Bisphosphine-Ligated Nickel Pre-catalysts in C(sp2)–N Cross-Couplings of Aryl Chlorides: A Comparison of Nickel(I) and Nickel(II)

Article abstract of DOI:10.1002/adsc.201700672

The influence of ancillary ligand and nickel oxidation state in the nickel-catalyzed C(sp²)–N cross-coupling of aryl chlorides is examined by use of experimental and DFT methods for the first time, focusing on (L)NiCl and (L)Ni(o-tolyl)Cl pre-catalysts (PAd-DalPhos, L1; dppf, L2). Whereas Ni(II) pre-catalysts generally out-performed Ni(I) species in our study, the viability and in some cases superiority of Ni(I) pre-catalysts in challenging aminations is established. Computational analyses support the viability of Ni(0)/Ni(II) cycles featuring rate-limiting C–N reductive elimination, as well as parallel Ni(I)/Ni(III) mechanisms involving rate-limiting C–Cl oxidative addition. (Figure presented.).

Full text of DOI:10.1002/adsc.201700672

Title: Bisphosphine-Ligated Nickel Pre-catalysts in C(sp2)-N Cross-
Couplings of Aryl Chlorides: A Comparison of Ni(I) and Ni(II)
Authors: Christopher Lavoie, Robert McDonald, Erin Johnson, and
Mark Stradiotto
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10.1002/adsc.201700672
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Bisphosphine-Ligated Nickel Pre-catalysts in C(sp2)-N Cross-
Couplings of Aryl Chlorides: A Comparison of Ni(I) and Ni(II)
Christopher M. Lavoie,a Robert McDonald,b Erin R. Johnson,*,a and Mark Stradiotto*,a
a
Department of Chemistry, Dalhousie University, Halifax, Nova Scotia B3H 4R2 (Canada)
erin.johnson@dal.ca; mark.stradiotto@dal.ca
X-Ray Crystallography Laboratory, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2
b
(Canada)
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The influence of ancillary ligand and Ni oxidation state in the Ni-catalyzed C(sp2)-N cross-coupling of
aryl chlorides is examined by use of experimental and DFT methods for the first time, focusing on (L)NiCl and
(L)Ni(o-tolyl)Cl pre-catalysts (PAd-DalPhos, L1; dppf, L2). Whereas Ni(II) pre-catalysts generally out-performed
Ni(I) species in our study, the viability and in some cases superiority of Ni(I) pre-catalysts in challenging aminations
is established. Computational analyses support the viability of Ni(0)/Ni(II) cycles featuring rate-limiting C-N
reductive elimination, as well as parallel Ni(I)/Ni(III) mechanisms involving rate-limiting C-Cl oxidative addition.
Keywords: nickel; C-N cross-coupling; mechanism; DFT; ligand design
and Ni(I)/Ni(III) cycles, as well as single-electron
transfer linking these reaction manifolds, must be
considered (Figure 1B).[9b, 12]
Introduction
The Pd-catalyzed cross-coupling of NH substrates and
(hetero)aryl (pseudo)halides (i.e., Buchwald-Hartwig
amination,[1] BHA) is widely employed for the
synthesis of (hetero)anilines.[2] The preponderance of
evidence supports a Pd(0)/Pd(II) mechanism for BHA
(Figure 1A),[3] which has guided the development of
Pd(0) or Pd(II) pre-catalysts featuring bulky, electron-
rich alkylphosphine and N-heterocyclic carbene
ancillary ligands[2] that give rise to LnPd(0) (n = 1 or
2)[4] species capable of challenging C(sp2)-X
oxidative additions (e.g. X = Cl[5]).[6]
The high cost and scarcity of Pd, as well as the
desire to effect transformations for which Pd has
proven ineffective, provides motivation for the
development of base-metal variations of BHA. This
Figure 1. Palladium and nickel catalyzed C(sp2)-N
cross-coupling, and the Ni(I) and Ni(II) pre-catalysts
under investigation herein.
has contributed to a renaissance in Ni-catalyzed
C(sp2)-N (herein C-N) cross-coupling chemistry,[7]
leading
transformations involving relatively inexpensive
(hetero)aryl and phenol-derived
chlorides[8]
to
outstanding
Ni
catalysts
for
While Ni(0) and Ni(II) pre-catalysts are
commonly employed in C-N cross-coupling,[13] data
pertaining to the mechanism of such reactions are
limited.[14] In the context of reactions of aryl
chlorides,[15] the Ni(I) pre-catalyst [(BINAP)Ni(-
Cl)]2 proved inactive[16] for alkylamine arylation
under conditions whereby high conversion was
achieved by use of a Ni(II)[16] or Ni(0)[17] pre-catalyst.
Control experiments conducted by Green and
Hartwig[18] demonstrate that JosiPhos-ligated Ni(0)
and Ni(II) pre-catalysts promote C-N cross-couplings
of ammonia or primary alkylamines in the absence of
free aryl radicals. Conversely, the intermediacy of
electrophiles.[7, 9] However, our understanding of the
factors that give rise to effective Ni catalysts in such
transformations is primitive. The smaller size of Ni
versus Pd, as well as the greater propensity of Ni(0) to
engage in C(sp2)-X oxidative additions,[5, 10] suggest
that ancillary ligands optimized for BHA are unlikely
to be broadly effective with Ni.[11] Furthermore, the
widely accessible oxidation state range (commonly 0
to III) and propensity for single-electron chemistry
creates a complex mechanistic landscape for Ni-
catalyzed C-N cross-coupling, whereby Ni(0)/Ni(II)
1
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10.1002/adsc.201700672
Advanced Synthesis & Catalysis
Ni(I) species in C-N cross-couplings of haloarenes
and diarylamines has been invoked given the efficacy
of [(IPr)Ni(-Cl)]2 and (L)Ni(IPr)Cl Ni(I) pre-
catalysts,[19] and based on the lack of reactivity
observed between main group diphenylamides and
Ni(II) catalytic intermediates of the type
(PPh3)2Ni(aryl)X.[20]
The room temperature cross-coupling of 1-
chloronaphthalene (1) and n-octylamine (2) to afford
3 was selected to compare the catalytic abilities of
PAdNiI and PAdNiII, given the established utility of
PAdNiII in this transformation (Table 1).[8] The
performance of PAdNiI and PAdNiII proved
indistinguishable at 5 mol% loading (entries 1 and 2).
The efficacy of PAdNiI under these mild conditions is
significant, in that it represents the first example of a
Ni(I) pre-catalyst being employed competitively in
Collectively, these isolated reports support the
viability of either Ni(0)/Ni(II) or Ni(I)/Ni(III)
catalytic cycles. However, more systematic
comparative analyses are required to inform the
rational development of superlative Ni pre-catalysts
for C-N cross-coupling. Herein we disclose the results
of a combined experimental and DFT study focusing
on PAd-DalPhos (L1) and dppf (L2) ligated Ni(I) and
Ni(II) pre-catalysts (Figure 1) in the C-N cross-
coupling of aryl chlorides. Computational analyses
support the feasibility of both Ni(0)/Ni(II) and
Ni(I)/Ni(III) mechanisms. Moreover, we establish that
while the performance of the Ni(II) pre-catalysts
Ni-catalyzed
C-N
cross-couplings
beyond
diphenylamine variants, and contrasts the inactivity of
[(BINAP)Ni(-Cl)]2 in an analogous transformation
of 2.[16] On lowering the loading to 0.5 mol% Ni,
PAdNiI proved inferior to PAdNiII (entries 3 and 4), and
poor performance for both pre-catalysts was noted at
0.1 mol% Ni (entries 5 and 6). Addition of catalytic
quantities of TEMPO (2,2,6,6-tetramethylpiperine-1-
oxyl) caused a significant decrease in product
formation in the case of PAdNiI (entry 7); a lesser
effect was found with PAdNiII (entry 8). Observations
by Wolf and co-workers[25] establishing that Ni(I)
species can be trapped by TEMPO support a similar
inhibitory processes involving PAdNiI.
(
PAdNiII and dppfNiII) is in general superior to that of
Ni(I) species (PAdNiI and dppfNiI), dramatic exceptions
to this trend are possible for given ancillary ligand
and substrate combinations.
Table
1.
Comparative
cross-coupling
of
1-
Results and Discussion
chloronaphthalene and n-octylamine employing PAdNiI or
PAdNiII.[a]
PAd-DalPhos (L1)[8,
and dppf (L2)[22] were
21]
selected for our study, given the utility of derived
(L)Ni(o-tolyl)Cl pre-catalysts in C-N cross-couplings.
Whereas (L2)NiCl (dppfNiI) is known,[14a, 14b] its use as
a pre-catalyst in C-N cross-coupling chemistry has
not been described. The new Ni(I) complex (L1)NiCl
(
PAdNiI) was prepared as a red paramagnetic solid via
[8]
comproportionation of (L1)NiCl2 and presumptive
(L1)Ni(cod) (cod = 1,5-cyclooctadiene; see the
Experimental Section).[23] Single-crystal X-ray
analysis established PAdNiI as a mononuclear species
featuring a distorted Y-shape geometry at Ni, in
keeping with other L2NiCl complexes (Figure 2).[14a, 19,
24]
[a] Reaction conditions: 1 (1.0 equiv), 2 (1.1 equiv), toluene
(2 mL), NaOtBu (1.5 equiv). Conversion to product (3)
determined on the basis of calibrated GC analysis using
dodecane as an internal standard.
The superiority of PAdNiII over PAdNiI (Table 1)
may suggest that maintaining a higher concentration
of (L1)Ni(0/II) intermediates should lead to more
productive catalysis. In this vein, substantially higher
yields were achieved in the presence of phenylboronic
acid pinacol ester (PhBPin) as a reducing agent, using
either PAdNiI (entry 9) or PAdNiII (entry 10). The latter
result (entry 10) is significant in that 0.1 mol%
represents the lowest reported loading of a Ni-based
pre-catalyst in C-N cross-coupling chemistry.
Subsequent experimentation (Figure S1) confirmed
that an increase in reaction rate is achieved when
using PAdNiI with added PhBPin, and that PhBPin
generates (L1)Ni(0) species which, upon addition of
Figure 2. Single-crystal X-ray structure of PAdNiI, with
one of the two independent molecules shown at the 30%
probability level with H atoms omitted for clarity. Selected
interatomic distances (Å) and angles (º): Ni-P1 2.1646(6),
Ni-P2 2.1830(6), Ni-Cl 2.1503(6), P1-Ni-P2 88.47(2), P1-
Ni-Cl 126.90(3), P2-Ni-Cl 144.61(3).
2
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10.1002/adsc.201700672
Advanced Synthesis & Catalysis
cod, can be trapped as presumptive (L1)Ni(cod) on Whereas PAdNiI and PAdNiII[21] performed similarly
the basis of 31P NMR data (see the Experimental well, a striking difference was noted with the L2-
II
dppf
Section).
We then sought to evaluate the performance of
derived pre-catalysts:
Ni proved inactive, while
dppfNiI and dppfNiII in the cross-coupling of 4-
chlorobenzonitrile (4) and morpholine (5) to afford 6
(Table 2). Although dppfNiII is known to be competent
for this transformation,[26] dppfNiI had yet to be applied
in any Ni-catalyzed C-N cross-coupling chemistry.
Unlike PAdNiI and PAdNiII (Table 1), similar catalytic
performance was observed by use of either dppfNiI or
dppfNiII, with excellent conversion realized at the 5
mol% Ni level (entries 1 and 2), but less so at 0.5
mol% Ni (entries 3 and 4). The observation that
catalytic quantities of TEMPO significantly inhibited
product formation for both dppfNiI and dppfNiII (entries
5 and 6) suggests that L2-derived Ni(II) pre-catalysts
may be more prone to Ni(I) formation than L1 pre-
catalysts. Addition of PhBPin resulted in an increase
in product formation for reactions employing 0.5
mol% of either dppfNiI (entry 7) or dppfNiII (entry 8).
I
dppf
Ni afforded 8 in high yield. Notwithstanding
recent reports documenting the undesirable nature of
Ni(I) species in C(sp2)-E (E = C, S, N) cross-coupling
catalysis,[14, 16] the observed superiority of Ni over
I
dppf
II
dppf
Ni in this transformation highlights the potential
value of surveying Ni pre-catalysts in varied
oxidation states in reaction development.
Table 3. Comparative experimental and computational
survey of the cross-coupling of ammonia and substituted
aryl chlorides.[a]
Table
2.
Comparative
cross-coupling
of
4-
chlorobenzonitrile and morpholine employing dppfNiI or
dppfNiII.[a]
[a]
Reaction conditions: 4 (1.0 equiv), 5 (1.1 equiv), CPME
[a]
Reaction conditions: aryl chloride (1.0 equiv), NH3 (0.5
M in 1,4-dioxane, 7.0 equiv), toluene (0.50 mL), NaOtBu
(3.0 equiv). Conversion to the aniline product on the basis
(0.25 mL), LiOtBu (1.5 equiv). Conversion to product (6)
on the basis of calibrated GC analysis using dodecane as an
internal standard.
of calibrated GC analysis using dodecane as an internal
[b]
standard.
Complete conversion of the aryl chloride
observed, accompanied by substantial quantities of the
presumptive polyarylation products.
In examining the performance of the pre-catalysts
in reactions involving morpholine (Table S1), aniline
(Table S2), and ammonia (Table 3), we observed that:
L1 and L2 displayed their established nucleophile
preferences (vide supra), with L2-ligated pre-catalysts
proving superior in transformations of morpholine
and aniline, and L1-ligated pre-catalysts being better-
suited for the monoarylation of ammonia;[26] the
In considering viable mechanistic pathways, the
I
I
Ni(I) pre-catalysts PAdNi and Ni could give rise to
substrate turnover in C-N cross-coupling by way of a
Ni(I)/Ni(III) cycle, or via redox chemistry that
provides entry into a Ni(0)/Ni(II) cycle. We assessed
the feasibility of these scenarios via DFT calculations
using the B3LYP-XDM method[27] and the 6-
311+G(2d,2p) basis set, which is well-suited for
calculating 3d transition metal-ligand binding
energies.[27d] The geometry optimizations and
frequency calculations were performed with a smaller,
mixed basis set.[23] Computed data for Ni(0)/Ni(II)
pathways involving L1 or L2 for the cross-coupling
dppf
II
II
Ni(II) pre-catalysts (PAdNi and Ni ) were found to
dppf
be competitive with or superior to their Ni(I)
I
I
counterparts (PAdNi and Ni ); and where competent
catalysis was observed, higher substrate conversions
(including in some cases polyarylation) were achieved
by use of electron-poor electrophiles. A notable
exception was observed in the cross-coupling of 4-
chlorobenzonitrile (4) with benzamide (7) (eq. 1).
dppf
3
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10.1002/adsc.201700672
Advanced Synthesis & Catalysis
of chlorobenzene and either ammonia, aniline, confirmed the presence of 2,2'-dimethylbiphenyl (10)
morpholine, or benzamide are provided in Figure 3 in the product mixture, along with unreacted 1. The
and Figures S3-S6. Calculated bond lengths and formation of 10 may be viewed as being in keeping
angles for PAdNiI, PAdNiII, and (L1)Ni(Ph)Cl are in with comproportionation involving (L1)Ni(o-tolyl)Cl
excellent agreement with X-ray data (Table S3).
(
PAdNiII) outlined above, whereby 10 arises from the
In examining the Ni(0)/Ni(II) pathway for the subsequent disproportionation of (L1)Ni(o-tolyl) to
monoarylation of ammonia with chlorobenzene, each (L1)Ni(0) and (L1)Ni(o-tolyl)2, followed by biaryl
of the L1 (Figure 3) and L2 (Figure S6) derived Ni reductive elimination. In using excess 2 (2.2 equiv),
catalyst systems were modelled, including: a) arene neither residual 1 nor 10 was observed, suggesting
exchange with (L)Ni(2-toluene) to afford (L)Ni(2- that comproportionation to form (L1)Ni(I)X species is
PhCl); b) C-Cl oxidative addition to give (L)Ni(Ph)Cl inefficient from (L1)Ni(aryl)(n-octNH).
via TS-1; c) reaction with NH3 to give (L)Ni(Ph)NH2;
Two plausible L1-ligated Ni(I)/Ni(III) pathways
and d) C-N reductive elimination to afford (L)Ni(2- for the monoarylation of ammonia with
PhNH2) via TS-2.[23] The free energy activation chlorobenzene were then modelled (Figure 4), each
barriers to C-Cl oxidative addition (TS-1) are small leading
to
the
common
intermediate
(L1: 7.2 kcal mol-1, L2: 8.7 kcal mol-1), and ground (L1)Ni(Ph)(Cl)NH2 (11). The first involves: a) C-Cl
state calculations show that formation of oxidative addition involving (L1)NiCl(2-PhCl) to
(L)Ni(Ph)NH2 is exergonic by 8.3 kcal mol-1 (L1) and yield (L1)Ni(Ph)Cl2; b) reaction with NH3 to give
8.6 kcal mol-1 (L2). Notably, both pathways suffer (L1)Ni(Ph)(Cl)NH2 (11); and c) C-N reductive
from comparatively high free energy barriers to C-N elimination to generate (L1)NiCl(2-PhNH2).
reductive elimination of the product aniline (TS-2) Although steps b) and c) are thermodynamically
(L1: 18.6 kcal mol-1, L2: 18.5 kcal mol-1). These data favorable on the basis of the computed free energies
suggest that sterically encumbered yet electron-poor (-12.5 and -40.1 kcal mol-1), the C-Cl oxidative
ancillary ligands, which promote C-N reductive addition step was calculated to be endergonic by 6.4
elimination, are likely to prove useful in such kcal mol-1 and to have a free energy barrier (TS-3) of
transformations.[8] By comparison (Table 3) the free 17.5 kcal mol-1. On the basis of these data, this
energy activation barriers to C-N reductive Ni(I)/Ni(III) pathway, when compared to the
elimination for electron-rich para-anisidine were Ni(0)/Ni(II) cycle (Figure 3), is less feasible. An
computed to be high (L1: 20.9 kcal mol-1, L2: 20.3 alternative Ni(I)/Ni(III) pathway was considered,
kcal
mol-1)
versus
electron-poor
para- whereby the aforementioned intermediate 11 was
aminobenzonitrile (L1: 15.3 kcal mol-1, L2: 14.0 kcal instead accessed via thermodynamically favourable
mol-1). The empirically observed poor performance of amination of (L1)NiCl to yield (L1)Ni(NH2) (-1.9
L2 in this ammonia chemistry (Table 3) may arise kcal mol-1), followed by binding of chlorobenzene
from catalyst inhibition processes not captured by our and subsequent C-Cl oxidative addition (Figure 4,
computational survey.
inset).
Figure 3. Relative free energies (kcal mol-1) calculated for
C-N cross-coupling reaction steps involving (L1)Ni species
within a Ni(0)/Ni(II) cycle.
Figure 4. Relative free energies (kcal mol-1) calculated for
C-N cross-coupling reaction steps involving (L1)Ni species
within
a
Ni(I)/Ni(III) cycle commencing from
14d]
In modelling the comproportionation[14c,
of
(L1)NiCl(2-PhCl). Inset: Alternative C-Cl oxidative
addition pathway from (L1)Ni(NH2)(2-PhCl) leading to
the common intermediate (L1)Ni(Ph)(Cl)NH2.
(L1)Ni(o-tolyl)Cl and (L1)Ni(2-toluene) to form
(L1)NiCl(2-toluene) and (L1)Ni(o-tolyl), the
reaction was calculated to have an associated free
energy change of -5.3 kcal mol-1. Calibrated GC
analysis of catalytically relevant stoichiometric
reactions involving the combination of PAdNiII, 1, 2,
and NaOtBu (1:1:1.2:1.5 equiv; 16 h at 25 ˚C)
In contrast to the previous scenario, C-Cl oxidative
addition from (L1)Ni(NH2)(2-PhCl) to give
(L1)Ni(Ph)(Cl)NH2 (11) is thermodynamically
4
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10.1002/adsc.201700672
Advanced Synthesis & Catalysis
Synthesis of PAdNiI
favored (-6.0 kcal mol-1). Given that the free energy
barrier to C-N reductive elimination from the
common intermediate 11 (TS-4: 6.3 kcal mol-1) is
small relative to that of C-Cl oxidative addition
involving (L1)Ni(NH2)(2-PhCl) (TS-3’: 18.0 kcal
mol-1), the latter is apparently rate-limiting. Thus, we
view a Ni(I)/Ni(III) cycle involving the binding of
chlorobenzene to (L1)Ni(NH2), followed by rate-
limiting C-Cl oxidative addition, as being a viable
competitor to the Ni(0)/Ni(II) pathway (Figure 3) for
C-N cross-couplings of ammonia, and possibly other
substrates.
Within a glovebox, a vial containing a magnetic stir bar
was charged with L1 (0.243 g, 0.481 mmol, 1.05 equiv.)
and Ni(cod)2 (0.126 g, 0.458 mmol, 1.0 equiv.). To the
solid mixture was added benzene (6.0 mL), and the
resulting heterogeneous mixture was stirred magnetically at
25 ˚C for 0.5 h. Analysis of the reaction mixture at this
stage by use of 31P{1H} NMR methods revealed partial
consumption of L1 and the appearance of two resonances
at 46.1 and 38.4 ppm (JPP = 40.5 Hz), which we tentatively
assign to (L1)Ni(cod). The reaction vial was then charged
with (L1)NiCl2 (0.290 g, 0.16 mmol, 1.0 equiv.), and the
reaction mixture was stirred magnetically at 25 ˚C for 0.5 h.
Within a glovebox, hexanes (ca. 4 mL) was added to the
crude reaction mixture to induce precipitation of the
complex, and the resulting mixture was filtered through a
glass sintered frit. The retained solid on the frit was washed
with hexanes (ca. 5 x 3 mL) and dried in vacuo to afford
PAdNiI as a red paramagnetic solid (0.443 g, 81%). Anal.
Found (Calcd) for C30H34ClNiO3P2: C 59.94 (60.17), H
Conclusions
In summary, this integrated experimental and
computational study illuminates the complex
interplay between bisphosphine ancillary ligand
(PAd-DalPhos or dppf), pre-catalyst oxidation state,
and nucleophile in the Ni-catalyzed C-N cross-
coupling of aryl chlorides. Generally, Ni(II) pre-
catalysts out-performed Ni(I) species in our study,
although the efficacy and in some cases superiority of
Ni(I) pre-catalysts in challenging aminations was also
noted when employing dppf ligation. Computational
studies establish the viability of competitive
Ni(0)/Ni(II) cycles featuring rate-limiting C-N
reductive elimination, as well as parallel Ni(I)/Ni(III)
cycles involving rate-limiting C-Cl oxidative addition.
Beyond seeking a better understanding of the factors
that influence such mechanistic partitioning, our
ongoing studies are focussed on determining the role
of Ni(I) species in C-N cross-couplings and beyond,
either as kinetically competent catalytic intermediates,
and/or as a source of active Ni(0) or Ni(II) species.
o
5.53 (5.73), N <0.5 (0.0) %. eff = 1.2 B (25 C, C6H6;
Evan’s method). A single crystal suitable for X-ray
diffraction analysis was obtained via slow evaporation of a
toluene solution of the target complex.
Protocol for the cross-coupling of 1-chloronapthalene
and octylamine (GPA)
In a nitrogen-filled glovebox, pre-catalyst PAdNiI (3.6 mg,
0.006 mmol, 5 mol %) or PAdNiII (4.1 mg, 0.006 mmol, 5
mol %), 1-chloronaphthalene (16.3 L, 0.12 mmol, 1.0
equiv.), sodium tert-butoxide (17.3 mg, 0.18 mmol, 1.5
equiv.), and octylamine (21.8 L, 0.13 mmol, 1.1 equiv.)
were added to a screw capped vial containing a magnetic
stir bar, followed by the addition of toluene (2.0 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 the 25 oC for 16 h.
The reaction vial was then removed from the heating block,
followed by addition of dodecane internal standard (1.0
equiv.). The product yield was determined by calibrated
GC analysis using authentic products according to the
Workup Method.
Protocol for the cross-coupling of 1-chloronapthalene
and octylamine using stock solutions of pre-catalyst
(GPB)
Experimental Section
General Considerations
For reactions requiring <3 mg of pre-catalyst, the pre-
catalyst was delivered by use of stock solutions. PAdNiI:
Unless otherwise stated, all reactions were setup inside a 42.9 L (0.10 mol%) or 214.5 L (0.50 mol%) taken from
nitrogen-filled inert atmosphere glovebox using oven-dried a 0.0084 M toluene stock solution, PAdNiII: 98.8 L (0.10
glassware, and were worked up in air using benchtop mol%) or 494.0 L (0.50 mol%) taken from a 0.0036 M
procedures. Toluene and hexanes were deoxygenated by toluene stock solution.
sparging with nitrogen followed by passage through a
double column solvent purification system packed with
Protocol for the cross-coupling of 1-chloronapthalene
and octylamine with TEMPO (GPC)
alumina and copper-Q5 reactant, and storage over activated
4 Å molecular sieves. Cyclopentyl methyl ether (CPME)
was degassed by use of three repeated freeze-pump-thaw
Reactions were conducted on a 0.36 mmol scale otherwise
cycles and was stored over activated 4 Å molecular sieves.
as per GPA, with the only deviation being the addition of
1,4-Dioxane was dried over Na/benzophenone followed by
TEMPO (5.6 mg, 0.036 mmol, 0.1 equiv.) following
distillation under a nitrogen atmosphere. Pre-catalysts
(L1)NiCl2,[8] PAdNiII,[8] dppfNiI,[14b] and dppfNiII,[22] were
synthesized following literature procedures. Gas
chromatography data were obtained on an instrument
equipped with a SGE BP-5 column (30 m, 0.25 mm i.d.),
addition of base, prior to the addition of octylamine. The
product yield was determined by calibrated GC analysis
using authentic products according to the Workup Method.
and were calibrated by using authentic materials using Protocol for the cross-coupling of 1-chloronapthalene
dodecane as an internal standard. Authentic reaction and octylamine with PhBPin (GPD)
products
4-(4-methoxyphenyl)morpholine,[28]
4-
morpholinobenzonitrile,[26] napthelen-1-amine,[8] N-(1-
naphthyl)-octylamine,[8] and 4-(cyanophenyl)benzamide,[21]
used for calibrated GC analysis were synthesized following
literature procedures. All catalytic experiments were
conducted in duplicate (minimum). The magnetism of
PAdNiI was examined by use of Evan’s method.[29]
Otherwise, all other GC standards, reagents, solvents, and
materials were used as received from commercial sources.
Reactions were conducted on a 0.36 mmol scale otherwise
as per GPB, with the only deviation being the addition of
PhBPin (12.3 L, 0.054 mmol, 0.15 equiv.) following
addition of base, prior to the addition of octylamine. The
product yield was determined by calibrated GC analysis
using authentic products according to the Workup Method.
5
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10.1002/adsc.201700672
Advanced Synthesis & Catalysis
Protocol for the cross-coupling of 4-chlorobenzonitrile as a 0.5 M solution in 1,4-dioxane (1.68 mL, 0.84 mmol,
and morpholine (GPE)
7.0 equiv.), were added to a screw capped vial containing a
magnetic stir bar, followed by the addition of toluene (0.5
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 the
stated temperature for 16 h. The reaction vial was then
removed from the heating block and left to cool to ambient
temperature, followed by addition of dodecane internal
standard (1.0 equiv.). The product yield was determined by
calibrated GC analysis using authentic products according
to the Workup Method.
In a nitrogen-filled glovebox, pre-catalyst dppfNiI (3.9 mg,
0.006 mmol, 5 mol %) or dppfNiII (4.4 mg, 0.006 mmol, 5
mol %), 4-chlorobenzonitrile (16.5 mg, 0.12 mmol, 1.0
equiv.), lithium tert-butoxide (14.4 mg, 0.18 mmol, 1.5
equiv.), and morpholine (11.4 L, 0.13 mmol, 1.1 equiv.)
were added to a screw capped vial containing a magnetic
stir bar, followed by the addition of CPME (0.25 mL). The
vial was sealed with a cap containing a PTFE septum,
removed from the glovebox and placed in a temperature-
o
controlled aluminum heating block set to 110 C for 16 h.
The reaction vial was then removed from the heating block Protocol for the pre-catalyst reactivity comparison in
and left to cool to ambient temperature, followed by the cross-coupling of aniline and chlorobenzene (GPK)
addition of dodecane internal standard (1.0 equiv.). The
product yield was determined by calibrated GC analysis
In a nitrogen-filled glovebox, pre-catalyst (0.006 mmol, 5
using authentic products according to the Workup Method.
mol %), chlorobenzene (12.3 L, 0.12 mmol, 1.0 equiv.),
sodium tert-butoxide (17.3 mg, 0.18 mmol, 1.5 equiv.), and
Protocol for the cross-coupling of 4-chlorobenzonitrile aniline (12.1 L, 0.132 mmol, 1.1 equiv.), were added to a
and morpholine using stock solutions of pre-catalyst screw capped vial containing a magnetic stir bar, followed
(GPF)
by the addition of toluene (2.0 mL). The vial was sealed
with a cap containing a PTFE septum, removed from the
glovebox and placed in a temperature-controlled aluminum
For reactions requiring <3 mg of pre-catalyst, the pre-
catalyst was delivered by use of stock solutions. dppfNiI:
233.0 L (0.50 mol%) taken from a 0.008 M toluene stock
solution, dppfNiII: 494.0 L (0.50 mol%) taken from a 0.003
M toluene stock solution. After all reaction components
were added, CPME was added to bring the total volume of
solvent to 0.75 mL.
o
heating block set to 110 C for 16 h. The reaction vial was
then removed from the heating block and left to cool to
ambient temperature, followed by addition of dodecane
internal standard (1.0 equiv.). The product yield was
determined by calibrated GC analysis using authentic
products according to the Workup Method.
Protocol for the pre-catalyst reactivity comparison in
Protocol for the cross-coupling of 4-chlorobenzonitrile
and morpholine with TEMPO (GPG)
the
cross-coupling
of
benzamide
and
4-
chlorobenzonitrile (GPL)
Reactions were conducted on a 0.36 mmol scale otherwise
as per GPE, the only deviation being the addition of
TEMPO (5.6 mg, 0.036 mmol, 0.1 equiv.) following
addition of base, prior to the addition of octylamine. The
product yield was determined by calibrated GC analysis
using authentic products according to the Workup Method.
In a nitrogen-filled glovebox, pre-catalyst (0.006 mmol, 5
mol %), 4-chlorobenzonitrile (16.5 mg, 0.12 mmol, 1.0
equiv.), tripotassium monophosphate (38.2 mg, 0.18 mmol,
1.5 equiv.), and benzamide (16.0 mg, 0.13 mmol, 1.1
equiv.), were added to a screw capped vial containing a
magnetic stir bar, followed by the addition of tert-butanol
(1.0 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 90
oC for 16 h. The reaction vial was then removed from the
Protocol for the cross-coupling of 4-chlorobenzonitrile
and morpholine with PhBPin (GPH)
Reactions were conducted on a 0.36 mmol scale otherwise heating block and left to cool to ambient temperature,
as per GPF, with the only deviation being the addition of followed by addition of dodecane internal standard (1.0
PhBPin (24.6 L, 0.108 mmol, 0.30 equiv.) following equiv.). The product yield was determined by calibrated
addition of base, prior to the addition of octylamine. The GC analysis using authentic products according to the
product yield was determined by calibrated GC analysis Workup Method.
using authentic products according to the Workup Method.
Protocol for the reaction rate comparison for pre-
Protocol for the pre-catalyst reactivity comparison in catalysts in the cross-coupling of octylamine and 1-
the cross-coupling of chloroarenes with morpholine chloronaphthalene (GPM)
(GPI)
In a nitrogen-filled glovebox, pre-catalyst (0.0024 mmol,
In a nitrogen-filled glovebox, pre-catalyst (0.006 mmol, 5 1.0 mol %), 1-chloronaphthalene (32.6 L, 0.24 mmol, 1.0
mol %), aryl chloride (0.12 mmol, 1.0 equiv), lithium tert- equiv.), sodium tert-butoxide (34.6 mg, 0.36 mmol, 1.5
butoxide (14.4 mg, 0.18 mmol, 1.5 equiv.), and morpholine equiv.), PhBPin (11.0 L, 0.048 mmol, 0.20 equiv., where
(11.4 L, 0.13 mmol, 1.1 equiv.) were added to a screw applicable), dodecane internal standard (1.0 equiv.), and
capped vial containing a magnetic stir bar, followed by the octylamine (45.6 L, 0.26 mmol, 1.1 equiv.), were added
addition of CPME (0.25 mL). The vial was sealed with a to a screw capped vial containing a magnetic stir bar,
cap containing a PTFE septum, removed from the glovebox followed by the addition of toluene (4.0 mL). The vial was
and placed in a temperature-controlled aluminum heating sealed with a cap containing a PTFE septum, and placed on
block set to the stated temperature for 16 h. The reaction a stir plate inside the glovebox; 200 L aliquots were taken
vial was then removed from the heating block and left to at the designated time intervals and the product yield (N-(1-
cool to ambient temperature, followed by addition of naphthyl)-octylamine, 3) was determined by calibrated GC
dodecane internal standard (1.0 equiv.). The product yield analysis using authentic products according to the Workup
was determined by calibrated GC analysis using authentic Method. See Figure S1.
products according to the Workup Method.
Protocol for the reaction of PAdNiI with PhBPin, cod
Protocol for the pre-catalyst reactivity comparison in and base (GPN)
the cross-coupling of ammonia and chloroarenes (GPJ)
PAdNiI (10 mg, 0.17 mmol, 1.0 equiv.), sodium tert-
In a nitrogen-filled glovebox, pre-catalyst (0.006 mmol, 5 butoxide (32.7 mg, 0.34 mmol, 2.0 equiv.), PhBPin (7.6 L,
mol %), aryl chloride (0.12 mmol, 1.0 equiv.), sodium tert- 0.033 mmol, 2.0 equiv.), and 1,5-cyclooctadiene (750 L
butoxide (34.6 mg, 0.36 mmol, 3.0 equiv.), and ammonia from a 0.05 M C6D6 stock solution, 0.037 mmol, 2.2
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700672
Advanced Synthesis & Catalysis
equiv.), were added to a screw capped vial containing a
magnetic stir bar. The vial was sealed with a cap containing
a PTFE septum, and placed on a temperature-controlled
We are grateful to the NSERC of Canada (RGPIN-2014-04807
and RGPIN-2016-05795; CGSD for C.M.L.) and Dalhousie
University for their support of this work, as well as Compute
Canada (ACEnet and Westgrid) for computational resources.
o
aluminum heating block set to 65 C for 4 h. The vial was
then brought into the glovebox, and an NMR sample was
prepared. The 31P{1H} NMR spectra of the crude reaction
mixture revealed mutual doublets with chemical shifts of
46.1 and 38.4 ppm, which we attribute to the putative
(L1)Ni(cod) species (see Synthesis of PAdNiI).
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obtained at -100 °C on a Bruker D8/APEX II CCD
diffractometer equipped with a CCD area detector using
graphite-monochromated Mo K ( = 0.71073 Å)
radiation employing a sample that was mounted in inert oil
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7
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10.1002/adsc.201700672
Advanced Synthesis & Catalysis
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8
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Advanced Synthesis & Catalysis
COMMUNICATION
Bisphosphine-Ligated Nickel Pre-catalysts in
C(sp2)-N Cross-Couplings of Aryl Chlorides: A
Comparison of Ni(I) and Ni(II)
Adv. Synth. Catal. Year, Volume, Page – Page
Christopher M. Lavoie, Robert McDonald, Erin R.
Johnson,* and Mark Stradiotto*
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Advanced Synthesis & Catalysis
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