A comparative reactivity survey of some prominent bisphosphine nickel(II) precatalysts in C-N cross-coupling

Article abstract of DOI:10.1021/acs.organomet.6b00650

The synthesis and characterization of the new air-stable precatalyst (L1)Ni(o-tol)Cl (C1; where L1 = JosiPhos CyPF-Cy) is reported, along with the results of a comparative reactivity survey involving C1 and analogous PAd-DalPhos- and DPPF-containing precatalysts (C2 and C3, respectively) in representative nickel-catalyzed C(sp²)-N cross-coupling reactions. Precatalyst C1 was found to be competitive with, and in some cases complementary to, C2 in the monoarylation of ammonia and primary alkylamines with (hetero)aryl chlorides, including in otherwise challenging room temperature transformations. (Pseudo)halide comparison studies involving the cross-coupling of furfurylamine at room temperature revealed that in contrast to C2 precatalyst C1 performs less effectively with aryl bromides. Whereas C3 was found to be ineffective for such transformations, this DPPF-derived precatalyst proved superior to C1 and C2 in reactions involving the secondary dialkylamine test substrate morpholine.

Full text of DOI:10.1021/acs.organomet.6b00650

Article
pubs.acs.org/Organometallics
A Comparative Reactivity Survey of Some Prominent Bisphosphine
Nickel(II) Precatalysts in C−N Cross-Coupling
Jillian S. K. Clark,† Christopher M. Lavoie,† Preston M. MacQueen,† Michael J. Ferguson,‡
and Mark Stradiotto*,†
†Department of Chemistry, Dalhousie University, 6274 Coburg Road, P.O. Box 15000, Halifax, Nova Scotia B3H 4R2, Canada
‡X-ray Crystallography Laboratory, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
S
* Supporting Information
ABSTRACT: The synthesis and characterization of the new air-
stable precatalyst (L1)Ni(o-tol)Cl (C1; where L1 = JosiPhos CyPF-
Cy) is reported, along with the results of a comparative reactivity
survey involving C1 and analogous PAd-DalPhos- and DPPF-
containing precatalysts (C2 and C3, respectively) in representative
nickel-catalyzed C(sp2)−N cross-coupling reactions. Precatalyst C1
was found to be competitive with, and in some cases
complementary to, C2 in the monoarylation of ammonia and
primary alkylamines with (hetero)aryl chlorides, including in
otherwise challenging room temperature transformations.
(Pseudo)halide comparison studies involving the cross-coupling
of furfurylamine at room temperature revealed that in contrast to
C2 precatalyst C1 performs less effectively with aryl bromides.
Whereas C3 was found to be ineffective for such transformations, this DPPF-derived precatalyst proved superior to C1 and C2 in
reactions involving the secondary dialkylamine test substrate morpholine.
methods.8 Consequently, our understanding of the influence
1. INTRODUCTION
of ancillary ligation on such nickel-catalyzed C(sp2)−N bond-
The palladium-catalyzed cross-coupling of NH substrates and
forming reactions is rather limited. Despite the potential for
(hetero)aryl (pseudo)halides (i.e., Buchwald−Hartwig amina-
both single-electron chemistry and Ni(I)/(III)9 catalytic
tion, BHA) is a well-established C(sp2)−N bond-forming
cycles,10 recent studies support an active Ni(0)/Ni(II) cycle
methodology that is employed widely in the synthesis of
in C(sp2)−N11 (as well as C(sp2)−S)12 cross-couplings
biologically active molecules and functional materials.1 Building
involving phosphine-ligated nickel species with aryl (pseudo)-
on the initial development of such transformations over 20
years ago,2 state-of-the-art catalyst systems for BHA collectively
halides, in keeping with BHA. However, the smaller atomic
radius and lower electronegativity of nickel versus those of
enable the cross-coupling of a broad spectrum of aryl
palladium, as well as the greater propensity for C(sp2)−Cl
electrophiles and NH substrates. The remarkable expansion
oxidative addition to phosphine-ligated Ni(0) versus Pd(0),5a,13
of BHA chemistry can be attributed in large part to the design
suggest that ancillary ligands optimized for use with palladium
and application of electron-rich and sterically demanding
alkylphosphine and N-heterocyclic carbene ancillary ligands3
in BHA are unlikely to be universally effective in related nickel
that promote the formation of low-coordinate,4 electron-rich
chemistry. In this regard, the systematic evaluation of known
and newly identified/developed ancillary ligands sharing a
LPd(0) complexes that are predisposed toward otherwise
challenging oxidative additions (e.g., X = Cl).5
common donor atom motif will serve to illuminate important
structure−reactivity trends, thereby directing the evolution of
Notwithstanding the utility of BHA chemistry, the cost and
increasingly effective nickel catalysts for use in C(sp2)−N cross-
relative scarcity of palladium, as well as the desire to access new
substrate classes in C(sp2)−N cross-coupling reactions,
coupling chemistry.
Bisphosphine ligands, including commercially available
provides motivation for the development of base-metal catalysts
JosiPhos CyPF-Cy (L1),14 PAd-DalPhos (L2),15 and DPPF
for such transformations. Nickel-based catalysts are particularly
attractive in this regard, especially in light of their ability to
(L3)8,16 have proven effective in supporting useful nickel
catalysts for C(sp2)−N cross-coupling chemistry (Scheme 1).
promote alternative cross-couplings involving a diversity of
Our group,14 as well as Green and Hartwig,11c independently
phenol-derived electrophiles.6 In this context it is surprising
that the application of nickel-based catalysts in C(sp2)−N
cross-coupling has received comparatively little attention7
because the first report of such transformations involving aryl
chlorides coincided with the early development of BHA
disclosed the first examples of nickel-catalyzed ammonia
Received: August 12, 2016
© XXXX American Chemical Society
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Scheme 1. Nickel-Catalyzed C(sp2)−N Cross-Coupling
Employing C1−C3
sought to prepare (L1)Ni(o-tol)Cl (C1). Combination of L1
with NiCl2(DME) to give the putative intermediate (L1)NiCl2,
followed by treatment with (o-tol)MgCl afforded (L1)Ni(o-
tolyl)Cl (C1) in 76% overall isolated yield (Figure 1, eq 1).
monoarylation, in which relatively electron-rich JosiPhos-type
ligands were employed at elevated temperatures (≥100 °C); in
our report14 on such chemistry, Ni(COD)2/L1 catalyst
mixtures were used with success in combination with
(hetero)aryl bromides, chlorides, and tosylates. Subsequent
application of nickel precatalyst (L2)Ni(o-tol)Cl (C2),
featuring new and relatively electron-poor bisphosphine L2,
enabled the first examples of nickel-catalyzed room temperature
transformations of primary alkylamines and ammonia in
combination with an unprecedented scope of (hetero)aryl
electrophiles.15 Ligand L3 was employed in the pioneering
report on nickel-catalyzed C(sp2)−N cross-coupling8 and
remains a prominent ligand for such transformations. Notably,
Buchwald and co-workers have demonstrated that the L3-
supported nickel precatalyst (L3)Ni(o-tol)Cl (C3) is effective
for cross-couplings of secondary amines and anilines in
combination with (hetero)aryl chlorides, sulfamates, mesylates,
and triflates.16 While collectively L1−L3 cover a broad scope of
NH substrates, individually the successful application of each of
these ancillary ligands in nickel-catalyzed C(sp2)−N cross-
coupling chemistry is demonstrated only for selected substrate
classes (vide supra). In an effort to learn more about the relative
abilities of L1−L3 in nickel-catalyzed C(sp2)−N cross-
couplings, we sought to carry out a head-to-head reactivity
comparison employing a representative selection of aryl
electrophiles and structurally varied NH substrates. Given the
efficacy of catalysts based on either electron-rich ligand L1 or
comparatively electron-poor ligand L2 in rather challenging
nickel-catalyzed ammonia monoarylation chemistry, we were
particularly interested in comparing directly the reactivity
behavior of structurally analogous nickel precatalysts featuring
these electronically divergent ancillary ligand sets; in the case of
L1, this required preparation of the hitherto unknown
precatalyst (L1)Ni(o-tol)Cl (C1). Herein we report on the
synthesis and characterization of C1 and on the results of a
comparative reactivity survey of C1−C3 in representative
nickel-catalyzed C(sp2)−N cross-coupling reactions.
Figure 1. Single-crystal X-ray structure of C1, shown with 30%
thermal ellipsoids and with hydrogen atoms omitted for clarity.
Selected interatomic distances (Å) and angles (deg) for C1: Ni−P1
2.1774(8), Ni−P2 2.2721(8), Ni−Cl 2.2078(8), Ni−C(aryl) 1.925(3),
P1−Ni−P2 97.84(3), P1−Ni−C(aryl) 89.16(10), P2−Ni−C1
89.54(3), Cl−Ni−C(aryl) 84.34(10).
The diamagnetic, air-stable complex C1 was characterized by
use of NMR spectroscopic and single-crystal X-ray diffraction
techniques (Figure 1). The crystal structure of C1 reveals a
distorted square planar geometry at nickel (Σangles at Ni ≈ 360°),
whereby the κ2-P,P-L1 ligand features chloride trans to the
trialkylphosphine donor fragment. The cis-chelating bisphos-
phine in C1 exhibits a P−Ni−P bite angle (∼97.8°) that is
intermediate between those found in the crystal structures of
C2 (∼86.5°)15 and C3 (∼102.0°).16
2.2. Nickel-Catalyzed Monoarylation of Ammonia.
Ammonia is one of the most widely produced commodity
chemicals and as such represents an attractive synthon in the
synthesis of nitrogen-containing organic molecules.18 However,
the selective monoarylation of ammonia with (hetero)aryl
electrophiles has proven to be a significant challenge due in part
to the fact that for most catalyst systems the sought-after
primary (hetero)aniline products are often better substrates
than ammonia itself, leading to uncontrolled polyarylation.19 In
this regard, ammonia monoarylation provides a useful testing
ground for ancillary ligand design in metal-catalyzed C(sp2)−N
cross-coupling chemistry. Whereas palladium-based catalysts
have traditionally offered optimal performance for the cross-
coupling of ammonia with (hetero)aryl chlorides,20 the scope
of reactivity exhibited by C2, both in terms of the breadth of
electrophilic partners and the varied reaction conditions
tolerated including room temperature transformations, was
found to exceed that achieved by use of any known catalyst
system.15 We previously demonstrated that Ni(COD)2/L1
mixtures were effective in ammonia monoarylation chemistry
conducted at elevated temperatures (vide supra); under
analogous conditions, the performance of Ni(COD)2/L3 was
found to be comparatively poor.14 Given the potential for
catalyst inhibition by COD,21 we sought to compare directly
the performance of precatalysts C1−C3 in ammonia
monoarylation chemistry at both 25 and 110 °C, involving 1-
chloronaphthalene, 3-chloroanisole, 4-chloroanisole, and 5-
2. RESULTS AND DISCUSSION
2.1. Synthesis and Characterization of Precatalyst C1.
From a practical perspective, there is considerable interest in
the development of air-stable nickel(II) precatalysts that can be
reduced to the requisite nickel(0) species under catalytic
conditions, without the required addition of an exogenous
reductant. Given the utility of precatalysts of the type
LnNi(aryl)X17 in this regard, including C215 and C3,16 we
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chlorobenzo[b]thiophene as representative ortho-substituted,
electron-poor, electron-rich, and heterocyclic aryl chlorides,
respectively (Scheme 2). For these transformations as well as
conversion to 4-aminobenzonitrile was achieved with C1,
whereas poor conversion to 4-aminobenzonitrile was observed
when using C2, along with the formation of higher molecular
weight byproducts.
Improved catalytic performance in ammonia monoarylation
was observed for C1 and C2 at 110 °C, with each of these
precatalysts affording synthetically useful conversions to 1a, 1b,
and 1d. Divergent performance was noted in reactions
involving the relatively electron-rich substrate, 4-chloroanisole,
whereby selectivity for conversion to 1c with C2 (80%)
exceeded that achieved by use of C1 (40%). Collectively, these
results provide preliminary evidence that the catalytic perform-
ance of C1 is competitive with, and in some ways
complementary to, C2 in otherwise challenging ammonia
monoarylation chemistry.
Scheme 2. Comparative Catalytic Screening of C1−C3 in the
a
Nickel-Catalyzed Monoarylation of Ammonia
2.3. Nickel-Catalyzed Monoarylation of Primary and
Secondary (Di)alkylamines. The selective monoarylation of
primary alkylamines with (hetero)aryl (pseudo)halides remains
a relatively challenging class of transformations in nickel-
catalyzed C(sp2)−N cross-coupling chemistry.7 Notwithstand-
ing two isolated entries involving the arylation of n-hexylamine
with aryl chlorides by use of Ni(COD)2/L3 catalyst mixtures at
110 °C that are present in Wolfe and Buchwald’s8 pioneering
paper, the first broadly useful nickel precatalyst for the selective
monoarylation of primary alkylamines, (rac-BINAP)Ni(η2-NC-
Ph), was disclosed in 2014 by Hartwig and co-workers.11b Use
of this (rac-BINAP)Ni(0) precatalyst enabled the cross-
coupling of a range of functionalized primary alkylamines
with (hetero)aryl chlorides and bromides under relatively mild
conditions (1−4 mol % Ni; 50−80 °C). Stewart and co-
workers22 subsequently reported on analogous transformations
employing (rac-BINAP)Ni(P(OPh)3)2 as a precatalyst. We
have demonstrated that C2 is a superlative precatalyst for such
transformations that promotes the cross-coupling of a broad
spectrum of electron-rich and -poor (hetero)aryl (pseudo)-
halides with linear and branched primary alkylamines, including
the first examples of nickel-catalyzed room temperature
transformations of this type.15 Encouraged by the efficacy of
C1 in nickel-catalyzed ammonia monoarylation (Scheme 2), we
initiated a reactivity comparison of C1−C3 in the cross-
coupling of furfurylamine or sec-butylamine with 1-chloronaph-
thalene, 3-chloroanisole, 4-chloroanisole, or 5-chlorobenzo[b]-
thiophene.
Whereas each of C1−C3 proved effective as a precatalyst for
the monoarylation of furfurylamine and 1-chloronaphthalene
under mild conditions (25 °C, 0.5 mol %) leading to 2a, related
transformations involving the other electrophiles proved
challenging for C3 (Scheme 3). Conversely, under the
screening conditions employed each of C1 and C2 provided
useful levels of conversion to the target monoarylation products
2b−d at room temperature, with slightly higher conversions to
the target aniline achieved in each transformation by use of C2.
The efficacy of C1 and C2 as precatalysts in the monoarylation
of ammonia (Scheme 2) and primary alkylamine furfurylamine
(Scheme 3) prompted us to examine the relative preference of
these precatalysts for such substrates within a competition
scenario (Scheme 4). Interestingly, in cross-couplings employ-
ing equal amounts of ammonia and methylamine with limiting
amounts of 1-chloronaphthalene (25 °C, 5 mol %), C1
exhibited a marked preference for ammonia monoarylation
leading to 1a, whereas preferential monoarylation of methyl-
amine leading to 2e was achieved by use of C2. The observed
1a/2e selectivity drops to 2:1 (for C1) and 1:2 (for C2) for
a
Reactions using 0.5 M stock solutions of ammonia in 1,4-dioxane,
employing the mol % C1−C3 as indicated. Conditions: 0.10 M 1-
chloronaphthalene and ammonia (25 °C, 3 equiv; 110 °C, 5 equiv),
otherwise 0.07 M Ar−Cl and ammonia (7 equiv). Estimated
conversion to product after 16 h (unoptimized) is based on GC
b
data, with product yield based on 1H NMR data in parentheses. 80%
c
conversion to 1b employing 10 mol % C1. Significant amounts of
higher molecular weight byproducts observed.
related cross-couplings involving alternative amine substrates
(vide infra), somewhat challenging reaction conditions (e.g.,
low catalyst loading) were intentionally selected in an effort to
differentiate the catalytic abilities of C1−C3. For the majority
of the transformations reported herein, poor product formation
was accompanied by low conversion of the electrophile.
The room temperature monoarylation of ammonia employ-
ing 1-chloronaphthalene leading to 1a was readily achieved by
use of either C1 or C2 (1 mol %, 90%); however, in both cases
efforts to reduce the catalyst loading to 0.5 mol % resulted in
<20% conversion to 1a under similar conditions. In monitoring
the rate of formation of 1a in such reactions employing C1 or
C2 (25 °C, 1 mol %), 50% conversion to 1a was observed after
20 min with C2, whereas 20% conversion was achieved by use
of C1. After 1 h, 60% conversion to 1a was achieved with each
C1 and C2. While we are hesitant to definitively ascribe
mechanistic significance to these limited observations, it
appears that C2 is more easily activated under the specific
reaction conditions employed. Notably, C3 proved ineffective
for ammonia monoarylation involving 1-chloronapthalene and
the other electrophiles examined in the survey.
Related room temperature reactions involving more
challenging test electrophiles leading to 1b−d were less
successful (Scheme 2). In the transformation of relatively
electron-poor 3-chloroanisole, 40% conversion to 1b was
achieved by use of C1 (5 mol %); in doubling the catalyst
loading, 80% conversion to 1b was achieved. Under analogous
conditions using C2 (25 °C, 5 mol %), <20% conversion to 1b
was observed. This trend was retained in the monoarylation of
ammonia with electron-poor 4-chlorobenzonitrile under
analogous conditions (25 °C, 5 mol % precatalyst); >90%
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Scheme 3. Comparative Catalytic Screening of C1−C3 in the
Scheme 5. Comparative Catalytic Screening of C1−C3 in the
a
a
Nickel-Catalyzed Monoarylation of Furfurylamine
Nickel-Catalyzed Monoarylation of sec-Butylamine
a
Reactions: 1.1 equiv of furfurylamine; 0.16 M 5-chlorobenzo[b]-
thiophene, otherwise 0.24 M Ar−Cl; mol % C1−C3 as indicated.
Estimated conversion to product after 16 h (unoptimized) is based on
GC data, with isolated yields in parentheses.
a
Scheme 4. Competitive Monoarylation of Ammonia and
Methylamine with 1-Chloronaphthalene Using C1 and C2
Reaction conditions: 1.1 equiv of sec-butylamine; at 25 °C, 0.16 M 1-
a
chloronaphthalene, otherwise 0.12 M Ar−Cl; at 110 °C, 0.32 M 1-
chloronaphthalene or 0.12 M 4-chloroanisole, otherwise 0.24 M Ar−
Cl; mol % C1−C3 as indicated. Estimated conversion to product after
16 h (unoptimized) is based on GC data, with isolated yields in
parentheses.
Scheme 6. Comparative Catalytic Screening of C1−C3 in the
a
Nickel-Catalyzed N-Arylation of Morpholine
a
Estimated product ratio is based on GC data; full conversion of the
aryl chloride observed.
analogous reactions conducted at 110 °C. While it is plausible
to conclude that the less electron-donating nature of PAd-
DalPhos (L2) versus that of CyPF-Cy (L1) gives rise to
reactive nickel intermediates that favor binding and turnover of
more basic amines (e.g., methylamine over ammonia), the
scenario is likely more nuanced; for example, the contribution
of steric differences between L1 and L2 on the observed
selectivity outlined in Scheme 4 is also likely to be important.
The monoarylation of the more sterically demanding sec-
butylamine was examined subsequently (Scheme 5). Precatalyst
C2 proved effective in the cross-coupling of 1-chloronaph-
thalene leading to 3a (80%) at room temperature; under
analogous conditions, the performance of each of C1 (40%)
and C3 (20%) was inferior. Whereas related room temperature
transformations involving 3-chloroanisole, 4-chloroanisole, and
5-chlorobenzo[b]thiophene leading to 3b−d also proved
feasible with C1 and C2, it is apparent that the cross-coupling
of sec-butylamine with 4-chloroanisole to give 3c is challenging
in comparison to reactions involving less-hindered furfuryl-
amine (Scheme 3). Efforts to improve catalytic performance by
conducting reactions at 110 °C, albeit at lower loadings of C1−
C3, met with some success, with the improved formation of 3a
and 3c by use of C1 being notable.
a
Reactions using morpholine (1.5 equiv), LiOt-Bu (1.5 equiv), and 0.5
M in ArCl in CPME. Estimated conversion to product after 16 h
(unoptimized) is based on GC data, with isolated yields in
parentheses.
employed were based on those described by Buchwald and co-
workers16 in their report pertaining to the use of C3 in related
cross-couplings. Moderate conversion to 4a (60%) was
achieved by use of C1; otherwise, C1 and C2 proved ineffective
in such transformations. Conversely, the use of C3 enabled
high (>90%) conversion to 4a and 4b under analogous
conditions, in keeping with the literature.16
2.4. Aryl (Pseudo)halide Selectivity Involving C1 and
C2. In an effort to learn more about the electrophile tolerance
and selectivity preferences of C1 and C2 beyond the
(hetero)aryl chlorides examined thus far, we turned our
attention to the room temperature cross-coupling of furfuryl-
amine and aryl bromides (Scheme 7). Whereas high conversion
to the target aniline 5a was achieved when using C1 or C2 in
The cross-coupling of morpholine and either 4-chlorobenzo-
nitrile or 5-chlorobenzo[b]thiophene by use of C1−C3 leading
to 4a or 4b was examined in an effort to briefly compare the
abilities of these precatalysts in the N-arylation of a prototypical
secondary dialkylamine (Scheme 6). The reaction conditions
D
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Scheme 7. Halide Compatibility in the Arylation of
Furfurylamine Using C1 and C2 at Room Temperature
3. CONCLUSIONS
a
Our comparative catalytic survey of C1−C3 in selected
representative nickel-catalyzed C(sp2)−N cross-coupling re-
actions establishes the new air-stable precatalyst C1 as being
competitive with, and in some cases complementary to, C2 in
challenging transformations including the room-temperature
monoarylation of ammonia and primary alkylamines with
(hetero)aryl chlorides. Although C3 proved ineffective for such
transformations, this DPPF-based precatalyst was found to be
superior to C1 and C2 in combination with the secondary
dialkylamine test substrate, morpholine. The comparable
reactivity of C1 and C2 in the monoarylation of ammonia
and primary alkylamines is intriguing in light of the differing
electronic characteristics of the ligand sets features in these
precatalysts, with C1 featuring much more electron-rich
phosphorus donor groups relative to those in C2; the
comparatively poor performance of C3 with such substrates
suggests that significant steric demand is a prerequisite for
successful ancillary ligands in these difficult cross-coupling
applications. Notwithstanding the generally similar reactivity
profiles exhibited by C1 and C2, competition experiments
revealed a differing preference for ammonia versus methyl-
amine monoarylation, with C1 favoring ammonia monoar-
ylation. Furthermore, (pseudo)halide comparison studies at
room temperature revealed that C1 is less effective than C2 in
transformations of aryl bromides. In the absence of additional
data, we are unable to comment definitively regarding the
manner in which the structurally varied ancillary ligand
structures featured in C1−C3 give rise to the differences
observed herein with regard to substrate compatibility.
Nonetheless, in the context of bisphosphine ligation it is
evident that C1−C3 represent a complementary and useful set
of precatalysts for use in addressing a broad spectrum of NH
nucleophiles in nickel-catalyzed C(sp2)−N cross-coupling
chemistry. Given the potentially important role of ancillary
ligand design in promoting elementary catalytic steps, as well as
in controlling desired oxidation states of derived catalytic
intermediates, we are continuing to pursue the development of
new and effective bisphosphine ancillary ligand motifs for use in
nickel-catalyzed C(sp2)−N cross-coupling and beyond. We will
report on this work in due course.
a
Estimated conversion to product after 16 h (unoptimized) is based
b
on GC data, with isolated yields in parentheses. Significant quantities
of starting material remaining. Significant quantities of byproducts
c
detected.
combination with 4-chlorotoluene, comparatively poor catalytic
performance was displayed by C1 in analogous reactions
employing 4-bromotoluene. This trend was retained in
analogous cross-couplings employing 1-bromo-4-butylbenzene,
leading to 5b. Whereas modest conversion to 5b (40%)
occurred by use of C1, clean conversion to 5b (>90%) was
achieved with C2 under analogous conditions.
The competitive preference of C1 and C2 for chloride versus
bromide or tosylate electrophiles in room temperature cross-
couplings employing limiting furfurylamine was examined
subsequently (Scheme 8). In keeping with challenging aryl
Scheme 8. (Pseudo)halide Competition in the Arylation of
Furfurylamine Using C1 and C2 at Room Temperature
4. EXPERIMENTAL SECTION
4.1. General Considerations. All reactions were assembled inside
a nitrogen-filled inert atmosphere glovebox and were worked up in air
using benchtop procedures. When used within the glovebox, toluene,
pentane, and dichloromethane were deoxygenated by sparging with
nitrogen gas followed by passage through an mBraun double-column
solvent purification system packed with alumina and copper-Q5
reactant. Anhydrous CPME was degassed via three freeze−pump−
thaw cycles and was stored over 4 Å molecular sieves for 24 h prior to
use. Tetrahydrofuran and diethyl ether were dried over Na/
benzophenone followed by distillation under an atmosphere of
nitrogen gas. All solvents used within the glovebox were stored over
activated 4 Å molecular sieves. 4-Ethylphenyl tosylate,23 2e,15 C2,15
and C316 were prepared using literature procedures, and L1 was
purchased from Strem Chemicals. All other chemicals were obtained
from commercial suppliers and were used as received. GC data were
obtained on an instrument equipped with a SGE BP-5 column (30 m,
0.25 mm i.d.). Flash column chromatography was carried out using
Silicycle Siliaflash 60 silica (particle size 40−63 μm; 230−400 mesh).
a
Estimated conversion to product after 16 h (unoptimized) is based
b
on 1H NMR data. Estimated conversion to products after 16 h
(unoptimized) is based on GC data.
bromide reactivity involving C1, incomplete conversion of
furfurylamine was observed, accompanied by a modest
preference for uptake of the aryl chloride. Conversely, complete
consumption of the amine occurred when using C2, with the
aryl bromide being the preferred electrophile. In analogous
competitions involving 4-chlorotoluene and 4-ethylphenyl
tosylate, modest and inverted electrophile selectivity was
exhibited by C1 and C2.
1
Unless stated, H NMR (500 and 300 MHz), 13C{1H} NMR (125.8
and 75.5 MHz), and 31P{1H} NMR (202.5 and 121.4 MHz) spectra
were recorded at 300 K in CDCl3 with chemical shifts expressed in
parts per million (ppm). Splitting patterns are indicated as follows: br,
E
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broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Mass
spectra were obtained using ion-trap (ESI) instruments operating in
positive mode.
LiOt-Bu (1.5 equiv), aryl chloride (1.0 equiv), and cyclopentyl methyl
ether (0.5 M in aryl chloride) were added to a screw-capped vial
containing a magnetic stir bar, followed by the addition of morpholine
(1.5 equiv). The vial was sealed with a cap containing a PTFE septum,
removed from the glovebox, and placed in a temperature-controlled
aluminum heating block set to 100 °C for 16 h. After cooling to room
temperature, reactions were monitored using both TLC and GC
methods. The product was isolated or analyzed by using one of the
described workup methods A−C.
4.6. Procedure for Aryl (Pseudo)halide Competition Studies
(GP4). Precatalyst C1 or C2 (0.006 mmol, 0.05 equiv), furfurylamine
(46.4 μL, 0.525 mmol, 1.05 equiv), NaOt-Bu (96.1 mg, 1.0 mmol, 2.0
equiv), 4-chlorotoluene (59.1 μL, 0.5 mmol, 1.0 equiv), and 1-butyl-4-
bromobenzene or 4-ethylphenyl tosylate (0.5 mmol, 1.0 equiv) were
added to a screw-capped vial containing a magnetic stir bar, followed
by the addition of toluene (4.2 mL). The vial was sealed with a cap
containing a PTFE septum, removed from the glovebox, and placed in
a temperature-controlled aluminum heating block set to 25 °C for 16
h. After cooling to room temperature, the reaction mixture was diluted
with ethyl acetate (ca. 30 mL), washed with brine (3 × ca. 30 mL), and
the organic layer dried over sodium sulfate. The resultant mixture was
adsorbed onto silica gel to form a dry pack and eluted with hexanes
(200 mL) on a silica plug to remove the residual starting materials.
The product was then eluted through the dry pack with ethyl acetate
(200 mL), the eluent collected, and the solvent removed in vacuo via
rotary evaporation. Where NMR analysis was employed, ferrocene was
subsequently added to the dry reaction mixture as an internal standard
(18.6 mg, 0.1 mmol, 0.2 equiv), and the reaction mixture was taken up
in CDCl3 (3 mL). A drop of D2O was added to the sample to
eliminate the exchangeable NH proton peak in the spectrum. The
resultant solution was subjected to NMR analysis.
4.7. Procedure for the Monitoring of Reaction Progress via
NMR Analysis (GP5). Precatalyst C1 or C2 (0.006 mmol, 0.01
equiv), 0.5 M ammonia in 1,4-dioxane (3.6 mL, 1.8 mmol, 3.0 equiv),
NaOt-Bu (115.3 mg, 1.2 mmol, 2.0 equiv), and 1-chloronaphthalene
(81.7 μL, 0.6 mmol, 1.0 equiv) were added to a screw-capped vial
containing a magnetic stir bar, followed by the addition of toluene (2.4
mL). The procedure was repeated individually eight times, one for
each designated time interval. The vials were sealed with caps
containing PTFE septa, removed from the glovebox, and placed in a
temperature-controlled aluminum heating block set to 25 °C. Each
reaction vial was removed from the heating block after incremental
time intervals of 15 min, diluted with ethyl acetate (ca. 30 mL),
washed with brine (3 × ca. 30 mL), and the organic layer dried over
sodium sulfate. The solvent was removed in vacuo via rotary
evaporation and dodecane subsequently added to the dry reaction
mixture as an internal standard (13.6 μL, 0.06 mmol, 0.1 equiv), and
the reaction mixture was taken up in CDCl3 (3 mL). The resultant
solution was subjected to NMR analysis.
4.8. Workup Method A (Purification via Chromatography).
Following GP1, GP2, or GP3 (employing between 0.6 and 1.0 mmol
aryl (pseudo)halide), after cooling to room temperature, the reaction
mixture was diluted with ethyl acetate (ca. 30 mL), washed with brine
(3 × ca. 30 mL), and the organic layer dried over sodium sulfate. The
solvent was removed in vacuo via rotary evaporation, and the
compound was purified by flash column chromatography on silica gel.
4.9. Workup Method B (Procedure for the Preparation of
Samples for NMR Quantification). Following GP1 (employing
between 0.48 and 0.5 mmol aryl chloride), after cooling to room
temperature, the reaction mixture was diluted with ethyl acetate (ca.
30 mL), washed with brine (3 × ca. 30 mL), and the organic layer
dried over sodium sulfate. The solvent was removed in vacuo, followed
by the addition of the internal standard (dodecane or ferrocene, 10−
20 mol %) to the vial containing the product mixture. The resultant
mixture was taken up in CDCl3 (3 mL) and then subjected to NMR
spectroscopic analysis. In select cases where the resultant aniline was
volatile and thus subject to evaporation in vacuo, the reaction mixture
was not dried exhaustively, resulting in residual solvent impurity peaks
in the NMR spectra.
4.2. Synthesis of C1. On the basis of a literature protocol,15 within
an inert atmosphere glovebox a vial containing a magnetic stir bar was
charged with NiCl2(DME) (0.095 g, 0.43 mmol) and L1 (0.25 g, 0.41
mmol). To the solid mixture was added THF (2 mL), and the
resulting heterogeneous mixture was stirred magnetically at room
temperature for 2 h. The reaction vial was removed from the glovebox,
and in air the reaction mixture was treated with cold pentane (4 °C, 2
mL) thereby generating a precipitate. The solid was isolated via
suction filtration, washed with cold pentane (4 °C; 5 × 2 mL), and
dried in vacuo to afford the presumptive intermediate product
(L1)NiCl2 as a dark purple solid (0.29 g, 97%) that was used without
further purification. Within an inert atmosphere glovebox, the isolated
(L1)NiCl2 (0.29 g, 0.40 mmol) was transferred to a vial containing a
magnetic stir bar, followed by the addition of THF (3 mL). The
resultant heterogeneous mixture was cooled to −30 °C for 0.5 h,
followed by the addition of precooled (o-tol)MgCl (−30 °C, 1.0 M in
THF; 0.48 mL); the mixture was allowed to warm to room
temperature under the influence of magnetic stirring. After 4 h, the
reaction vial was removed from the glovebox, and in air the reaction
mixture was treated with cold methanol (4 °C; 1 mL) and cold
pentane (4 °C; 2 mL) thereby generating a precipitate. The solid was
isolated via suction filtration and washed with cold methanol (4 °C; 4
× 1 mL) followed by cold pentane (4 °C; 5 × 2 mL). The resulting
material was dried in vacuo to afford desired product C1 as an orange
solid (0.25 g, 78%). A single crystal suitable for X-ray diffraction was
obtained via vapor diffusion of diethyl ether into a dichloromethane
solution of C1. The NMR spectra of C1 exhibit broadened signals at
300 K, potentially arising due to restricted rotation about the Ni−C
bond, as observed for C2.15 1H NMR (300 K, 500 MHz, CDCl3, δ)
6.95 (s, 1H, ArH), 6.84 (s, 1H, ArH), 6.73 (m, 2H, ArH), 4.81 (s, 1H,
Cp−P), 4.51 (s, 1H, Cp−P), 4.44 (s, 1H, Cp−P), 4.25 (s, 5H, C5H5),
3.23−3.03 (m, 6H, CH3 and CH), 2.42−0.96 (m, 46H, CH2 and CH),
0.32−0.30 (m, 1H, CH); 13C{1H} NMR (300 K, 125.8 MHz, CDCl3,
δ) 144.6 (br m), 135.7 (br m), 128.0, 123.9, 122.2, 93.7 (br m), 73.0,
70.5 (br m), 69.2, 68.7, 68.4, 38.5 (d, JCP = 15.1 Hz), 34.3 (br m), 32.0
(br m), 31.3, 30.5, 29.9 (m), 28.7−26.0 (overlapping m), 16.1;
31P{1H} NMR (300 K, 202.5 MHz, CDCl3, δ) 47.3 (br m), 7.9
(apparent d, JPP = 34.4 Hz); 31P{1H} NMR (200 K, 121.4 MHz,
CDCl3, δ) 46.9 (d, JPP = 34.0 Hz), 7.3 (d, JPP = 34.0 Hz). Anal. Calcd
for C43H63Cl1Fe1Ni1P2: C, 65.22; H, 8.02; N, 0. Found: C, 64.84; H,
7.93; N, <0.3.
4.3. General Procedure for the Monoarylation of Ammonia
with Aryl Chlorides (GP1). Precatalyst C1, C2, or C3 (0.01−0.10
equiv), NaOt-Bu (2.0 equiv), aryl chloride (1.0 equiv), and toluene
(0.06−0.1 M in aryl chloride) were added to a screw-capped vial
containing a magnetic stir bar, followed by the addition of ammonia
(0.5 M in 1,4-dioxane, 3.0−7.0 equiv). The vial was sealed with a cap
containing a PTFE septum, removed from the glovebox, and placed in
a temperature-controlled aluminum heating block set to either 25 or
110 °C for 16 h. After cooling to room temperature, reactions were
monitored using both TLC and GC methods. The product was
isolated or analyzed by using one of the described workup methods
A−C.
4.4. General Procedure for the Monoarylation of Primary
Amines with Aryl (Pseudo)halides (GP2). Precatalyst C1, C2, or
C3 (0.01−0.10 equiv), NaOt-Bu (2.0 equiv), and aryl (pseudo)halide
(1.0 equiv), and toluene (0.12−0.32 M in aryl (pseudo)halide) were
added to a screw-capped vial containing a magnetic stir bar, followed
by the addition of primary amine (1.1 equiv). The vial was sealed with
a cap containing a PTFE septum, removed from the glovebox, and
placed in a temperature-controlled aluminum heating block set to
either 25 or 110 °C for 16 h. After cooling to room temperature,
reactions were monitored using both TLC and GC methods. The
product was isolated or analyzed by using one of the described workup
methods A−C.
4.5. General Procedure for the N-Arylation of Morpholine
with Aryl Chlorides (GP3). Precatalyst C1, C2, or C3 (0.05 equiv),
F
DOI: 10.1021/acs.organomet.6b00650
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
4.10. Workup Method C (Procedure for the Preparation of
Samples for GC Analysis). Following GP1, GP2, or GP3
(employing between 0.12 and 0.48 mmol aryl (pseudo)halide), the
reaction mixture was diluted using ethyl acetate (1 mL) and in turn
passed through a Pasteur pipet filter containing Celite and silica gel.
The eluent was collected and subjected to GC analysis with
comparison to authentic materials.
4.11. Crystallographic Solution and Refinement Details.
Crystallographic data for C1 were obtained at 193(2) K on a Bruker
D8/APEX II CCD diffractometer equipped with a CCD area detector
using graphite-monochromated Mo Kα (α = 0.71073 Å) radiation
employing a sample that was mounted in inert oil and transferred to a
cold gas stream on the diffractometer. Data reduction, correction for
Lorentz polarization, and absorption correction (Gaussian integration;
face-indexed) were each performed. Structure solution by using
intrinsic phasing was carried out, followed by least-squares refinement
on F2. All non-hydrogen atoms were refined with anisotropic
displacement parameters, while all hydrogen atoms were added at
calculated positions and refined by use of a riding model employing
isotropic displacement parameters based on the isotropic displacement
parameter of the attached atom.
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ASSOCIATED CONTENT
* Supporting Information
■
(12) Yin, G. Y.; Kalvet, I.; Englert, U.; Schoenebeck, F. J. Am. Chem.
Soc. 2015, 137, 4164−4172.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00650.
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Complete experimental details, characterization data, and
NMR spectra (PDF)
Crystallographic data for C1 (CCDC 1496592) (CIF)
(15) Lavoie, C. M.; MacQueen, P. M.; Rotta-Loria, N. L.; Sawatzky,
R. S.; Borzenko, A.; Chisholm, A. J.; Hargreaves, B. K. V.; McDonald,
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AUTHOR INFORMATION
Corresponding Author
*E-mail: mark.stradiotto@dal.ca.
■
(17) For the synthesis and crystallographic characterization of related
precatalyst complexes, see Standley, E. A.; Smith, S. J.; Muller, P.;
Jamison, T. F. Organometallics 2014, 33, 2012−2018.
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Notes
The authors declare the following competing financial
interest(s): Dalhousie University has filed patents on L2 and
C2 used in this work, from which royalty payments may be
derived.
(19) Klinkenberg, J. L.; Hartwig, J. F. Angew. Chem., Int. Ed. 2011, 50,
86−95.
ACKNOWLEDGMENTS
(20) Stradiotto, M. Ancillary ligand design in the development of
palladium catalysts for challenging selective monoarylation reactions.
In New Trends in Cross-Coupling: Theory and Application; Colacot, T. J.,
Ed.; Royal Society of Chemistry: Cambridge, U.K., 2014; pp 228−253.
(21) Standley, E. A.; Jamison, T. F. J. Am. Chem. Soc. 2013, 135,
1585−1592.
■
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (Discovery Grant RGPIN-2014-
04807 and I2I Grant I2IPJ/485197-2015) and Dalhousie
University for their support of this work. We thank Dr.
Michael Lumsden (NMR-3, Dalhousie) for ongoing technical
assistance in the acquisition of NMR data and Mr. Xiao Feng
(Maritime Mass Spectrometry Laboratories, Dalhousie) for
technical assistance in the acquisition of mass spectrometric
data.
(22) Kampmann, S. S.; Skelton, B. W.; Wild, D. A.; Koutsantonis, G.
A.; Stewart, S. G. Eur. J. Org. Chem. 2015, 2015, 5995−6004.
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DOI: 10.1021/acs.organomet.6b00650
Organometallics XXXX, XXX, XXX−XXX