Controlling first-row catalysts: Amination of aryl and heteroaryl chlorides and bromides with primary aliphatic amines catalyzed by a BINAP-ligated single-component Ni(0) complex

Article abstract of DOI:10.1021/ja411911s

First-row metal complexes often undergo undesirable one-electron redox processes during two-electron steps of catalytic cycles. We report the amination of aryl chlorides and bromides with primary aliphatic amines catalyzed by a well-defined, single-component nickel precursor (BINAP)Ni(η²-NC- Ph) (BINAP = 2,2′-bis(biphenylphosphino)-1,1′-binaphthalene) that minimizes the formation of Ni(I) species and (BINAP)₂Ni. The scope of the reaction encompasses electronically varied aryl chlorides and nitrogen-containing heteroaryl chlorides, including pyridine, quinoline, and isoquinoline derivatives. Mechanistic studies support the catalytic cycle involving a Ni(0)/Ni(II) couple for this nickel-catalyzed amination and are inconsistent with a Ni(I) halide intermediate. Monitoring the reaction mixture by ³¹P NMR spectroscopy identified (BINAP)Ni(η²-NC-Ph) as the resting state of the catalyst in the amination of both aryl chlorides and bromides. Kinetic studies showed that the amination of aryl chlorides and bromides is first order in both catalyst and aryl halide and zero order in base and amine. The reaction of a representative aryl chloride is inverse first order in PhCN, but the reaction of a representative aryl bromide is zero order in PhCN. This difference in the order of the reaction in PhCN indicates that the aryl chloride reacts with (BINAP)Ni(0), formed by dissociation PhCN from (BINAP)Ni(η²-NC-Ph), but the aryl bromide directly reacts with (BINAP)Ni(η²-NC-Ph). The overall kinetic behavior is consistent with turnover-limiting oxidative addition of the aryl halide to Ni(0). Several pathways for catalyst decomposition were identified, such as the formation of the catalytically inactive bis(amine)-ligated arylnickel(II) chloride, (BINAP)₂Ni(0), and the Ni(I) species [(BINAP)Ni(μ-Cl)] ₂. By using a well-defined nickel complex as catalyst, the formation of (BINAP)₂Ni(0) is avoided and the formation of the Ni(I) species [(BINAP)Ni(μ-Cl)]₂ is minimized.

Full text of DOI:10.1021/ja411911s

Article
pubs.acs.org/JACS
Controlling First-Row Catalysts: Amination of Aryl and Heteroaryl
Chlorides and Bromides with Primary Aliphatic Amines Catalyzed by
a BINAP-Ligated Single-Component Ni(0) Complex
Shaozhong Ge, Rebecca A. Green, and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: First-row metal complexes often undergo undesir-
able one-electron redox processes during two-electron steps of
catalytic cycles. We report the amination of aryl chlorides and
bromides with primary aliphatic amines catalyzed by a well-
defined, single-component nickel precursor (BINAP)Ni(η2-NC-
Ph) (BINAP = 2,2′-bis(biphenylphosphino)-1,1′-binaphthalene)
that minimizes the formation of Ni(I) species and (BINAP)2Ni.
The scope of the reaction encompasses electronically varied aryl
chlorides and nitrogen-containing heteroaryl chlorides, including
pyridine, quinoline, and isoquinoline derivatives. Mechanistic studies support the catalytic cycle involving a Ni(0)/Ni(II) couple
for this nickel-catalyzed amination and are inconsistent with a Ni(I) halide intermediate. Monitoring the reaction mixture by 31
P
NMR spectroscopy identified (BINAP)Ni(η2-NC-Ph) as the resting state of the catalyst in the amination of both aryl chlorides
and bromides. Kinetic studies showed that the amination of aryl chlorides and bromides is first order in both catalyst and aryl
halide and zero order in base and amine. The reaction of a representative aryl chloride is inverse first order in PhCN, but the
reaction of a representative aryl bromide is zero order in PhCN. This difference in the order of the reaction in PhCN indicates
that the aryl chloride reacts with (BINAP)Ni(0), formed by dissociation PhCN from (BINAP)Ni(η2-NC-Ph), but the aryl
bromide directly reacts with (BINAP)Ni(η2-NC-Ph). The overall kinetic behavior is consistent with turnover-limiting oxidative
addition of the aryl halide to Ni(0). Several pathways for catalyst decomposition were identified, such as the formation of the
catalytically inactive bis(amine)-ligated arylnickel(II) chloride, (BINAP)2Ni(0), and the Ni(I) species [(BINAP)Ni(μ-Cl)]2. By
using a well-defined nickel complex as catalyst, the formation of (BINAP)2Ni(0) is avoided and the formation of the Ni(I)
species [(BINAP)Ni(μ-Cl)]2 is minimized.
species. Indeed, nickel complexes have been shown to catalyze
the amination of aryl chlorides and phenol derivatives (Scheme
1).5−24 Such nickel-catalyzed amination reactions could be
more practical than palladium-catalyzed amination reactions on
large scale because the metal is much less expensive, and much
INTRODUCTION
■
The transition-metal-catalyzed amination of aryl halides has
become one of the most powerful methods to construct
arylamines.1 The development of methods to couple aryl
halides with amines has been studied extensively in the past
decade. Most studies have focused on palladium and copper
complexes as catalysts. Palladium-catalyzed reactions occur with
a broad scope of both coupling partners, high functional group
tolerance, and good selectivity for monoarylation of the amine
nucleophile.2,3 However, this scope is accomplished at a price.
Both the palladium metal and the ligands used for this reaction
are costly, and the ligand is difficult to recycle.
Scheme 1. Methods for Nickel-Catalyzed C−N Coupling
Reactions
For these types of reasons, much interest has been paid
recently to develop reactions catalyzed by first-row metal
complexes that are typically catalyzed by precious metals. For
example, copper complexes have been studied extensively for
the coupling of aryl iodides, and to a lesser extent aryl
bromides, with nitrogen nucleophiles.4 Yet, the scope of such
coupling with electron-rich bromoarenes, ortho-substituted
bromoarenes, unactivated aryl chlorides, and heteroaryl halides
is limited.
Many of the first-row metals are more electropositive than
those of the second row and form electron-rich low-valent
Received: November 22, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
simpler ligands on the nickel center are needed for the catalyst
to react with aryl chlorides. For example, Hidai showed over 40
years ago that Ni(PPh3)4 adds phenyl chloride at room
temperature to form (PPh3)2Ni(Ph)(Cl), whereas Pd(PPh3)4
does not react with aryl chlorides.25 However, the scope of the
nickel-catalyzed amination of aryl halides has been limited to
the coupling of secondary alkylamines and arylamines.11−19
Primary alkylamines, one of the most significant classes of
amines for such cross coupling, have been shown to couple
only with activated aryl chlorides.11,17
In addition to the limitations on the scope of the coupling of
aryl halides with amines, the mechanism of the coupling of aryl
halides with amines catalyzed by nickel complexes has not been
studied. Many papers cite the potential of Ni(I) intermedi-
ates,26 either as part of a one-electron redox event or as part of
a mechanism involving Ni(I) and Ni(III) intermediates. In
contrast, the mechanism for the palladium-catalyzed amination
of aryl electrophiles has been studied in detail, including the
kinetic behavior of the catalytic reaction and stoichiometric
reactions of isolated intermediates.27−30 Such studies have not
been conducted on nickel-catalyzed couplings to form C−N
bonds, but are particularly important if one is to determine how
to create catalysts of nickel that are as long-lived as those of
palladium and that react with similarly broad scope.
Here, we present the first nickel-catalyzed amination of
unactivated aryl chlorides with primary aliphatic amines. The
reaction occurs with aryl and heteroaryl chlorides and bromides
catalyzed by a single-component BINAP-ligated nickel(0)
precursor. Kinetic studies have been conducted on the reaction,
and studies on the relative rates of the reaction with various
isolated nickel complexes have been conducted. These studies
rule out a catalytic cycle occurring through a Ni(I) halide
intermediate and are consistent with a Ni(0)/Ni(II) catalytic
cycle for the amination of aryl chlorides and aryl bromides,
which react with different Ni(0) species.
Table 1. Evaluation of Nickel Precursors and Ligands for
Amination of 3-Chloroanisole with Octylamine
a
entry
ligand (mol %)
conv (%)
yield (%)
1
PPh3 (2)
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
31
44
71
75
98
3
<2
3
2
PPh3 (4)
3
PCy3 (2)
PCy3 (4)
DPPE (1)
DPPE (2)
PDPP (1)
DPPP (2)
DPPB (1)
DPPB (2)
DPPF (1)
DPPF (2)
BINAP (1)
BINAP (2)
4
<2
<2
<2
<2
<2
<2
<2
16
32
66
67
92
5
6
7
8
9
10
11
12
13
14
15
b
[Ni0] (1)
a
Conditions: 3-chloroanisole (0.400 mmol), octylamine (0.600
mmol), NaOtBu (0.600 mmol), 24 h. Conversion and yield were
determined by GC analysis using dodecane as internal standard.
b
[Ni0] = (BINAP)Ni(η2-NC-Ph).
a
Table 2. Nickel-Catalyzed Amination: Aryl Chloride Scope
RESULTS AND DISCUSSION
■
Evaluation of Ligands for the Ni-Catalyzed Amination
Reaction. We initiated our studies of nickel-catalyzed
amination of aryl chlorides with primary aliphatic amines by
studying the reaction between 3-chloroanisole and octylamine.
We investigated nickel complexes generated in situ from
Ni(COD)2 and various phosphine ligands as catalysts. These
results are listed in Table 1. These reactions were conducted
with NaOtBu as base in toluene at 50 °C. Reactions catalyzed
by the combination of Ni(COD)2 and monophosphines, such
as PPh3 and PCy3, afforded only trace amounts of the desired
amine product (entries 1−4). Similar results (<5% conversion
and <2% yield) were obtained for reactions catalyzed by the
combination of Ni(COD)2 (1 mol %) and DPPE, DPPP, or
DPPB (1 or 2 mol %) (Entries 5−10). However, reactions
catalyzed by the combination of Ni(COD)2 and DPPF or
BINAP gave significant amounts of product (16−67%, entries
11−14). In particular, the reaction catalyzed by the single
component catalyst (BINAP)Ni(η2-NC-Ph) afforded the
product in 92% yield (entry 15). An explanation for the high
activity of this catalyst will be revealed during the presentation
of our mechanistic studies.
a
Conditions: ArCl (0.400 mmol), octylamine (0.600 mmol),
(BINAP)Ni(η2-NC-Ph) (4.0 μmol, 1 mol %), NaOtBu (0.600
mmol), toluene (1 mL); temperature, 50 °C; reaction time, 24 h.
b
(BINAP)Ni(η2-NC-Ph) (16.0 μmol, 4 mol %).
Scope of the Ni-Catalyzed Amination of Aryl
Chlorides with Primary Aliphatic Amines. With an active
catalyst in hand and reliable conditions identified for this Ni-
catalyzed amination, we studied the scope of aryl chlorides that
undergo these amination reactions, and the results are
summarized in Table 2. In general, a range of electron-rich
(2a−2e), electron-neutral (2h), and electron-deficient (2i−2l)
aryl chlorides coupled with octylamine in high yields (76−96%)
under the developed conditions with 1 mol % of nickel complex
B
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
1. For very electron-rich aryl chlorides, 4 mol % of the catalyst
was required to obtain modest to good yields (2f and 2g). For
these two reactions, aryl chlorides were not fully converted, and
only trace amounts (<5%) of biaryl compounds were detected
by GC analysis. Mono-ortho-substituted aryl chlorides reacted
in high yields (2a, 2c−2e, 2h, and 2j). However, di-ortho-
substituted aryl chlorides, such as 2-chloro-1,3-dimethylben-
zene, did not couple with octylamine under the developed
conditions.
The scope of primary amines was studied by conducting the
amination reactions of 3-chloroanisole catalyzed by 2 mol %
complex 1. The results of this study are summarized in Table 3.
In general, a variety of primary aliphatic amines underwent this
amination process in good to excellent isolated yields (75−
96%).
selectively with the primary amine, leaving the secondary amine
intact (2x).
Nitrogen-containing heterocycles containing amino substitu-
ents are of particular importance for pharmaceutical applica-
tions. However, the C−N coupling reactions between nitrogen-
containing heteroaryl electrophiles and primary amines are
challenging, presumably because of the coordinating properties
of both pyridines and primary amines. Such coupling reactions
have been achieved only with palladium and copper
catalysts.31−35 Nickel catalysts have been reported for the
amination of heteroaryl chlorides, but the amine nucleophiles
are limited to secondary amines.21
Cross-coupling reactions between nitrogen-containing heter-
oaryl chlorides and primary amines catalyzed by 2 mol % of
complex 1 are summarized in Table 4. The scope of heteroaryl
chlorides that underwent this amination reaction encompassed
a range of 2-pyridyl (3a−3f), 3-pyridyl (3g−3l), and 4-pyridyl
Table 3. Nickel-Catalyzed Amination: Primary Amine
a
Scope
Table 4. Nickel-Catalyzed Amination of Heteroaryl Halides
a
with Primary Amines
a
Conditions: 3-chloroanisole (0.400 mmol), primary amine (0.600
mmol), (BINAP)Ni(η2-NC-Ph) (8.0 μmol, 2 mol %), NaOtBu (0.600
mmol), toluene (1 mL); temperature, 50 °C; reaction time, 24 h.
b
c
Temperature, 80 °C. (BINAP)Ni(η2-NC-Ph) (16.0 μmol, 4 mol %).
The steric bulk of the alkyl group of the primary amines
significantly influenced the yields of these reactions. The
reactions of an amine containing a primary alkyl group (2m)
afforded the product in higher yield than the reactions of
amines containing a secondary alkyl group (2n and 2o),
although the primary amines containing a secondary alkyl
group still coupled with aryl chlorides in good yield. However,
the amination of 3-chloroanisole with primary amines
containing a tertiary alkyl group, for example, tert-butylamime
and amylamine, gave only trace amounts of the desired
products. Amines containing aryl (2p), heteroaryl (2q and 2r),
allyl (2s), and cyano (2t) groups reacted in high yields (90−
96%). Primary amines bearing 1,3-dioxolane (2u and 2v) and
morpholine (2w) moieties also reacted in high yields (83−
88%). The reaction of N-isopropylethylenediamine, a substrate
containing both a primary and a secondary amine, occurred
a
Conditions: 3-chloroanisole (0.400 mmol), primary amine (0.600
mmol), (BINAP)Ni(η2-NC-Ph) (8.0 μmol, 2 mol %), NaOtBu (0.600
mmol), toluene (1 mL); temperature, 50 °C; reaction time, 24 h.
b
c
Temperature, 80 °C. (BINAP)Ni(η2-NC-Ph) (16.0 μmol, 4 mol %).
C
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(3m−3p) chlorides containing electron-donating groups (Me
and OMe) and electron-withdrawing groups (CN and CF3). In
general, these reactions afforded the corresponding heteroaryl
alkylamine in good to excellent isolated yields (57−96%,
average yield: 81%). This amination also occurred in high yields
with 2-chloroquinoline (3q) and 2-chloropyrazine (3r). 5-
Chloroisoquinoline also reacted in high yields (3s and 3t). The
scope of primary amines that underwent reactions with
chloropyridines was similar to that of the reactions of 3-
chloroanisole described in Table 3.
Nickel-Catalyzed Amination of Aryl Bromides. Com-
pared to the well-established palladium-catalyzed amination of
aryl bromides, the nickel-catalyzed amination of aryl bromides
has been less studied, and conditions for coupling of aryl
bromides with amines by nickel catalysts have not been
identified. Only two examples of nickel-catalyzed amination of
aryl bromides have been published,11,12 and these two reactions
occurred in poor yields (eqs 1 and 2). Having identified
conditions for the nickel-catalyzed amination of aryl chlorides,
we tested these conditions for the coupling of aryl bromides
with primary amines.
bromide, relative to the rate of decomposition of arylnickel(II)
chloride species.36
Improved Synthesis of (BINAP)Ni(η2-NC-Ph) from the
Air-Stable Nickel Precursor (DME)NiCl2. The catalyst
precursor employed in this study is a single-component
nickel(0) complex (BINAP)Ni(η2-NC-Ph) (1). Previously,
we reported the synthesis of this nickel complex by substitution
of the 1,5-cyclooctadiene (COD) in Ni(COD)2 by BINAP, and
benzonitrile.36 To avoid using the thermally labile, air- and
moisture-sensitive Ni(COD)2, we developed a new synthesis
(Scheme 2) of this complex starting from the air-stable nickel
Scheme 2
precursor (DME)NiCl2. Reaction of (DME)NiCl2 with 1 equiv
of BINAP in THF at 50 °C afforded (BINAP)NiCl2, which was
then reduced by zinc metal in the presence of COD. 31P NMR
analysis of this reaction indicated a clean formation of
(BINAP)Ni(COD). The byproduct ZnCl2 was removed by
washing the reaction mixture with degassed aqueous NaOH. At
this stage, all the volatile components of the reaction mixture
were removed under vacuum. The residue was suspended in
toluene and then allowed to react with benzonitrile. This
reaction sequence afforded (BINAP)Ni(η2-NC-Ph) in 74%
overall yield.
Synthesis of BINAP-Ligated Arylnickel Chloride
Complexes by Oxidative Addition of Aryl Chlorides to
(BINAP)Ni(η2-NC-Ph). Arylnickel halide complexes are
important intermediates in nickel-catalyzed cross-coupling
reactions. In general, arylnickel halides ligated by mono-
phosphines are synthesized by oxidative addition reactions of
aryl halides to Ni(PR3)x (R = alkyl or aryl),37−39 but arylnickel
halides ligated by bisphosphines are prepared by ligand
substitution reactions between monophosphine-ligated aryl-
nickel halide complexes with bisphosphines.40 The direct
oxidative addition of aryl halides to bisphosphine-ligated
Ni(0) has rarely been investigated, mainly due to the lack of
bisphosphine-ligated Ni(0) precursors that can react with aryl
halides at ambient temperature. Recently, we reported the
synthesis of BINAP-ligated arylnickel halide complexes by
reactions of aryl halides with (BINAP)Ni(COD) in the
presence of catalytic amounts of benzonitrile, and we identified
(BINAP)Ni(η2-NC-Ph) as the active Ni(0) species.36 In our
communication on the nickel-catalyzed asymmetric α-arylation
of ketones, we reported the single reaction of electron-deficient
4-chlorobenzotrifluoride with this newly defined Ni(0)
precursor 1 and no isolation of the products. Here we show
the results of the reactions of complex 1 with electronically
varied aryl chlorides.
The amination of aryl bromides catalyzed by benzonitrile
complex 1 in toluene with NaOtBu base occurred in good
yields in some cases, but the scope of the reaction was limited.
Bromobenzene and 4-bromobenzotrifluoride reacted with
octylamine in high GC-yields (98% and 94%, repectively)
under conditions listed in Table 2 with 3 mol % of complex 1
(eq 3). However, 3-bromoanisole coupled with 2-(1,3-dioxolan-
Electron-neutral and electron-deficient aryl chlorides reacted
smoothly with Ni(0) complex 1 in THF at room temperature
to afford the arylnickel(II) chloride complexes 4−7 in 76−89%
isolated yields (eq 5). These complexes are stable in the solid
state at ambient temperature for at least six months without
noticeable decomposition. However, upon standing in THF
solution at room temperature for about 48 h, they fully
decomposed to [(BINAP)Ni(μ-Cl)]2 (8) with concomitant
release of biaryls, as detected by GC-MS analysis. The isolated
2-yl)ethan-1-amine in only 55% GC-yield, whereas the reaction
of the same amine with 3-chloroanisole afforded the desired
product in 87% isolated yield (eq 4). This limited scope for the
amination of aryl bromides may stem from the faster thermal
decomposition of arylnickel(II) bromide species to nickel(I)
D
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
yields for this reaction were about 70% (eq 6). However, the
reaction of electron-rich 4-chloroanisole with complex 1 in
THF did not form the arylnickel chloride complex resulting
from simple oxidative addition, as determined by 31P NMR
spectroscopy. Instead, 31P NMR signals corresponding to two
mutually trans phosphine resonances (doublets at 24.2 and 14.4
ppm with JPP = 352 Hz) were observed.
Figure 1. Molecular structure of the nickelacyclic compound 9. All the
ellipsoids are drawn at the 50% probability and all the hydrogen atoms
are omitted for clarity.
spectroscopic analysis. In addition, we conducted the amination
reaction of 4-chlorobenzotrifluoride with octylamine in the
presence of NaOtBu catalyzed by 2 mol % of (BINAP)NiCl-
(C6H4-4-CF3) at room temperature (B, Scheme 3). Full
conversion of 4-chlorobenzotrifluoride was achieved in 2 h, and
this reaction afforded N-octyl-4-(trifluoromethyl)aniline in 91%
isolated yield. The same reaction catalyzed by 2 mol % of
[(BINAP)Ni-μ-Cl]2 did not afford any amination product (C,
Scheme 3). These results show clearly that the BINAP-ligated
arylnickel(II) chloride compound is kinetically and chemically
competent to be an intermediate in the catalytic process and
the BINAP-ligated nickel(I) halide is not.
Identity of Nickel Species in the Catalytic Reaction
Mixture. To identify the resting state of the catalyst in this
nickel-catalyzed amination reaction, we monitored by 31P{1H}
NMR spectroscopy the reaction of 4-chlorobenzotrifluoride
with octylamine in the presence of NaOtBu catalyzed by 2 mol
% of (BINAP)Ni(η2-NC-Ph) (1) at room temperature. During
the first 50% conversion of 4-chlorobenzotrifluoride, only
Single-crystal X-ray diffraction of the isolated material (Figure
1) showed that this product is complex 9 (eq 7). Complex 9
contains a coordinated monophosphine ligand Ph2P(C6H4-4-
OMe) and a six-membered nickelacyclic structure. Nickel-
acyclic complex 9 contains a small dihedral angle between the
two naphthyl groups of 63°, and the nickel center consists of a
distorted square planar geometry. Complex 9 is formed by P−
C bond cleavage of the BINAP backbone after the initial
formation of BINAP-ligated arylnickel chloride complex
(BINAP)NiCl(C6H4-4-OMe). Similar P−C bond cleavage of
the BINAP backbone in a BINAP-ligated phenylpalladium
bromide complex was reported by our group previously.41
Complex 9 was tested as a catalyst for the amination of 4-
chloroanisole with octylamine under the conditions described
in Table 2. Only trace (<5% by GC analysis) amounts of the
amination product were formed. Thus, the formation of
catalytically inactive complex 9 by the reaction of 4-
chloroanisole and nickel precursor 1 explained the high catalyst
loading required for the amination of electron-rich 4-
chloroanisole.
Scheme 3
Identification of Catalytically Active Species: (BINAP)-
NiII(Cl)(Ar) or [(BINAP)NiI(μ-Cl)]2? The oxidation state of the
nickel intermediates in the amination of aryl halides with
amines has been ambiguous, and pathways involving both
Ni(0)/Ni(II) and Ni(I)/Ni(III) couples have been proposed
for these reactions.11,17 With isolated, BINAP-ligated Ni(0),
Ni(I) halide, and ArNi(II) halide complexes in hand, we were
able to assess precisely the competence of these complexes to
be intermediates in the amination reactions.
To do so, we conducted the reaction of the isolated
(BINAP)NiCl(C6H4-4-CF3) (7) with octylamine and NaOtBu
in the presence of 1 equiv of BINAP to trap a Ni(0) product
(A, Scheme 3). This reaction afforded N-octyl-4-
(trifluoromethyl)aniline in quantitative yield in less than 5
min at room temperature, as indicated by 19F NMR
E
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(BINAP)Ni(η2-NC-Ph) was observed. However, during the
second 50% conversion, a new species corresponding to a
31P{1H} NMR resonance at δ 31.7 ppm gradually accumulated.
This new species is (BINAP)2Ni, as determined by
independently preparing this complex by reduction of (DME)-
NiCl2 with Zn metal in the presence of 2 equiv of BINAP in
THF and comparing the 31P NMR chemical shift.
To test the catalytic activity of (BINAP)2Ni for this
amination process, we conducted the reaction of 4-
chlorobenzotrifluoride with octylamine catalyzed by 5 mol %
of (BINAP)2Ni in the presence of NaOtBu at room
temperature. This reaction did not afford detectable amounts
of the amination product (A, Scheme 4). This result is
consistent with the early report that (BINAP)2Ni does not
undergo oxidative addition with aryl chlorides or bromides at
ambient temperatures.36
Formation of Bis(amine)-Ligated Arylnickel Chloride.
The formation of bis(amine)-ligated palladium complexes was
reported as one possible pathway for deactivation of the catalyst
in the palladium-catalyzed amination of aryl halides.42 These
bis(amine) complexes have been prepared and well charac-
terized. Formation of analogous bis(amine) complexes of nickel
was proposed to explain the much lower reactivity of primary
aliphatic amines than that of cyclic secondary aliphatic amines
and anilines in the nickel-catalyzed amination reaction.17
However, these bis(amine)-ligated nickel complexes have
never been prepared or characterized. In the nickel-catalyzed
amination of aryl chlorides with primary amines catalyzed by
(BINAP)Ni(η2-NC-Ph), we observed the formation of
(BINAP)2Ni. The stoichiometry of this conversion indicates
that there are nickel complexes lacking BINAP ligand in the
reaction mixture. Thus, we studied the ligand substitution
reactions between primary aliphatic amines and BINAP-ligated
Ni(0) and BINAP-ligated Ni(II) complexes.
Scheme 4
The reaction of (BINAP)Ni(η2-NC-Ph) with 50 equiv of n-
butylamine in toluene did not form any new nickel species, and
free BINAP was not detected by 31P NMR spectroscopy (A,
Scheme 5). This result is consistent with the affinity of the
Scheme 5
The same reaction catalyzed by 5 mol % (BINAP)2Ni in the
presence of a catalytic amount of PhCN (30 mol %) afforded
the amination product in 84% yield in 20 h (B, Scheme 4). For
comparison, we conducted the same reaction catalyzed by only
2 mol % (BINAP)Ni(η2-NC-Ph). This reaction afforded the
amination product in almost quantitative yield in 2 h at room
temperature (C, Scheme 4). Thus, (BINAP)Ni(η2-NC-Ph) is a
more active catalyst than the combination of (BINAP)2Ni and
PhCN.
To assess the origin of the effect of benzonitrile on the rate of
the catalytic reaction, we performed the reaction of
(BINAP)2Ni with benzonitrile and the reaction of (BINAP)-
Ni(η2-NC-Ph) with BINAP. The reaction of (BINAP)2Ni with
10 equiv of benzonitrile did not form detectable amounts of
(BINAP)Ni(η2-NC-Ph), as determined by 31P NMR spectros-
copy (D, Scheme 4). The reaction of (BINAP)Ni(η2-NC-Ph)
with 1 equiv of BINAP afforded (BINAP)2Ni quantitatively at
ambient temperature (E, Scheme 3). Based on these
stoichiometric reactions and the catalytic reactions in Scheme
3, we conclude that the formation of (BINAP)2Ni is reversible
in the presence of benzonitrile, but the equilibrium lies largely
on the side of (BINAP)2Ni and free nitrile.
electron-rich Ni(0) center for softer, π-accepting ligands.43
However, the reaction of (BINAP)NiCl(C6H4-4-CN) with 50
equiv of n-butylamine afforded free BINAP and trans-(n-
butylamine)2NiCl(C6H4-4-CN) (10) (B, Scheme 5). Complex
10 was isolated in 76% yield.
With the bis(amine)-ligated complex 10 in hand, we tested
its potential to serve as an intermediate in the amination
reaction. We conducted the reaction of 10 with 2 equiv of
NaOtBu in the presence or in the absence of 1 equiv of BINAP
(C, Scheme 5). These two reactions did not form the desired
amination product. This result indicates that the formation of
bis(amine)-ligated nickel complexes is one possible pathway for
decomposition of the nickel catalyst.
Kinetic Studies on Nickel-Catalyzed Amination of Aryl
Chlorides. After identifying the resting state of the nickel
catalyst and possible paths for catalyst deactivation, we sought
to identify the rate-limiting step for this nickel-catalyzed
amination process. To do so, we measured the dependence
of the initial rates of the amination reaction on the
F
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
concentrations of each reagent under conditions in which the
other reagents were present in large excess.
the reaction. These data indicate that oxidative addition of the
aryl chloride to (BINAP)Ni(0), formed by reversible
dissociation of PhCN from the catalyst resting state (BINAP)-
Ni(η2-NC-Ph), is the turnover-limiting step in the amination
reaction.
We chose the reaction of 4-chlorobenzotrifluoride with
octylamine in the presence of NaOtBu for the kinetic studies
because this reaction occurred at ambient temperature, and we
were able to monitor the reaction conveniently by both 31P and
19F NMR spectroscopy. Furthermore, no background nucleo-
philic aromatic substitution reaction was observed for this aryl
chloride and octylamine in the presence of NaOtBu.
For the initial rates to be a valid method for kinetic analysis
of this reaction, all reagents must be soluble in the reaction
medium, and no induction period can be present. The single-
component catalyst precursor 1 is only marginally soluble in the
reaction medium. Thus, we used (BINAP)NiCl(C6H4-4-CF3)
(7) as the source of nickel for our kinetic experiments because
it dissolves in seconds once mixed with other reagents.
Benzonitrile was added to the reaction mixture to trap the
BINAP-ligated Ni(0) species to form (BINAP)Ni(η2-NC-Ph),
which had been identified as the catalyst resting state. In the
absence of benzonitrile, the irreversible formation of
(BINAP)2Ni occurs quickly. Benzonitrile (10 equiv relative to
complex 7) was added so that catalyst decomposition was not
observed by 31P NMR spectroscopy over the time of the
reaction.
Kinetic Studies on Nickel-Catalyzed Amination of Aryl
Bromides. The mechanism of palladium-catalyzed cross-
coupling reactions with aryl halides as electrophiles has been
extensively studied. These studies reveal that the halide identity
has a dramatic effect on the mechanism for the oxidative
addition of aryl halides to Pd(0) species. The additions of the
less reactive aryl chlorides occurs through lower-coordinated
Pd(0) intermediate than the additions of more reactive aryl
iodides.44 However, such mechanistic data has not been gained
for the nickel-catalyzed amination of aryl halides. For the
nickel-catalyzed enantioselective α-arylation of ketones, we
found that aryl chlorides react in much higher yields and with
much higher enantioselectivities than aryl bromides, and we
attributed this dramatic effect of halide on the reaction yield
and enantioselectivity to the faster decomposition of the
arylnickel(II) bromide intermediate relative to the arylnickel-
(II) chloride intermediate to their corresponding Ni(I) halide
complexes.36
Because the Ni(0) complex 1 ligated by BINAP and PhCN
catalyzes the amination of both aryl chlorides and aryl
bromides, we can compare directly the kinetics and mechanism
of the amination reactions of aryl chlorides and aryl bromides
catalyzed by this nickel system. To do so, we conducted kinetic
experiments on the amination of aryl bromides that were
similar to those we conducted on the amination of aryl
chlorides.
The kinetic behavior was assessed for the coupling of 4-
chlorobenzotrifluoride with octylamine catalyzed by the
combination of complex 7 in the presence of PhCN and
NaOtBu at room temperature (eq 8). The initial rates were
We monitored by 31P NMR spectroscopy the reaction of 4-
bromobenzotrifluoride with octylamine catalyzed by (BINAP)-
Ni(η2-NC-Ph) in the presence of NaOtBu at room temperature.
As was the case in the reactions of chloroarenes, (BINAP)Ni-
(η2-NC-Ph) was identified as the resting state of the catalyst in
the reaction of 4-bromobenzotrifluoride with octylamine.
Kinetic studies were conducted on the reaction of 4-
bromobenzotrifluoride with octylamine catalyzed by (BINAP)-
NiBr(C6H4-4-CF3) (11) in the presence of added PhCN (eq
8). The initial rates were measured for various concentrations
of each reagent while keeping the other reagents in excess. The
plots of concentrations of N-octyl-4-(trifluoromethyl)aniline vs
time at various concentrations of each reagent are shown in
Figures S7−S11. The plots of the initial rates of the reaction vs
the concentrations of the catalyst, aryl chloride, and
benzonitrile are shown in Figure 3.
measured by 19F NMR spectroscopy using 4-OCF3-anisole as
the internal standard. The rate of the amination reaction was
determined by measuring the formation of N-octyl-4-
(trifluoromethyl)aniline with respect to time. The plots of
concentrations of N-octyl-4-(trifluoromethyl)aniline vs time at
various concentrations of each reagent are shown in Figures
S1−S5 in the Supporting Information. The plots of the initial
rates of the reaction vs the concentrations of the catalyst, aryl
chloride, and benzonitrile are shown in Figure 2. The kinetic
analysis showed that this nickel-catalyzed amination reaction of
aryl chlorides is first order in the nickel catalyst, first order in
aryl chloride, and inverse first order in PhCN. The remaining
reagents, NaOtBu and amine, did not affect the initial rate of
Figure 2. Plots of initial rates vs concentration of catalyst, aryl chloride, and benzonitrile for the amination of 4-chlorobenzotrifluoride (0.10−1.0 M)
with n-octylamine (0.30 M) catalyzed by (BINAP)NiCl(C6H4-4-CF3) (0.0060−0.018 M) in the presence of benzonitrile (0.090−0.180 M) and
NaOtBu (0.30 M) at room temperature.
G
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 3. Plots of initial rates vs concentration of catalyst, aryl bromide, and benzonitrile for the amination of 4-bromobenzotrifluoride (0.10−0.80
M) with n-octylamine (0.30 M) catalyzed by (BINAP)NiCl(C6H4-4-CF3) (0.0060−0.018 M) in the presence of benzonitrile (0.090−0.180 M) and
NaOtBu (0.30 M) at room temperature.
Like the amination of 4-chlorobenzotrifluoride, the amina-
tion of 4-bromobenzotrifluoride with octylamine is first order in
the nickel catalyst, first order in aryl halide, zero order in
NaOtBu, and zero order in amine. In contrast to the reaction of
4-chlorobenzotrifluoride, which is inverse first order in PhCN,
the amination of 4-bromobenzotrifluoride is zero order in
PhCN. This order in PhCN, in combination with the first order
in aryl bromide, indicates that the bromoarene reacts directly
with (BINAP)Ni(η2-NC-Ph) during the turnover-limiting step
of the amination of the bromoarene without dissociation of
PhCN. The different reactivities of aryl halides with BINAP-
ligated nickel complexes of different coordination numbers
parallels a trend in oxidative addition to Pd(0) complexes noted
in the introduction to this section.44
Overall Mechanism of Nickel-Catalyzed Amination of
Aryl Chlorides and Aryl Bromides. Based on the
stoichiometric reactions of the isolated BINAP-ligated arylnick-
el halides with primary amines in the presence of base and the
conducted kinetic studies, we propose a catalytic cycle depicted
in Scheme 6 for the nickel-catalyzed amination of aryl chlorides
and aryl bromides reported in this paper. The observed first
order rate-dependence on the concentrations of both the
catalyst and aryl halides indicates that the oxidative addition of
aryl halides to BINAP-ligated Ni(0) species to form (BINAP)-
NiAr(X) (X = Cl or Br) is the turnover-limiting step for both
amination processes. This BINAP-ligated arylnickel(II) halide
complex subsequently reacts with primary amine and NaOtBu
to form an arylnickel amido complex, followed by reductive
elimination of the N-alkyl aniline product in the presence of
PhCN to regenerate (BINAP)Ni(η2-NC-Ph), which was
confirmed as the catalyst resting state.
Interestingly, different rate-dependences on the concen-
tration of PhCN were observed for this nickel-catalyzed
amination of aryl chlorides and aryl bromides. The reaction
of aryl chlorides is inverse first order in PhCN, whereas the
reaction of aryl bromides is zero order in PhCN. These reaction
orders indicate that aryl chlorides and aryl bromides react with
different nickel(0) species. The aryl chlorides react after
reversible dissociation of PhCN from (BINAP)Ni(η2-NC-Ph)
to form the lower-coordinate nickel(0) species (BINAP)Ni(0)
and ultimately the BINAP-ligated arylnickel(II) chloride
complex. However, the aryl bromides react directly with
(BINAP)Ni(η2-NC-Ph) to form BINAP-ligated arylnickel(II)
bromide complex and the nitrile dissociates during or
immediately after the oxidative addition process. One could
imagine the zero-order dependence on added PhCN could
indicate that dissociation of this ligand is rate limiting, but the
first-order dependence of the reaction on the aryl bromide is
inconsistent with this proposal.
Scheme 6. Proposed Catalytic Cycle for the Nickel-Catalyzed
Amination of Aryl Chlorides and Bromides
In addition to the steps within the catalytic cycle that form
the arylamine product, there are several pathways that generate
catalytically inactive nickel species. First, the reaction of
(BINAP)NiAr(Cl) with amine RNH2 forms the catalytically
inactive (RNH2)2NiAr(Cl) and free BINAP. The released free
BINAP in the reaction mixture traps the (BINAP)Ni(0)
fragment generated by dissociation of PhCN from (BINAP)-
Ni(η2-NC-Ph) or reductive elimination of N-alkyl aniline from
the BINAP-ligated arylnickel(II) amido complex to form
(BINAP)2Ni. (BINAP)2Ni does not undergo oxidative addition
of the aryl halide and does not catalyze the amination reaction.
However, it can be reactivated by PhCN. Second, thermal
decomposition of (BINAP)NiAr(X) (Ar = electron-neutral and
electron-rich aryl groups) affords the catalytically inactive
[(BINAP)Ni(μ-X)]2 with concomitant formation of biaryl.
Third, for the amination of electron-rich aryl chlorides, P−C
bond cleavage of the BINAP backbone is a potential pathway
for the deactivation of the nickel catalyst. Indeed, this complex
was observed to accumulate (approximately 6.4 mM of the 16
mM concentration of initial catalyst) during the reaction of 4-
chloroanisole with octylamine.
H
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Competition Experiments. To gain information on the
relative rates of the amination of aryl chlorides and aryl
bromides and the effect of temperature and concentration of
PhCN on the selectivity of the amination reaction for an aryl
chloride versus an aryl bromide, we conducted a series of
reactions with an aryl halide containing both chloride and
bromide and a mixture of aryl halides in the presence of various
amounts of PhCN at room temperature or 50 °C. The results
of these reactions are summarized in Scheme 7.
This preferential intramolecular oxidative addition has recently
been observed for the Ni-catalyzed Kumada cross-coupling
reactions that are part of chain-growth polymerizations.45
To evaluate the effect of PhCN on the selectivity between
the amination of an aryl chloride and an aryl bromide, we
conducted the amination of equal amounts of 1-bromo-4-
butylbenzene and 4-chlorotoluene with octylamine catalyzed by
3 mol % of (BINAP)Ni(η2-NC-Ph) in the presence of 0.9 equiv
of PhCN (relative to octylamine) (D, Scheme 6). Because our
kinetic studies revealed different dependences of the reaction
rate on PhCN for this nickel-catalyzed amination (inverse first
order and zero order on PhCN for the reaction of aryl chloride
and aryl bromide, respectively), we considered that an
increased selectivity for the conversion of aryl bromide over
aryl chloride would be observed for reactions conducted with
higher concentrations of PhCN than for reactions conducted
with lower concentrations of PhCN.
Scheme 7
Consistent with this prediction, the selectivity was higher
(30:1 for the reaction at room temperature and 9:1 for the
reaction at 50 °C) for the amination of 1-bromo-4-
butylbenzene versus the amination of 4-chlorotoluene for
reactions run with higher concentrations (from 0.004 to 0.18
M) of benzonitrile at both room temperature and 50 °C for 24
h. These data show that the difference in Ni(0) species that
adds the different aryl halides can be used to beneficially affect
selectivity.
Comparison to Prior Ni Systems for Aryl Halide
Amination. Several first-row metal complexes catalyze cross
coupling reactions, and many catalyze the coupling of certain
classes of chloroarenes. However, no first row metal complex
has been shown to catalyze the coupling of primary alkylamines
with unactivated chloroarenes. Copper complexes couple
bromoarenes and iodoarenes with primary amines, but they
do not catalyze the coupling of chloroarenes with primary
amines.
Previously, the combination of Ni(COD)2 and DPPF was
shown to couple an electron-poor chloroarene with a primary
amine, but this catalyst did not couple unactivated chloroarenes
with primary amines.11 A set of preliminary studies we
conducted have shown that the complexes (DPPF)Ni(COD)
or (DPPF)2Ni generated in situ by the reaction of Ni(COD)2
and DPPF do not add aryl chlorides at ambient temperature,
and the reaction of chloroarenes with (DPPF)Ni(COD) or
(DPPF)2Ni at elevated temperatures forms (DPPF)Ni(I)Cl
and biaryl.
This formation of (DPPF)2Ni(0) and (DPPF)Ni(I)Cl at the
elevated temperatures required for oxidative addition of
chloroarene to occur, likely prevented productive coupling
reactions with unactivated chloroarenes. These observations
further illustrate the importance of the nitrile-ligated precursor
with the general formula L2Ni(η2-NC-Ph).
Nickel complexes of N-heterocyclic carbenes have been
shown to couple aryl chlorides and sulfonates with secondary
amines and with arylamines, but not primary alkylamines.
Mechanistic studies on the reactions of secondary amines
catalyzed by the complexes of N-heterocyclic carbenes are too
limited to determine the origin of their lack of reactivity with
primary amines, but recent studies have shown that the
arylnickel halide complexes containing hindered N-heterocyclic
carbenes are not formed by the reaction of (IMes)2Ni(0) with
chlorobenzene, bromobenzene, and iodobenzene.46 Instead,
Ni(I) species are formed, and this formation of Ni(I)
complexes could either constitute the pathway for catalyst
The amination of 1-bromo-4-chlorobenzene with octylamine
catalyzed by 3 mol % of (BINAP)Ni(η2-NC-Ph) at 50 °C
occurred selectively at the C−Br bond, and the product of the
reaction at the C−Cl bond was not detected by GC-MS
analysis. The product N-octyl-4-chloroaniline was isolated in
80% yield. (A, Scheme 7). However, side-by-side reactions of
chlorobenzene and bromobenzene under the same conditions
occurred in the same GC yield (98%) (B, Scheme 7).
The amination of equal amounts of 1-bromo-4-butylbenzene
and 4-chlorotoluene with octylamine catalyzed by 3 mol % of
(BINAP)Ni(η2-NC-Ph) was conducted at both room temper-
ature and 50 °C (C, Scheme 7). At both temperatures, these
reactions occurred in similar yields, but with different
selectivity. At room temperature, 1-bromo-4-butylbenzene
was converted selectively over 4-chlorotoluene, and a product
ratio of 3:1 was obtained. However, at 50 °C, 1-bromo-4-
butylbenzene and 4-chlorotoluene converted equally. Com-
pared with the full selectivity for amination of the C−Br bond
in 1-bromo-4-chlorobenzene (A, Scheme 7), the decreased
selectivity for amination of the C−Br bond over the C−Cl
bond in different haloarenes might stem from irreversible or
nearly irreversible binding of the haloarene to Ni(0) to form an
arene π-complex prior to cleavage of the carbon−halogen bond.
I
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
decomposition or a mechanism for reaction with this catalyst
involving odd-electron nickel intermediates.
this detrimental path, and to determine if Ni(I) complexes are
generated during oxidative addition of haloarenes will be the
subject of future work.
CONCLUSIONS
■
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedure, characterizations of all
compounds, and crystallographic data (CIF) for compound 9.
This material is available free of charge via the Internet at
http://pubs.acs.org.
We have shown that nickel complexes containing common aryl
bisphosphine ligands can catalyze the coupling of aryl chlorides
and bromides with primary amines. In particular, we have
shown that the mixed Ni(0) species (BINAP)Ni(η2-NC-Ph)
containing one bisphosphine and one side-bound nitrile is a
particularly active catalyst for the coupling of chloroarenes with
primary amines and is more active than the related
(BINAP)2Ni catalyst. A range of electronically varied aryl
halides and nitrogen-containing heteroaryl chlorides, including
pyridine, quinoline, and isoquinoline derivatives, couple with a
variety of aliphatic primary amines in high isolated yields.
Several aspects of the current system lead to the ability of this
first-row metal system to catalyze this class of amination
reaction. In general, we attribute the high yields for these
amination reactions to the facile oxidative addition of aryl
chlorides and heteroaryl chlorides to the (BINAP)Ni(η2-NC-
Ph) precatalyst at ambient temperatures.
Detailed studies on the mechanism of the amination reaction
have been conducted. The following conclusions about the
mechanism of this coupling process have been drawn from
these studies:
(1) The oxidative addition of aryl chlorides to (BINAP)Ni-
(η2-NC-Ph), together with the stoichiometric reactions of
(BINAP)NiAr(Cl) with primary aliphatic amines in the
presence of base, support a reaction pathway involving a
Ni(0)/Ni(II) couple in the catalytic cycle.
■
S
AUTHOR INFORMATION
Corresponding Author
jfhartwig@berkeley.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the financial support of this work
from NIH (GM058108) and the Dow Chemical Company.
R.A.G. acknowledges NSERC and FQRNT for graduate
fellowships. The authors thank Dr. Antonio DiPasquale for
collecting the crystallographic data and solving the structure of
compound 9. We thank Jerzy Klosin at the Dow Chemical
Company for helpful discussions and critical reading of the
manuscript.
REFERENCES
■
(1) Ricci, A. Modern Amination Methods; Wiley-VCH Verlag GmbH:
Weinheim, 2000.
(2) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
(3) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338.
(4) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
(5) Hie, L.; Ramgren, S. D.; Mesganaw, T.; Garg, N. K. Org. Lett.
2012, 14, 4182.
(2) The oxidative addition of aryl chlorides and heteroaryl
chlorides to the single-component nickel precursor (BINAP)-
Ni(η2-NC-Ph) at ambient temperatures prevents the formation
of inactive Ni species.
(3) Ni(I) intermediates, which have been observed in
oxidative addition studies to phosphine-ligated Ni(0) com-
plexes, appear to result from decomposition of the Ni(II)
product of oxidative addition as opposed to forming from one-
electron pathways for oxidative addition to Ni(0).26
́
(6) Iglesias, M. J.; Blandez, J. F.; Fructos, M. R.; Prieto, A.; Alvarez,
E.; Belderrain, T. R.; Nicasio, M. C. Organometallics 2012, 31, 6312.
(7) Ilies, L.; Matsubara, T.; Nakamura, E. Org. Lett. 2012, 14, 5570.
(8) Kuhl, S.; Fort, Y.; Schneider, R. J. Organomet. Chem. 2005, 690,
6169.
(9) Martin, A. R.; Makida, Y.; Meiries, S.; Slawin, A. M. Z.; Nolan, S.
P. Organometallics 2013, 32, 6265.
(10) Mesganaw, T.; Garg, N. K. Org. Process Res. Dev. 2012, 17, 29.
(11) (a) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
6054. (b) Park, N. H.; Teverovskiy, G.; Buchwald, S. L. Org. Lett.
2014, 16, 220.
(12) Brenner, E.; Fort, Y. Tetrahedron Lett. 1998, 39, 5359.
(13) Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron 1999, 55, 12829.
(14) Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2000, 41,
2881.
(4) The reaction of (BINAP)Ni(η2-NC-Ph) with electron-
rich aryl chlorides, such as 4-chloroanisole, leads to the P−C
bond cleavage of the backbone of BINAP and forms the nickel
complex 9 containing two monophosphine ligands. The
formation of the catalytically inactive complex 9 explains the
high catalyst loading required for the amination of electron-rich
aryl chlorides.
(5) Mechanistic and kinetic studies revealed that the
turnover-limiting step of these nickel-catalyzed amination
reactions of aryl chlorides is oxidative addition of the aryl
chloride to (BINAP)Ni(0), which is formed by dissociation of
PhCN from the catalyst resting state (BINAP)Ni(η2-NC-Ph).
(6) Mechanistic and kinetic studies imply that the turnover-
limiting step of the reactions of aryl bromides is also oxidative
addition, but that aryl bromides react with a different nickel
species, of composition (BINAP)Ni(η2-NC-Ph) containing a
bound nitrile.
(7) The formation of catalytically inactive bis(amine)-ligated
Ni(II) species (RNH2)2NiAr(Cl), Ni(I) species [(BINAP)Ni-
(μ-Cl)]2, and bis-BINAP-ligated Ni(0) species (BINAP)2Ni are
the major pathways for catalyst inactivation.
Further studies to improve the lifetime of the Ni-
bisphosphine catalysts, to determine the mechanism by which
the phosphine-ligated Ni(I) species form as a means to prevent
(15) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2000,
41, 2875.
(16) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2001,
42, 247.
(17) Desmarets, C.; Schneider, R.; Fort, Y. J. Org. Chem. 2002, 67,
3029.
(18) Omar-Amrani, R.; Thomas, A.; Brenner, E.; Schneider, R.; Fort,
Y. Org. Lett. 2003, 5, 2311.
(19) Chen; Yang, L.-M. J. Org. Chem. 2007, 72, 6324.
(20) Gao, C.-Y.; Yang, L.-M. J. Org. Chem. 2008, 73, 1624.
(21) (a) Manolikakes, G.; Gavryushin, A.; Knochel, P. J. Org. Chem.
2008, 73, 1429. (b) Iglesias, M. J.; Prieto, A.; Nicasio, M. C. Adv.
Synth. Catal. 2010, 352, 1949. (c) Fan, X.-H.; Li, G.; Yang, L.-M. J.
Organomet. Chem. 2011, 696, 2482.
J
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(22) Shimasaki, T.; Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed.
2010, 49, 2929.
(23) Mesganaw, T.; Silberstein, A. L.; Ramgren, S. D.; Nathel, N. F.
F.; Hong, X.; Liu, P.; Garg, N. K. Chem. Sci. 2011, 2, 1766.
(24) Ramgren, S. D.; Silberstein, A. L.; Yang, Y.; Garg, N. K. Angew.
Chem., Int. Ed. 2011, 50, 2171.
(25) Hidai, M.; Kashiwagi, T.; Ikeuchi, T.; Uchida, Y. J. Organomet.
Chem. 1971, 30, 279.
(26) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 6319.
(27) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 4708.
(28) Widenhoefer, R. A.; Buchwald, S. L. Organometallics 1996, 15,
2755.
(29) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232.
(30) Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.;
Blackmond, D. G.; Strieter, E. R.; Buchwald, S. L. J. Am. Chem. Soc.
2006, 128, 3584.
(31) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3490.
(32) Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
6586.
(33) Liu, Z.-J.; Vors, J.-P.; Gesing, E. R. F.; Bolm, C. Adv. Synth.
Catal. 2010, 352, 3158.
(34) Liu, Z.-J.; Vors, J.-P.; Gesing, E. R. F.; Bolm, C. Green Chem.
2011, 13, 42.
(35) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.;
Buchwald, S. L. Chem. Sci. 2011, 2, 57.
(36) Ge, S.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 16330.
(37) Hernan
́ ́ ̀
dez, M.; Miralrio, G.; Arevalo, A.; Bernes, S.; García, J. J.;
́
Lopez, C.; Maitlis, P. M.; del Rio, F. Organometallics 2001, 20, 4061.
(38) Retbøll, M.; Edwards, A. J.; Rae, A. D.; Willis, A. C.; Bennett, M.
A.; Wenger, E. J. Am. Chem. Soc. 2002, 124, 8348.
(39) Zeller, A.; Herdtweck, E.; Strassner, T. Eur. J. Inorg. Chem. 2003,
2003, 1802.
(40) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
195.
(41) Alcazar-Roman, L. M.; Hartwig, J. F.; Rheingold, A. L.; Liable-
Sands, L. M.; Guzei, I. A. J. Am. Chem. Soc. 2000, 122, 4618.
(42) Widenhoefer, R. A.; Buchwald, S. L. Organometallics 1996, 15,
3534.
(43) Orpen, A. G.; Connelly, N. G. Organometallics 1990, 9, 1206.
(44) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am. Chem.
Soc. 2009, 131, 8141.
(45) Bryan, Z. J.; Mcneil, A. J. Chem. Sci. 2013, 4, 1620.
(46) Zhang, K.; Conda-Sheridan, M. R.; Cooke, S.; Louie, J.
Organometallics 2011, 30, 2546.
K
dx.doi.org/10.1021/ja411911s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX