.3) is inconsistent with literature data
for stoichiometric reductive elimination reactions from
arylpalladium amido complexes, which are generally faster for
complexes with more electron-rich amido ligands (ρ < 0).39
When it is also considered that the stoichiometric reactions (see
Figure 3) suggest hydrolysis is kinetically facile (step ii), the
available data are not consistent with any on-cycle catalytic step
being clearly turnover-limiting. An alternative kinetic scenario
must then be operative during these catalytic reactions, and
spectroscopic data from additional stoichiometric experiments
at low temperature with isolated organometallic complexes
provided several key insights in this regard.
water-assisted mechanism to generate an ambiphilic Pd hydroxo
species. To probe the turnover-limiting step, the experimental
́
rate law (eq 1) was determined using either Bures’ variable time
normalization analysis38
d[3]
dt
= kobs[ArFBr]0[H2NPh]0[Et3N]0[1]0.9
(1)
or initial rate measurements for the reactions of 4-BrC6H4F
(ArFBr) with aniline under the standard conditions of Table 1
(see Figures S37−S41). The observation of a nominally zeroth-
order dependence of the initial rates on [ArFBr] and [Et3N]
suggest neither oxidative addition (step i) nor deprotonation of
water (step iii) are turnover-limiting, respectively, in the
catalytic reaction. These results contrast prior work on the
amination of aryl triflates where either a positive order
dependence on [DIPEA] signified rate-determining N−H
deprotonation using a tertiary amine base or a negative order
dependence on [DBU] under different conditions indicated
catalyst poisoning by this base.11a
While the nominally zeroth-order dependence of the rate on
[amine] is consistent with fast N−H heterolysis (step iv), it
could also be manifested in a scenario in which amine
coordination to Pd occurred reversibly and the equilibrium
saturated in the range of concentrations tested. To distinguish
between these possibilities, the kinetic isotope effect (KIE) was
The stoichiometric N−H heterolysis of H2NC6F5 by the Pd
hydroxo complex 32 in THF occurred with full conversion of 32
within 1 min at −25 °C to generate a new palladium species (δP
58.8 ppm) in 84% yield (Figure 6a). The stoichiometry of μ-OH
and μ-NHC6F5 resonances versus Pd(PAd3) and Pd(4-FC6H4)
1
resonances (1:2, respectively) in the H NMR and single
resonance in the 31P NMR spectra suggests a syn-dinuclear
complex (34), which is structurally analogous to a
{Pd2(PPh3)2Ph2(μ-OH)(μ-NHtBu)} species that was crystallo-
graphically characterized by Driver and Hartwig.25,40 When 34
was allowed to warm to room temperature, C−N reductive
elimination occurred completely to form 4 in 93% yield, relative
to both [Pd]−ArF equivalents in the starting dimer complex 32,
as determined by 19F NMR versus octafluorotoluene as
F
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Figure 7. 31P NMR spectra of stoichiometric reactions of aryl-Pd
complexes 32 or 33 with amines shown in Figure 6.
to shunt catalyst away from an inactive state (e.g., 35) toward
active intermediates, such as [Pd(PAd3)Ar(OH2)]+ and Pd-
(PAd3)Ar(OH). The rapid generation of the active Pd−OH
species upon the addition of water to the deactivated species 35
over 1 min at 0 °C is consistent with this notion (see Figures 3b
and S32). In total, these mechanistic data strongly support a
catalytic pathway unique from previous work on amination of
aryl triflates using weak base for which the resting state is an off-
cycle base-coordinated Pd species, an undesirable poisoned state
that can be circumvented by the action of water together with
the coordinative unsaturation enforced by the PAd3 ligand.
Figure 6. Stoichiometric N−H heterolysis reactions between aryl-
palladium complexes, H2NC6F5, and Et3N with or without added water
and characterization of the resulting amido-Pd or amino-Pd
intermediates. Dashed lines indicate NOE-correlated 1H nuclei.
aRelative to both [Pd]−ArF equivalents in 32. ArF = 4-FC6H4.
standard. A yield of product 4 in excess of 50% necessitates the
μ-OH ligand in the dinuclear intermediate 34 to further react
with the remaining H2NC6F5 in solution after C−N bond
formation is triggered. The identification of this dinuclear
species (34) can also resolve the issue of the turnover-limiting
step during catalysis. Specifically, the observed reaction constant
of ρ = +0.3 is consistent with rate-determining fragmentation of
the μ-anilido ligand in species analogous to 34, which should be
faster with decreasing ligand σ-donicity induced by withdrawing
anilido substituents. Fragmentation of this dinuclear species can
also rationalize the fractional dependence of the catalytic rate on
[1] (0.9) within the mechanistic pathway outlined in Scheme 2
(see the Supporting Information for full details).
CONCLUSION
■
A method for amination of chloro- and bromo(hetero)arenes
has been developed that operates efficiently with Et3N as a mild,
soluble base in combination with water in toluene. The
nucleophile classes applicable to this transformation span a
wide pKa range from relatively acidic amides and electron-
deficient anilines to poorly acidic aliphatic secondary amines.
The mild conditions are also compatible with a range of base
sensitive functional groups that can be problematic under classic
strong base conditions, which includes carboxylic acids, esters,
nitrile, nitro, and enolizable keto groups. Amination in complex
settings was validated by the reactions of the chloroaryl group in
the pharmaceuticals indomethacin, fenofibrate, and haloperidol
as well as in five drug-like bromo(hetero)arenes. Reactions can
also be conducted in neat water for applications requiring single
solvent conditions.
Mechanistic experiments support multiple roles for water
assistance in the catalytic mechanism. An initial hydrolysis of the
organopalladium halide complex formed after oxidative addition
is facilitated kinetically by the PAd3-enforced coordinative
unsaturation of the complex as well as thermodynamically driven
through sequestration of the halide byproduct into the aqueous
phase of a biphasic system. Importantly, this ionization occurs
even for more strongly coordinated halide ions derived from
commercially abundant bromo- and chloroarenes, which
contrasts the typically difficult task of ionization Pd(II)
complexes in nonpolar media that traditionally requires organic
electrophiles with better leaving groups or halide scavengers.
Deprotonation of an acidified aqua ligand in the cationic
intermediate can occur readily even with Et3N, which
corresponds to a considerable influence of the catalyst on
The reaction of cationic complex 33 with H2NC6F5, excess
water, and Et3N in THF also occurred within 1 min at −25 °C to
generate the same dinuclear intermediate 34 (Figure 6b). In
contrast, an analogous reaction of 33 with Et3N in the absence of
added water (Figure 6c) led to the consumption of starting
material but generated a distinct product (δP 41.5 ppm) as
1
shown in Figure 7. Characterization of this species by H and
1H−1H NOESY NMR is consistent with a cationic, Et3N-
coordinated structure (35). Importantly, repetition of the
reaction with added H2NC6F5 led to the formation of the
same species (Figure 7), but upon warming to room
temperature, only a trace (4%) of C−N coupling product 4
formed after 1 h. We interpret these results as suggesting that
aniline substrates struggle to displace coordinated Et3N at Pd,
and catalyst inhibition should occur using a soluble base as was
observed previously by Buchwald and co-workers.11a Because
this does not appear to occur during the catalytic reactions of
this work (reactions are zeroth-order rather than inverse-order
in [Et3N]), we postulate that another role of excess water can be
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relative acidities (ΔpKaDMSO = 22). The ambiphilic Pd(PAd3)-
(Ar)OH intermediate that is readily accessible from water and
Et3N in these reactions features both Lewis acidic and Brønsted
basic properties that, upon coordination of the amine substrate,
triggers an intramolecular N−H cleavage under very mild
conditions.
Stoichiometric experiments with aryl-palladium complexes
implicate another unanticipated role of water in shunting
catalyst speciation away from inactive, base-coordinated
intermediates, which has been a challenge in other recently
developed weak base amination methods. To our knowledge,
this water-assisted mechanism for C−N coupling reactions has
not been previously observed and could potentially be effective
in promoting other catalytic processes involving element−
hydrogen bond activation under weak base conditions. The
persistent coordinative unsaturation of the (Ad3P)Pd catalyst
thus appears to engender a number of kinetic benefits in
accessing unique catalytic mechanisms for carbon−carbon and
now carbon−heteroatom bond-forming reactions that are
attractive for catalysis in the most sensitive settings.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09275.
■
sı
Experimental procedures; reaction optimization details,
kinetics data, and spectral data for new compounds
(PDF)
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AUTHOR INFORMATION
Corresponding Author
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Brad P. Carrow − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0003-4929-8074; Email: bcarrow@
princeton.edu
Authors
Sii Hong Lau − Department of Chemistry, Princeton University,
Princeton, New Jersey 08544, United States
Peng Yu − Department of Chemistry, Princeton University,
Princeton, New Jersey 08544, United States
Liye Chen − Department of Chemistry, Princeton University,
Princeton, New Jersey 08544, United States
Christina B. Madsen-Duggan − Chemical Process
Development, Bristol Myers Squibb, Summit, New Jersey
07902, United States
Michael J. Williams − Chemical Process Development, Bristol
Myers Squibb, Summit, New Jersey 07902, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09275
Notes
The authors declare the following competing financial
interest(s): A patent was filed by Princeton University: Carrow,
B. P.; Chen, L. WO2017/075581 A1, May 4, 2017.
ACKNOWLEDGMENTS
■
Support was provided by the National Institutes of Health
(R35GM128902). We thank Prof. Guy Lloyd-Jones for
assistance with kinetic modeling, Kiwoon Baeg and Lucy
Wang for assistance with preliminary catalyst development,
and Michael Peddicord for HR-MS analyses.
H
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