The Quest for the Ideal Base: Rational Design of a Nickel Precatalyst Enables Mild, Homogeneous C-N Cross-Coupling

Article abstract of DOI:10.1021/jacs.0c00286

Palladium-catalyzed amination reactions using soluble organic bases have provided a solution to the many issues associated with heterogeneous reaction conditions. Still, homogeneous C-N cross-coupling approaches cannot yet employ bases as weak and economical as trialkylamines. Furthermore, organic base-mediated methods have not been developed for Ni(0/II) catalysis, despite some advantages of such systems over those employing Pd-based catalysts. We designed a new air-stable and easily prepared Ni(II) precatalyst bearing an electron-deficient bidentate phosphine ligand that enables the cross-coupling of aryl triflates with aryl amines using triethylamine (TEA) as base. The method is tolerant of sterically congested coupling partners, as well as those bearing base- and nucleophile-sensitive functional groups. With the aid of density functional theory (DFT) calculations, we determined that the electron-deficient auxiliary ligands decrease both the pKa of the Ni-bound amine and the barrier to reductive elimination from the resultant Ni(II)-amido complex. Moreover, we determined that the preclusion of Lewis acid-base complexation between the Ni catalyst and the base, due to steric factors, is important for avoiding catalyst inhibition.

Full text of DOI:10.1021/jacs.0c00286

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Article
The Quest for the Ideal Base: Rational Design of a Nickel
Precatalyst Enables Mild, Homogeneous C–N Cross-Coupling
Richard Y. Liu, Joseph Michael Dennis, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00286 • Publication Date (Web): 10 Feb 2020
Downloaded from pubs.acs.org on February 10, 2020
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The Quest for the Ideal Base: Rational Design of a Nickel Precatalyst
Enables Mild, Homogeneous C–N Cross-Coupling
Richard Y. Liu,† Joseph M. Dennis,† and Stephen L. Buchwald*
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Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
ABSTRACT: Palladium-catalyzed amination reactions using soluble organic bases have provided a solution to the many issues
associated with heterogeneous reaction conditions. Still, homogeneous C–N cross-coupling approaches cannot yet employ bases as
weak and economical as trialkylamines. Furthermore, organic base-mediated methods have not been developed for Ni(0/II) catalysis,
despite some advantages of such systems over analogous Pd-based catalysts. We designed a new air-stable and easily prepared Ni(II)
precatalyst bearing an electron-deficient bidentate phosphine ligand that enables the cross-coupling of aryl triflates with aryl amines
using triethylamine (TEA) as base. The method is tolerant of sterically-congested coupling partners, as well as those bearing base-
and nucleophile-sensitive functional groups. With the aid of density functional theory (DFT) calculations, we determined that the
electron-deficient auxiliary ligands decrease both the pKa of the Ni-bound amine and the barrier to reductive elimination from the
resultant Ni(II)–amido complex. Moreover, we determined that precluding Lewis acid-base complexation between the Ni catalyst
and the base, due to steric factors, is important for avoiding catalyst inhibition.
INTRODUCTION
(A) Traditional Methods: Inorganic Bases
The development of metal-catalyzed carbon–nitrogen
R
(C–N) bond-forming reactions has had a transformative impact
NaOt-Bu, Cs2CO3,
K3PO4, LHMDS
N
X
H
N
R
on the synthesis of pharmaceuticals, agrochemicals, organic
materials and fine chemicals.1 Catalysts based on palladium and
copper have been broadly employed to facilitate the cross-
coupling of aryl (pseudo)halides with amine nucleophiles, but
these reactions have traditionally required the addition of
inorganic bases.2 In recent years, however, there has been
increased interest in the use of soluble organic bases in place of
commonly used inorganic reagents for cross-coupling reactions
generally.3 These single-phase reactions are easily transferrable
to high-throughput reaction screening settings, continuous flow
chemistry, and microfluidic screening platforms.4 Moreover,
the use of weak organic bases avoids functional group
incompatibility issues associated with nucleophilic alkoxide
and metal amide bases, especially in combination with amines.5
Previously, several phosphazene,6 guanidine,6 amidine,7 and
alkyl amine8 bases have been shown to facilitate Pd- and Cu-
catalyzed9 C–N bond formation. The weakest among these,
alkyl amine bases stand out as an attractive class of reagents,
particularly since their steric properties, nucleophilicity, and
basicity can be precisely tuned.10 Furthermore, many
trialkylamine reagents, including triethylamine (TEA), are
produced on large scale directly from alcohols and ammonia,11
making them as inexpensive as common organic solvents.
Previously, our research group demonstrated that a
Pd Ni Cu
Het
Het
+
R
R
Pd, Ni, Cu, Precat.
(B) Soluble Organic Bases: Mid-to-High Cost
R
N
X
H
N
DBU, MTBD, P2Et
Pd Precat.
R
R
Dreher
Pd
Het
Het
Het
Het
+
Buchwald
R
R
Anilines, 1°, 2°
R
N
DABCO,
quinuclidine
X
H
MacMillan
Buchwald
Miyake
Ni
Ni
N
+
R
R
Ni, (Ir Photocat.)
1° and 2°
R
N
X
H
N
DBU
R
Baran
Het
Het
+
R
R
Ni, Undivided Cell
1° and 2°
(C) Soluble Organic Bases: Low Cost
H
NH2
OTf
N
NEt3
Ni
Het
Het
+
Het
Het
Ni Precat.
Anilines
Figure 1. (A) Inorganic bases used in traditional Pd-, Ni-, and
Cu-catalyzed C–N cross-coupling methods. (B) Amidine,
guanidine, and phosphazene bases used in Pd-catalyzed
amination and Ni-catalyzed photo- or electrocatalysis. (C)
Nickel-catalyzed C–N cross coupling of aryl triflates and
amines facilitated by triethylamine.
bulky, electron-deficient Pd catalyst can facilitate C–N bond
formation in the presence of 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU).12 Mechanistic investigations13 and in-depth reaction
optimization studies14 suggested that other organic bases,
including TEA and diisopropylethylamine (DIPEA, Hünig’s
base) could facilitate the cross-coupling of aryl triflates and
anilines, albeit with
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slower reaction rates. We considered whether an electron-
(DABCO) and DIPEA, could be used instead of TEA, but with
lower reaction yields.
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7
8
deficient catalyst based on nickel might allow for these very
mild and inexpensive trialkylamine bases to be used more
effectively in C–N cross-coupling.
The use of Ni was of particular interest to us because
the use of weak, soluble organic bases in Ni-catalyzed aryl
amination has not yet been systematically explored. Since the
first reports of Ni-catalyzed amination,15 the transformation has
been significantly improved in terms of scope and efficiency
through rational ligand design,16 the development of
photocatalytic variants,17 and using electrochemistry.18 While
these efforts have greatly expanded the number and type of
electrophiles19 and nucleophiles20 that can be cross-coupled
under practical conditions, the majority of Ni-catalyzed
methods remain predominantly reliant on inorganic bases such
as metal tert-butoxides and phosphates to facilitate C–N
formation (Figure 1A). Many useful solutions that are
compatible with organic bases take advantage of energy input
through either photo- or electrocatalysis. These protocols are
primarily limited to the coupling of strongly coordinating
nucleophiles such as aliphatic amines (Figure 1, B).17,18
Providing a complementary approach, we herein describe the
rational discovery of a Ni (pre)catalyst capable of effecting
arylation of weakly binding aniline nucleophiles using a
trialkylamine base.
Table 1. Comparison of ligands and bases in the Ni-catalyzed
cross-coupling of phenyl triflate (1) and aniline.
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RESULTS AND DISCUSSION
Our studies began with an evaluation of commercially
available bidentate phosphine ligands and organic bases in a
model transformation, the Ni-catalyzed cross-coupling of
phenyl triflate (1) and aniline. Selected results from these
studies are summarized in Table 1 (see Supporting Information
for further experimental details). When we used Ni(COD)2 (4
mol%) and 1,1′-bis(diphenylphosphino)ferrocene (L1, DPPF)
as precatalysts and triethylamine (TEA) as base, a 6% yield of
the desired product was observed, with unreacted 1 making up
the remainder of the mass balance. As in our previous work on
Pd-catalyzed amination, we predicted that a more electron-
deficient metal center would better facilitate the deprotonation
of an amine-bound Ni complex by a base as weak as TEA.12a
Accordingly, we prepared several DPPF derivatives bearing
electron-withdrawing trifluoromethyl (–CF3) substituents on
the P-aryl groups.21 Indeed, use of the fourfold
trifluoromethylated ligand L2 ([CF3]4-DPPF) resulted in 32%
yield of the desired product. The yield was further increased to
94% by employing the further trifluoromethylated ligand L3
([CF3]8-DPPF). A Ni-based catalyst bearing this ligand had
previously been shown to facilitate the cross-coupling of aryl
chlorides with indoles and primary aliphatic amines using
NaOt-Bu as the base. 22
aGC yields were determined relative to hexamethylbenzene
internal standard and are reported as a single run. Reaction
conditions: phenyl triflate (0.20 mmol), aniline (0.24 mmol),
base (0.40 mmol), Ni(COD)2 (0.016 mmol, 4 mol% Ni),
ligand (0.016 mmol, 4 mol%), and 2-MeTHF (0.40 mL, 0.50
M). 2-MeTHF = 2-methyltetrahydrofuran.
Ar
Ar
OTf
Me
Cl
Cl
1. L3, THF, 10 min, rt
P
Me
)
Me
(
Ni
Ni
Ni
Fe
2. TMS-OTf (2.0 equiv)
THF, 30 min, rt
P
Ar
Ar
P1
CF3
CF3
F3C
CF3
Me
P
Ni
CF3
Fe
P
TfO
CF3
CF3
The ferrocene backbone was also found to be
P1
[CF3]8-DPPF OA
F3C
important to the success of these reactions: other ligands
containing similar trifluoromethylated aryl groups, such a 1,2-
bis(diphenylphosphino)benzene (DPPBz) derivative (L5,
[CF3]8-DPPBz) were less effective in promoting the C–N
coupling reaction. TEA, besides being advantageous in terms of
cost and mildness, was also uniquely efficacious as a base.
Several stronger bases that had been reported to facilitate Pd-
catalyzed amination reactions, including DBU and 7-methyl-
1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), were essentially
unable to promote our Ni-catalyzed transformation. Other
alkylamine bases, such as 1,4-diazabicyclo[2.2.2]octane
Figure 2. Synthesis and crystal structure of an L3-bound
methallyl triflate–nickel oxidative addition complex.
Thermal ellipsoids are shown at 50% probability. Hydrogen
atoms are omitted for clarity.
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Table 2. Amination of Aryl Triflates using P1a
1
2
3
4
Ar
P1 (4 mol% Ni)
NEt3 (2.0 equiv)
Ar
OTf
Me
H
N
CF3
OTf
NH2
P
P1
R1
R2
R1
R2
Ni
+
Ar =
Het
Het
Het
Het
Fe
[CF3]8-OA
2-MeTHF (0.50 M)
P
5
6
7
8
Ar
N2, 100 °C, 16 h
Ar
CF3
(1.2 equiv)
MeO2C
F
O
O
OMe
H
N
Me
H
MeO
CF3
H
N
OMe
H
N
H
H
N
N
Me
F3C
F3C
N
CN
9
Me
N
S
N
F
N
Ph
N
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O
OMe
2a
93%
2b
74%
2c
94%
2d
88%
2e
82%
2f
94%, 93%b, 88%c
O
Me
H
Ph
F
H
H
N
O
N
O
O
N
N
H
N
H
N
N
O
O
MeO
NC
OMe
OEt
F3C
Me
O
OMe
2g
87%
2h
91%
2i
95%
2j
81%
2k
89%
2l
86%
O
O
MeO
O
O
OEt
O
MeO
Ph
H
H
N
H
N
N
H
N
N
OCF3
H
N
O
Me
MeS
N
MeO
Me
Me
NC
N
CF3
O
2m
84%c
2n
86%
2o
83%
2p
81%
2q
70%
2r
84%
aIsolated yields are reported as the average of two runs. Unless noted, standard reaction conditions: aryl triflate (1.0 mmol), aryl
amine (1.2 mmol), triethylamine (2.0 mmol), P1 (0.04 mmol, 4% Ni), 2-MeTHF (2.0 mL, 0.5 M), 100 °C for 16 h. bSingle reaction
performed without stirring. c5.0 mmol scale reaction using 2.0% Ni. d1.5 equiv of aryl amine was used.
Although Ni(COD)2 is a convenient source of Ni(0) for
reaction discovery and mechanistic studies, the complex is highly
sensitive to air and moisture, generally requiring the use of an inert
atmosphere glovebox to handle.23 To alleviate the associated
operational complications, we aimed to develop an air-stable Ni
precatalyst bearing L3, the most effective ligand.24 Our initial
efforts focused on the use of σ-aryl “oxidative addition” (OA)
complexes of aryl bromides and chlorides.25 However, OA
complexes bearing L3 and various aryl groups,26 including o-tolyl
and mesityl, were unable to facilitate the reaction, even when
activated with reducing additives including phenylboronic acid and
activated olefins. We hypothesized that the presence of strongly
associating halide anions inhibits C–N coupling by outcompeting
aniline for binding to Ni (see below for further mechanistic
discussion).27 Predicated on this lack of reactivity, we sought to
prepare OA complexes bearing non-coordinating triflate anions.28
However, due to the propensity of coordinatively unsaturated Ni(II)
complexes to undergo bimetallic decomposition pathways, our
attempts to isolate Ni(II) σ-aryl complexes bearing triflate anions
were not successful. Based on the work of Nolan29 and Hazari,30 we
hypothesized that the introduction of an η3-allyl group would
saturate the Ni coordination sphere without introducing new
strongly-coordinating ligands such as halides. Combining a
commercially available methallyl nickel chloride dimer with L3 in
the presence of THF led to the formation of L3-Ni(Cl)(η3-
methallyl).31 This complex was not purified, but immediately
treated with trimethylsilyl triflate (TMS–OTf), upon which a
methallyl nickel triflate complex was rapidly formed.32 The
Figure 3. The proposed catalytic cycle for the nickel-
catalyzed cross-coupling of aryl halides with anilines: I,
activation of P1; II, oxidative addition of an aryl triflate; III,
aniline binding to OA complex; IV, deprotonation of an
amine-bound OA complex; V, reductive elimination of an
amido complex.
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structure of this complex (P1) was unambiguously characterized using X-ray diffraction (Figure 2). Under optimized reaction
conditions, this precatalyst (P1) facilitated the C–N coupling reaction and provided the desired product in
1
2
3
4
LNi
OTf
II-TS
OTf
0.0
-1.1
5
6
LNi(0)
L Ni
N
VI-TS
H2
I
Ph
7
8
9
LNi NHPh
V
-10.1
OTf
LNi
IV
H
N
DGo
kcal/mol
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sol
L Ni
Ph
L
Ni OTf
Ph
-13.4
VI
-19.7
II
CF3
CF3
Ar
V
VI
P
H2N
-29.1
Ph-NHPh
Fe
-29.8
P
Ar
Ar
-36.6
L Ni OTf
Et3NHOTf
Et3N
L = L3, [CF3]8-DPPF
Ph
III
-43.2
I
binding
oxidative addition
ligand exchange
deprotonation
reductive elimination
II-TS
V
VI-TS
VI
Figure 4. Computed energy profiles for the Ni-catalyzed cross-coupling of 1 and aniline. Gibbs free energy values calculated with
M06/6-311+G(d,p)-SDD(Ni,Fe)//B3LYP/6-31G(d)-SDD(Ni,Fe).
98% yield in 2 h. Analysis of the crude reaction mixture
(GC/MS) showed that N-methallyl aniline was formed during
the reaction, consistent with activation of P1 through outer-
sphere nucleophilic attack by aniline at the methallyl ligand.33
could be arylated in high yields.22 We note, however, that
aliphatic amines do not react under these conditions, likely due
to their decreased acidity compared to anilines.34 Coupling
partners containing heterocycles, including pyridines (2a, 2r), a
quinoline (2e), a thiophene (2c), and a pyrrole (2i) were
tolerated well. Several electrophilic functional groups,
including methyl esters (2a-c, 2h, 2n) and nitriles (2c, 2g, 2p),
remained intact under the mildly basic reaction conditions. An
α,ß-unsaturated ester (2j), and a coumarin derivative (2k) could
be cross-coupled under these reaction conditions, despite their
potential to react with anilines in metal-catalyzed aza-Michael
reactions.35 Moreover, substrates bearing redox-sensitive
functional groups, including an anthraquinone (2l) are
tolerated.36 Finally, because reproducibility issues associated
with stirring rate can occur in amination protocols featuring
inorganic bases37 or electric potentials,18b we wished to
demonstrate that this method is not dependent on mixing
efficiency. To show this, we prepared 2f without using a stir bar
or external agitation. The desired product was obtained in 93%
yield, which is in line with that obtained when magnetic stirring
Using this new precatalyst, we explored the scope of
the cross-coupling reaction by testing a variety of aryl triflate
electrophiles and amine nucleophiles. In contrast to some Pd-
catalyzed amination procedures, in particular those facilitated
by soluble organic bases, this methodology is tolerant of
sterically encumbered coupling partners. Specifically, aryl
triflates and anilines bearing bulky ortho-substituents, such as
trifluoromethyl (2b), benzyl (2h), morpholino (2m) and phenyl
(2n), underwent coupling in high yields. In contrast to
traditional Ni-catalyzed amination protocols that work well for
strongly coordinating alkylamine nucleophiles, the current
method is especially effective for weakly coordinating anilines,
including those bearing cyano (2c), trifluoromethoxy (2q), and
carbonyl substituents (2a, 2j). Additionally, secondary aryl
amines, including indoline (2g) and a 3-substituted indole (2p)
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was used. This result suggests that these single-phase reactions The proposed catalytic cycle of this Ni-catalyzed
amination reaction is summarized in Figure 3.20b,38 First,
activation of P1 via nucleophilic attack of the aniline at the
methallyl group provides a L3-supported Ni(0) catalyst. Next,
Ni undergoes oxidative insertion into the aryl triflate. Then, the
amine binds to the Lewis acidic Ni(II) metal center, acidifying
its hydrogens for deprotonation by TEA. Finally, reductive
elimination from resultant Ni(II)–amido complex affords the
desired product and regenerates the Ni(0) catalyst. Although
this proposed mechanism is directly analogous to that of other
Ni- and Pd- catalyzed C–N cross-coupling reactions,13 it was
important to determine how the highly fluorinated ligand L3
might affect the elementary steps, and importantly, how it is
able to facilitate the catalytic transformation using such a weak
base (TEA).
1
2
3
4
5
6
7
8
are less prone to reproducibility issues when varied stirring
techniques are used.
Table 3. Ligand effects on deprotonation and reductive
elimination. a
OTf
Et3N
L
i
N
L
i
N
L
i
N
‡
NH
Ph
NH2
Ph
NH
Ph
DGDeprot.
DG
RE
9
pKa
10
11
12
13
14
15
16
17
18
19
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23
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V
VI
VI-TS
DG‡
(kcal/mol)
DG‡
DGDeprot.
+
RE
pKa
(THF)
Yield
(%)
DGDeprot.
(kcal/mol)
RE
Ligand for V
L1
L2
L3
L5
15.3
13.4
12.2
13.0
6.4
2.0
-0.6
1.3
17.2
16.7
16.4
17.9
23.6
18.7
15.8
19.2
6%
Using density functional theory (DFT) calculations
we obtained a model of the catalytic mechanism using phenyl
triflate (1) and aniline as substrates. The energy profile of this
mechanism is illustrated in Figure 4. The binding of phenyl
triflate to L3-Ni(0) (complex I) was found to be exergonic by
10.1 kcal/mol (II). From this π-complex, oxidative addition
through an SNAr-type mechanism39 was predicted to be
extremely rapid, with a barrier of only 9.0 kcal/mol (II-TS), and
thermodynamically favorable, releasing 26.5 kcal/mol of free
energy (III). In the ground state of the resultant Ni(II) complex
III, the triflate anion was bound to Ni, although its dissociation
appeared possible under the reaction conditions (+16.9
kcal/mol, IV). Regardless, the displacement of the triflate
ligand by aniline is only slightly endergonic (+7.5 kcal/mol, V).
Interestingly, deprotonation of this cationic Ni–aniline complex
by TEA was predicted to be slightly favorable in free energy (-
0.7 kcal/mol, VI). Reductive elimination from this amido
complex through a three-membered transition state (+16.4
kcal/mol, VI-TS) would then provide the diphenylamine
product.
32%
94%
23%
PhNH2
28.5
Et3N•HOTf
12.5 (experimental, see ref. 41)
Ar
Ar
Ar
Ar
Ar
L1: Ar = Ph
P
P
P
L5
L2: Ar = 4-CF3
L3: Ar = 3,5-CF3
Fe
Ar = 3,5-CF3
P
Ar
Ar
Ar
aGibbs free energy values and acidities calculated with
M06/6-311+G(d,p)-SDD(Ni,Fe)//B3LYP/6-31G(d)-
SDD(Ni,Fe), except for the pKa of Et3NHOTf, used as a
reference, which was obtained from the literature.40
Ar
Ar
P
Considering our original hypothesis that the electron-
+7.8
F3C
Fe
CF3
Ph
deficiency of the ligand had a favorable influence on the
thermodynamics of the deprotonation step, we more closely
examined the effect of varying the phosphine ligand on this
process. Table 3 shows the pKa of several amine-bound Ni(II)
complexes analogous to Vas well as triethylammonium triflate
and aniline for comparison purposes. The free energy change
associated with the proton transfer step can be calculated on the
basis of pKa differences. The deprotonation of weakly acidic
aniline (pKa = 28) by triethylamine (pKaH+ = 12.5)40 is
thermodynamically highly disfavored. However, association of
the aniline to cationic Ni(II) results in dramatic acidification, to
the extent of roughly 13 pKa units in THF when the ligand is
DPPF (L1). With the addition of electron-withdrawing groups
on the ligand, the amine is further acidified. Indeed, in the
complex with L3, the aniline is sufficiently activated that it is
predicted to be more acidic (pKa = 12.2) than triethylammonium
triflate. Thus, deprotonation by triethylamine is in this case
slightly thermodynamically favorable.
Ni
Fe
NEt3
P
Ar
Ar Ar
P
P
Ni Ph
0.0
Ar
Ar
Ni
Ar
P
Ph
Ar
Fe
Ph
N
P
H2
Ar
Ar
P
Ar Ar
L3-Ni-Ph
-9.4
Ph
Ni
Fe
OTf
P
Go
sol
-16.9
-20.8
Ar Ar
kcal/mol
Ar
Ar
P
Ph
N
Ni
Fe
P
N
Ar Ar
We also found that the barrier to reductive elimination
Figure 5. Relative binding energies of triethylamine, triflate
anion, and DBU to an L3-supported, cationic nickel complex.
Gibbs free energy values calculated with M06/6-311+G(d,p)-
SDD(Ni,Fe)//B3LYP/6-31G(d)-SDD(Ni,Fe).
is also somewhat affected by the electronic properties of the
phosphine ligand: as the number of trifluoromethyl substituents
on the catalyst increase, the reductive elimination is
increasingly facile. For comparison, we also evaluated an
analogue derived of L3 from DPPBz (L4). With the L4-ligated
catalyst, the free energy of deprotonation and barrier to
reductive elimination were both higher (+1.9 kcal/mol and +1.5
kcal/mol, respectively) than from the L3-bound complexes.
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Thus, not only the identity of the P-aryl groups, but the
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backbone structure of the chelating ligand significantly
influences these steps. The combined barrier from
deprotonation–reductive elimination sequence is also shown in
Table 3. The net activation energies are qualitatively consistent
with the experimentally determined yields using these catalysts.
Finally, our model also explained the superior
ACKNOWLEDGMENT
Research reported in this publication was supported by the
National Institutes of Health (R35GM122483) and the NSF
Graduate Research Fellowship Program under Grant No.
1122374 (J.M.D.). Any opinions, findings, conclusions, or
recommendations expressed in this material are those of the
authors and do not necessarily reflect the views of the NIH or
NSF. The authors thank Dr. Frieda Zhang for her assistance in
elucidating the substrate scope of this methodology and Jacob
Rodriguez for assistance with mass spectroscopy experiments.
We acknowledge Dr. James Bour for helpful discussions
throughout the duration of this study and Dr. Peter Müller for
crystallographic analysis. We also thank Dr. Scott McCann, Dr.
Alexander Schuppe, and Dr. Christine Nguyen for their
assistance in the preparation of this manuscript.
performance of triethylamine compared to other organic bases,
even those that were significantly stronger bases. Previously, in
experimental13a and theoretical13b mechanistic studies of Pd-
catalyzed amination using DBU, we found that off-cycle
binding of the base to Pd could have an inhibitory effect. We
investigated the relative binding ability of TEA, DBU, and
aniline to the cationic intermediate IV (Figure 5). As a
reference, we had found earlier that the binding of triflate to IV
is exergonic by 16.9 kcal/mol. Due presumably to steric
interactions, the binding of TEA to IV is significantly
disfavored (∆G° = +7.8 kcal/mol), in a manner similar to well-
known “frustrated” Lewis acid-base pairs.41 Accordingly,
aniline can outcompete the base for binding (∆G° = –9.4
kcal/mol for aniline binding to IV), and the productive reaction
can take place. In contrast, when DBU is present, we found that
it tightly coordinates to IV (∆G° = –20.8 kcal/mol),
sequestering Ni in this off-cycle resting state and thus
increasing the overall activation energy for cross-coupling. We
believe that this effect explains the unique effectiveness of TEA
compared to stronger, more nucleophilic organic bases.
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CONCLUSION
In summary, we have developed a novel Ni(II)
precatalyst bearing an electron-deficient DPPF-derived ligand
(L3) that is able to facilitate the cross-coupling of aryl triflates
with primary anilines, as well as indolines and indoles. The
precatalyst is a rare example of a bench-stable cationic Ni(II)
triflate complex and represents a new class of halide-free Ni
precatalysts that might have general applicability to reactions
currently requiring Ni(COD)2. Using DFT calculations,
relationships between ligand structure and the energetics of the
key deprotonation and reductive elimination steps were
elucidated. Moreover, we determined that the unique
effectiveness of alkylamine bases can be attributed to their
steric bulk, which prevents unwanted binding to cationic Ni
intermediates. We anticipate that these mechanistic insights can
assist in the development of new Ni-catalyzed cross-coupling
methodologies that employ soluble organic bases.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures; computational, spectral, and reaction
optimization data; X-ray data.
AUTHOR INFORMATION
Corresponding Author
sbuchwal@mit.edu
Author Contributions
†R.Y.L. and J.M.D contributed equally to this work.
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