Nickel-Catalyzed N-Arylation of Cyclopropylamine and Related Ammonium Salts with (Hetero)aryl (Pseudo)halides at Room Temperature

Article abstract of DOI:10.1021/acscatal.7b02014

Whereas the metal-catalyzed C(sp²)-N cross-coupling of cyclopropylamine with aryl electrophiles represents an attractive route to pharmaceutically relevant N-arylcyclopropylamines, few catalysts that are capable of effecting such transformation

Full text of DOI:10.1021/acscatal.7b02014

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Article
Nickel-Catalyzed N-Arylation of Cyclopropylamine and Related
Ammonium Salts with (Hetero)aryl (Pseudo)halides at Room Temperature
Joseph Tassone, Preston M. MacQueen, Christopher M. Lavoie,
Michael J Ferguson, Robert McDonald, and Mark Stradiotto
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02014 • Publication Date (Web): 26 Jul 2017
Downloaded from http://pubs.acs.org on July 26, 2017
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NickelꢀCatalyzed NꢀArylation of Cyclopropylamine
and Related Ammonium Salts with (Hetero)aryl
(Pseudo)halides at Room Temperature
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Joseph P. Tassone, Preston M. MacQueen, Christopher M. Lavoie, Michael J. Ferguson,
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1,
Robert McDonald, and Mark Stradiotto *
1
Department of Chemistry, Dalhousie University, 6274 Coburg Road, PO Box 15000, Halifax,
Nova Scotia, Canada, B3H 4R2
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XꢀRay Crystallography Laboratory, Department of Chemistry, University of Alberta,
Edmonton, Alberta, Canada, T6G 2G2
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ABSTRACT. Whereas the metalꢀcatalyzed C(sp )ꢀN crossꢀcoupling of cyclopropylamine with
aryl electrophiles represents an attractive route to pharmaceutically relevant Nꢀ
arylcyclopropylamines, few catalysts that are capable of effecting such transformations have
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been identified. Herein, the nickelꢀcatalyzed C(sp )ꢀN crossꢀcoupling of cyclopropylamine and
related nucleophiles, including ammonium salts, with (hetero)aryl (pseudo)halides is reported for
the first time, with the demonstrated scope of reactivity exceeding that displayed by all
previously reported catalysts (Pd, Cu, or other). Our preliminary efforts to effect the Nꢀarylation
of cyclopropylamine with (hetero)aryl chlorides at room temperature by use of (L)NiCl(oꢀtolyl)
preꢀcatalysts (L = PAdꢀDalPhos, C1; L = JosiPhos CyPFꢀCy, C2) were unsuccessful, despite the
established efficacy of C1 and C2 in transformations of other primary alkylamines. However,
systematic modification of the ancillary ligand (L) structure enabled success in such
transformations, with crystallographically characterized (L)NiCl(oꢀtolyl) preꢀcatalysts
incorporating oꢀphenyleneꢀbridged bisphosphines featuring either phosphatrioxaadamantane and
PCy (L = L3, CyPAdꢀDalPhos; C3), P(oꢀtolyl) and P(tꢀBu) (L = L4; C4), or PCy and P(tꢀ
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Bu) (L = L5; C5) donor pairings proving to be particularly effective. In employing the airꢀstable
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preꢀcatalyst C3 in crossꢀcouplings of cyclopropylamine, substituted electrophiles encompassing
an unprecedentedly broad range of heteroaryl (pyridine, isoquinoline, quinoline, quinoxaline,
pyrimidine, purine, benzothiophene, and benzothiazole) and (pseudo)halide (chloride, bromide,
mesylate, tosylate, triflate, sulfamate, and carbamate) structures were employed successfully, in
the majority of cases under mild conditions (3 mol% Ni, 25 °C). Preliminary studies also
confirmed the ability of C3 to effect the Nꢀarylation of cyclopropanemethylamine hydrochloride
and cyclobutylamine hydrochloride under similar conditions. A notable exception in this
chemistry was observed specifically in the case of electronꢀrich aryl chlorides, where the use of
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C4 in place of C3 proved more effective. In keeping with this observation, catalyst inhibition by
4ꢀchloroanisole was observed in the otherwise efficient crossꢀcoupling of cyclopropylamine and
3ꢀchloropyridine when using C3. Competition studies involving C3 revealed a (pseudo)halide
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reactivity preference (Cl > Br, OTs).
KEYWORDS: nickel, CꢀN crossꢀcoupling, cyclopropylamine, amination, ligand design
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. Introduction
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NꢀArylcyclopropylamines are an important core structure in several commercially
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available pharmaceuticals including fluoroquinone antibiotics (e.g. ciprofloxacin) as well as
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reverse transcriptase inhibitors (e.g. nevirapine), and can serve as effective mechanistic probes
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in biological and organic reactions. Because cyclopropyl halides are poorly reactive toward
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nucleophilic substitution by aromatic amines, the development of alternative methods for
preparing Nꢀarylcyclopropylamines under mild conditions represents an important challenge.
The reaction of 1ꢀbromoꢀ1ꢀethoxycyclopropane or (1ꢀethoxycyclopropoxy)trimethylsilane with
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anilines, followed by the reduction of the corresponding hemiaminals, as well as the baseꢀ
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mediated, Smiles rearrangement of 2ꢀaryloxyꢀNꢀcyclopropylacetamides, each furnish Nꢀ
arylcyclopropylamines, but these approaches employ harsh conditions in twoꢀstep procedures.
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Whereas the application of ubiquitous copper or palladium catalyzed C(sp )ꢀN crossꢀcoupling
methods employing cyclopropylamine and (hetero)aryl (pseudo)halides as substrates would
appear to be wellꢀsuited to the assembly of Nꢀarylcyclopropylamines, successful examples of
such transformations are quite rare (Figure 1). Only a single entry in each of four isolated
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publications employing copper catalysis with (hetero)aryl bromides and iodides have been
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disclosed (Figure 1A), and prior to 2016, the scope of such transformations achieved by use of
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palladiumꢀcatalysis was rather limited. Indeed, the first broadly useful palladiumꢀcatalyzed Nꢀ
arylation of cyclopropylamine with (hetero)aryl bromides (at room temperature) and chlorides
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110 °C) was documented only recently by Colacot and coꢀworkers (Figure 1B).
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Figure 1. Copperꢀ and palladiumꢀcatalyzed Nꢀarylation of cyclopropylamine (A and B), as well
as the new nickelꢀcatalyzed transformations (C) reported in this work.
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Despite the utility of palladiumꢀcatalyzed C(sp )ꢀN crossꢀcoupling methods, the high cost
and low abundance of palladium has prompted the development of related catalytic
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methodologies employing comparatively inexpensive, Earthꢀabundant metals. Consequently,
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nickelꢀbased catalyst systems have emerged as suitable alternatives, exhibiting comparable or
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superior performance versus palladiumꢀbased systems for C(sp )ꢀN bond formation, especially in
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transformations of phenolꢀderived electrophiles (e.g., sulfonates, sulfamates, and carbamates).
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However, the growing number of reports of nickelꢀcatalyzed C(sp )ꢀN and related crossꢀ
couplings has not been met with concomitant effort toward the rational design of ancillary
ligands for use specifically with nickel. Indeed, the majority of successful nickelꢀbased catalyst
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systems for C(sp )ꢀN crossꢀcoupling that have been identified to date rely on the ‘repurposing’ of
ligands that were developed and optimized for use with palladium, with little regard to the subtle,
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yet distinct, characteristics of nickel versus palladium. As part of our effort to address this
deficiency, our group recently developed the PAdꢀDalPhos (L1, Chart 1) ancillary ligand for use
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in nickelꢀcatalyzed C(sp )ꢀN bond formation. Whereas electronꢀrich phosphine ligands are
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employed almost exclusively in palladiumꢀcatalyzed C(sp )ꢀN crossꢀcoupling to facilitate
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challenging C(sp )ꢀX oxidative additions, the sterically demanding design of L1 was intended
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primarily to facilitate C(sp )ꢀN reductive elimination, given the ease with which nickel can
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participate in oxidative addition chemistry. Accordingly, the airꢀstable preꢀcatalyst (L1)NiCl(oꢀ
tolyl) (C1) has been shown to effect the monoarylation of a diverse and challenging set of
nitrogenꢀbased nucleophiles, including ammonia, primary alkylamines, anilines, primary amides,
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and lactams, using (hetero)aryl (pseudo)halides under mild conditions.
Chart 1. Ancillary ligands examined in this investigation.
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The success of PAdꢀDalPhos (L1) in nickelꢀcatalyzed C(sp )ꢀN crossꢀcoupling has
prompted us to investigate the application of this and related ancillary ligands in transformations
of other challenging amine nucleophiles, with the dual aims of providing useful synthetic
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advances, and furthering our understanding of the ancillary ligand designs that give rise to
superior catalytic performance. Given the lack of effective base metalꢀcatalyzed procedures for
the synthesis of Nꢀarylcyclopropylamines (vide supra), we targeted cyclopropylamine as a
candidate for such studies; in particular, we were interested in establishing broadly useful
transformations that proceed at room temperature, in light of the low boiling point of
cyclopropylamine (49ꢀ50 °C).
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We anticipated two major obstacles that could discourage the successful crossꢀcoupling
of cyclopropylamine with (hetero)aryl (pseudo)halides using nickel catalysis. Firstly, the
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cyclopropylaminyl radical is known to undergo rapid ring opening, which, given the propensity
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for nickel to engage in radical chemistry,
could lead to unwanted side reactions rather than
the desired crossꢀcoupled product. Additionally, the nickelꢀcatalyzed ring opening of substituted
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cyclopropanes is wellꢀdocumented, further restricting the potential use of cyclopropylamine in
this reaction. Notwithstanding such challenges, we anticipated that unwanted reactivity might be
circumvented through the application of an appropriately tailored ancillary ligand. Herein, we
report the first examples of the nickelꢀcatalyzed Nꢀarylation of cyclopropylamine and related
nucleophiles including ammonium salts with (hetero)aryl (pseudo)halides, which is enabled by
use of the airꢀstable, nickel preꢀcatalyst C3 (Figure 1C) that incorporates the CyPAdꢀDalPhos
ligand (L3, Chart 1). Notably, the catalytic performance of C3 is competitive with the best
catalysts known for such transformations, whereby a broad spectrum of substrates is
accommodated at room temperature, including the first examples of transformations involving
mesylate, tosylate, triflate, sulfamate, and carbamate (hetero)aryl electrophiles.
2. Results and Discussion
2.1. Screening of Pre-Catalysts C1 and C2 in the Nickel-Catalyzed N-Arylation of
Cyclopropylamine
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Preꢀcatalysts (L1)NiCl(oꢀtolyl) (C1) and (L2)NiCl(oꢀtolyl) (C2) were selected for use
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in a preliminary screen of the nickelꢀcatalyzed Nꢀarylation of cyclopropylamine (Scheme 1)
employing three challenging (hetero)aryl chlorides, under mild conditions (3 mol% Ni, 25 °C)
that had previously proven effective for the crossꢀcoupling of other primary alkylamines (e.g.,
furfurylamine) with C1 or C2. Notably, in each case only modest conversion to the desired Nꢀ
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hetero)arylcyclopropylamine (≤ 50% conversion to 3a-c) was achieved. However, the
observation of negligible byꢀproduct formation in these test reactions suggested that unwanted
sideꢀreactions (e.g., cyclopropane ringꢀopening, vide supra) are not dominant under the reaction
conditions employed.
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Scheme 1. Preꢀcatalyst screen of C1 and C2 in the nickelꢀcatalyzed Nꢀarylation of
cyclopropylamine. General conditions: (hetero)aryl chloride (1.0 equiv), cyclopropylamine (1.5
equiv), NaO(tꢀBu) (1.5 equiv), in toluene. Conversions to product are estimated on the basis of
calibrated GC data, reported as % 3aꢀc (% 1aꢀc remaining).
a a
2.2. Synthesis of Pre-catalysts C3-C5
Encouraged by the clean, though modest, conversion to the desired Nꢀ
(hetero)arylcyclopropylamine (3a-c) that was achieved by use of C1 and C2 in the nickelꢀ
catalyzed Nꢀarylation of cyclopropylamine (Scheme 1), we questioned if variants of C1 and C2,
incorporating modified ancillary ligands similar to L1 or L2, might promote the desired
transformations more effectively. As such, a selection of alternative ancillary ligands featuring
pairings of sterically demanding, yet electronically varied, phosphine donor fragments were
targeted (L3ꢀL5, Chart 1). Substitution of the sterically hindered, but relatively electron poor, diꢀ
oꢀtolylphosphino donor fragment in L1 for the similarly bulky, but comparatively more electronꢀ
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releasing, dicyclohexylphosphino group gives rise to CyPAdꢀDalPhos (L3). Alternatively,
replacement of the phosphatrioxaadamantane moiety in L1 with the more electronꢀrich and
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sterically similar diꢀtertꢀbutylphosphino group affords L4. Finally, exchange of the
phosphatrioxaadamantane cage in L3 for a diꢀtertꢀbutylphosphino group results in L5, whereby
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both phosphine donors are bulky and strongly electronꢀreleasing, similar to L2. While L3 and L4
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had previously been synthesized, L5 had not been prepared prior to this work. Ligand L5 was
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prepared via lithiation of (2ꢀbromophenyl)diꢀtertꢀbutylphosphine followed by quenching with
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ClPCy . Notably, whereas L3 and L4 are airꢀstable in the solid state, L5 was found to be airꢀ
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sensitive, requiring handling under inert atmosphere.
Given the established efficacy of nickel preꢀcatalysts of the form L NiCl(aryl) in crossꢀ
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coupling applications, including C(sp )ꢀN bond formation, we wished to develop (L)NiCl(oꢀ
tolyl) preꢀcatalysts incorporating L3ꢀL5 in order to assess their catalytic competency in the Nꢀ
arylation of cyclopropylamine. The desired complexes (L3)NiCl(oꢀtolyl) (C3), (L4)NiCl(oꢀtolyl)
(C4), and (L5)NiCl(oꢀtolyl) (C5) were prepared in a twoꢀstep procedure adapted from the
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literature (Scheme 2). Combination of each of L3ꢀL5 with NiCl (DME) (DME = 1,2ꢀ
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dimethoxyethane) in THF afforded the corresponding (L)NiCl species, the identities of which
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were confirmed via spectroscopic and microanalytical analysis. Subsequent treatment with oꢀ
tolylmagnesium chloride in THF afforded after workup C3ꢀC5 as airꢀstable solids that were
structurally characterized, including by use of singleꢀcrystal Xꢀray techniques (Figure 2). In all
cases a distorted square planar geometry is observed (∑∠≈ 360°), and the NiꢀP distance trans to
the aryl group is longer than the analogous distance trans to chloride.
Scheme 2. Synthesis of preꢀcatalysts C3ꢀC5.
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Figure 2. Singleꢀcrystal Xꢀray structures of C3 (left), C4 (middle), and C5 (right), represented
with thermal ellipsoids at the 30% probability level. Hydrogen atoms are omitted for clarity.
Selected interatomic distances (Å): for C3 NiꢀP1 2.2504(12), NiꢀP2 2.1575(11), NiꢀCl
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.2019(11), NiꢀC(41) 1.953(4); for C4 NiꢀP1 2.1380(5), NiꢀP2 2.2789(5), NiꢀCl 2.2056(6), Niꢀ
C(41) 1.941(2); for C5 NiꢀP1 2.2603(5), NiꢀP2 2.1452(5), NiꢀCl 2.2142(5), NiꢀC(41)
.9759(17).
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warrants further discussion (Figure 3). The solution P{ H} NMR spectrum of bulk (asꢀ
prepared, amorphous) C3 exhibits four pairs of doublets (Figure 3A), corresponding to four
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distinct species (C3AꢀC3D), as confirmed on the basis of Pꢀ P COSY data (see Figure S12 in
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the Supporting Information). Conversely, the solution P{ H} NMR spectrum of crystalline C3
Figure 3B) features only two pairs of doublets (~3:1 ratio) – a pattern that is similar to that of
(
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C1. Given that the crystal structure of C3 features the nickelꢀbound oꢀtolyl fragment trans to
the chiral (racemic) phosphatrioxaadamantane cage (Figure 2), we ascribe the two pairs of
doublets observed in Figure 3B as arising from the presence of two NiꢀC(aryl) rotational isomers
(C3A and C3B) that differ on the basis of the relative orientation of the methyl group of the
nickelꢀbound oꢀtolyl fragment above or below the square plane of the molecule. The emergence
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over time of the remaining two sets of doublets (C3C and C3D) in the solution P{ H} NMR
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spectrum of dissolved crystalline C3 (see Figure S13 in the Supporting Information) suggests
that C3C and C3D are structurally related to C3A and C3B. On the basis of these collective
observations, the proposed identities of C3AꢀD are depicted in Figure 3: C3A and C3B are
complexes in which the nickelꢀbound oꢀtolyl group is trans to the phosphatrioxaadamantane
cage, while C3C and C3D are isomeric complexes in which the nickelꢀbound oꢀtolyl group is
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trans to the PCy moiety. The chiral (racemic) nature of the phosphatrioxaadamantane cage,
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when paired with the relative orientation of the methyl group of the nickelꢀbound oꢀtolyl
fragment above or below the square plane, arising from hindered NiꢀC(aryl) rotation, affords
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1
four diastereomers in keeping with the solution P{ H} NMR spectrum of bulk C3 (Figure 3A).
Variableꢀtemperature solution NMR experiments suggest that C3A/B to C3C/D isomerization is
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1
slow on the NMR timescale, with only slight changes in the relative P{ H} NMR peak
intensities of C3AꢀD observed at elevated temperatures (see Figure S14 in the Supporting
3
1
1
Information). This notion is further supported by P{ H} NMR saturation transfer experiments,
in which chemical exchange was not observed between C3A/B and C3C/D at room temperature
(see Figure S15 in the Supporting Information). Though we did not conduct experiments to
determine the mechanism for this isomerization process, the interconversion of C3A/B to C3C/D
might occur through tetrahedral intermediates, or through dissociation of one phosphine donor
atom of L3 followed by rearrangement and subsequent reꢀchelation. Notably, only two
diastereomers likely arising from rotamers of the nickelꢀbound oꢀtolyl group are observed in
19
solution for C1. At first glance, it is tempting to rationalize the differing ancillary ligand
binding selectivity within each of C1 and C3 as being attributable to the more closely matched
transꢀdirecting ability of the dialkylphosphino donor fragments in C3 (leading to poor
selectivity), versus the phosphatrioxaadamantane (superior) and P(oꢀtolyl) (inferior) pairing in
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C1. However, the somewhat complex solution NMR behavior of C4 (vide infra), featuring P(oꢀ
tolyl) and P(tꢀBu) donors in analogy to C1, when contrasted with the observation of a single
2
2
diastereomer in solution for C5 which features two dialkylphosphino donors similar to C3,
suggests that the observed equilibrium distribution of isomers in preꢀcatalysts of this type may
result from a complex interplay of factors.
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Figure 3. P{ H} NMR spectrum (CDCl ) of A) bulk and B) recrystallized C3, with the
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proposed four diastereomers C3A-D depicted (P
=
PCy2; *P
=
chiral
phosphatrioxaadamantane cage).
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1
The solution P{ H} NMR spectrum of C4 (see Figure S21 in the Supporting
Information) exhibits four distinct resonances that exhibit varying degrees of lineꢀbroadening.
Compound C4 is distinct from C3 in that the orientation of the methyl group of the nickelꢀbound
oꢀtolyl fragment above or below the square plane is rendered enantiotopic (rather than
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diastereotopic, as in C3) in the absence of a secondary chiral element. Variableꢀtemperature
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solution P{ H} NMR studies of C4 revealed coalescence to two broad signals at elevated
temperatures (see Figure S22 in the Supporting Information). On this basis, we tentatively assign
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the four P{ H} NMR resonances observed for C4 as corresponding to two geometric isomers
in which the nickelꢀbound oꢀtolyl group is trans to either the P(oꢀtolyl) or P(tꢀBu) fragment.
2
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However, isomerism arising from hindered rotation involving the P(oꢀtolyl) and Ni(oꢀtolyl)
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moieties, in addition to possible equilibria involving tetrahedral and square planar species, is
also likely contributing to the observed line broadening behavior. In keeping with such a
1
scenario, the solution H NMR spectrum of (L4)NiCl is consistent with a C ꢀsymmetric
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1
structure arising from hindered rotation phenomena, whereas a C ꢀsymmetric structure is evident
S
for (L5)NiCl2.
2
.3. Screening of Pre-Catalysts C3-C5 in the Nickel-Catalyzed N-Arylation of
Cyclopropylamine
With the desired new preꢀcatalysts in hand, we set out to screen C3ꢀC5 for activity in the
2
nickelꢀcatalyzed C(sp )ꢀN crossꢀcoupling of cyclopropylamine (3 mol% Ni, 25 °C; Scheme 3),
employing the same three challenging (hetero)aryl chlorides for which C1 and C2 had performed
poorly (Scheme 1). Gratifyingly, both C3 and C5 demonstrated excellent performance in two of
these test transformations, with almost quantitative conversion being observed when utilizing the
heteroaryl or orthoꢀsubstituted aryl chloride 1a or 1c (leading to 3a and 3c, respectively). While
C4 performed comparatively poorly in transformations of 1a or 1c, this preꢀcatalyst proved
superior to C3 or C5 in the test transformation of electronꢀrich 4ꢀchloroanisole (1b) leading to
3
b. Substituting weaker bases such as Cs CO or K PO for NaO(tꢀBu) resulted in minimal
2 3 3 4
conversion to the desired product (<5% conversion to 3a when using C3). Furthermore, reducing
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the catalyst loading of C3 below 3 mol% resulted in poorer conversions (e.g., 65% conversion to
3a at 1 mol% catalyst loading). Given the similar reactivity profile of C3 and C5, we opted to
carry forward with C3 (and where appropriate, C4) in subsequent catalytic applications on the
basis of the practical consideration that L3 (unlike L5) is not airꢀsensitive.
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Scheme 3. Preꢀcatalyst screen of C3ꢀC5 in the nickelꢀcatalyzed Nꢀarylation of
cyclopropylamine. General conditions: (hetero)aryl chloride (1.0 equiv), cyclopropylamine (1.5
equiv), NaO(tꢀBu) (1.5 equiv), in toluene. Conversions to product are estimated on the basis of
calibrated GC data, reported as % 3aꢀc (% 1aꢀc remaining).
a a
22
From an ancillary ligand design perspective, the similar performance of C3 and C5 in
the successful formation of 3a and 3c indicates that the phosphatrioxaadamantane and P(tꢀBu)2
groups are interchangeable in terms of engendering desirable nickel catalysis in these particular
transformations. Knowing that the phosphatrioxaadamantane cage is a poorer electronꢀdonor
2
7
versus P(tꢀBu) , but that the two fragments possess a similar steric profile, suggests that the
2
selection of appropriate ancillary ligand sterics, rather than electronics, is a key design
consideration in this particular reaction setting. However, such simple conclusions do not
translate to the transformation leading to 3b, whereby poor conversion to product was noted with
the PAdꢀDalPhos (L1)ꢀderived preꢀcatalyst C1 featuring phosphatrioxaadamantane and P(oꢀ
tolyl) ancillary ligand donor pairings, yet excellent conversion was achieved with the analogous
2
preꢀcatalyst C4, which features P(tꢀBu) in place of the phosphatrioxaadamantane moiety. It is
2
plausible that the successful formation of 3b by use of C4 may arise in part from the more
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electronꢀrich nature of L4 versus L1, resulting in more facile C(sp )ꢀCl activation of the
electronically deactivated 4ꢀchloroanisole substrate. However, the poor performance of C2 or C5
in the formation of 3b, each featuring strongly electronꢀreleasing phosphine donor fragments,
supports the notion that a subtle balance of ancillary ligand steric and electronic properties must
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be achieved in order to engender desirable performance in nickelꢀcatalyzed C(sp )ꢀN crossꢀ
coupling of particular nucleophile and electrophile pairings. Indeed, while L1 and L2 proved
inferior to L3 and L4 in the nickelꢀcatalyzed Nꢀarylation of cyclopropylamine under examination
1
9, 25a
herein, the inverse trend has been observed for the monoarylation of ammonia.
It must also
2
be recognized that in contrast to the Pd(0)/Pd(II) cycle traversed in palladiumꢀcatalyzed C(sp )ꢀN
crossꢀcoupling, the mechanistic scenario is likely more complex for nickel, whereby the ancillary
ligand and substrates employed influence partitioning between Ni(0)/Ni(II) and Ni(I)/Ni(III)
30
reaction manifolds of differing productivity.
2
.4. Scope of the Nickel-Catalyzed N-Arylation of Cyclopropylamine
2
We then surveyed the electrophile scope in the C(sp )ꢀN crossꢀcoupling of
cyclopropylamine using C3 (Scheme 4). A variety of (hetero)aryl (pseudo)halide coupling
partners were successfully employed in this reaction, including those with electronꢀwithdrawing
(
3dꢀg) or orthoꢀsubstituents (3c, 3iꢀk). Heterocyclic electrophiles were also wellꢀtolerated,
including those featuring pyridine (3a), isoquinoline (3j), quinaldine (3k), quinoline (3l),
quinoxaline (3m), pyrimidine (3nꢀo), purine (3p), benzothiophene (3q), or benzothiazole (3r)
frameworks. In conducting such transformations on an 8.5 mmol scale in (hetero)aryl chloride by
use of C3 (3 mol%), each of 3a (1.004 g, 88%) and 3d (1.223 g, 91%) were obtained in excellent
yield. However, aryl electrophiles containing carbonyl moieties (e.g., ketone or ester) proved to
be ineffective coupling partners. The use of C3 enabled the Nꢀarylation of cyclopropylamine
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using (hetero)aryl chlorides, bromides, and phenolꢀderived electrophiles (tosylate, sulfamate, and
carbamate) at room temperature (3 mol% C3), as well as aryl triflate and aryl mesylate coupling
partners, albeit at higher catalyst loadings (5 mol% C3) and elevated temperatures (110 °C). Use
of C4 in place of C3 allowed the coupling of an electronꢀrich aryl chloride (3b) and aryl tosylate
(3h) at room temperature. Control experiments performed in the absence of nickel showed no
conversion to 3d or 3i, and only 10% conversion to 3p (as determined on the basis of GC
analysis), highlighting the essential nature of the preꢀcatalyst in promoting this transformation.
Notably, the transformations depicted in Scheme 4 represent the first examples of room
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temperature C(sp )ꢀN crossꢀcouplings of cyclopropylamine employing (hetero)aryl chlorides, as
well as the first examples of such crossꢀcouplings involving phenolꢀderived electrophiles under
any conditions. Collectively, the scope of reactivity demonstrated herein can be viewed as
exceeding that displayed by all previously reported catalysts (Pd, Cu, or other) for the Nꢀ
arylation of cyclopropylamine.
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a a
Scheme 4. Scope of the nickelꢀcatalyzed Nꢀarylation of cyclopropylamine. General conditions:
(hetero)aryl (pseudo)halide (1.0 equiv), cyclopropylamine (1.5 equiv), NaO(tꢀBu) (1.5 equiv), in
b
c
toluene. Isolated yields reported. Isolated as the corresponding Nꢀacyl derivative. Conducted
using 3 mol% C4. Conducted using 5 mol% C3 and K PO (3.0 equiv) at 110 °C. 1,4ꢀdioxane
d
e
3
4
used as solvent.
Given that a variety of (hetero)aryl electrophiles proved to be viable coupling partners
when using C3, we conducted a brief (pseudo)halide competition study with limiting
cyclopropylamine to assess the relative preference of this preꢀcatalyst (Scheme 5). The aryl
components of the electrophiles employed in our competition study were purposefully chosen to
be sterically and electronically similar in order to minimize any reactivity bias, while still
enabling rational analysis of the product mixtures. When an aryl chloride and bromide were used
as competing crossꢀcoupling partners, a modest preference for the aryl chloride was observed,
with an overall 80% combined conversion to both products (3s and 3t). In the case of the aryl
chloride or bromide versus the aryl tosylate, a sizeable preference for the aryl halide was
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observed. However, the total conversion to 3s and 3t under these conditions was significantly
lower (< 50%), suggesting a potential inhibitory effect when the aryl tosylate engages with C3.
Preꢀcatalyst C2 displayed a similar intolerance to certain aryl electrophiles in the crossꢀcoupling
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25a
primary alkylamines.
a
a
Scheme 5. (Pseudo)halide competition study employing C3.
cyclopropylamine (1.5 equiv), NaO(tꢀBu) (1.5 equiv), in toluene. Reported product distributions
and total conversions to 3s and 3t were estimated on the basis of calibrated GC data.
General conditions:
In our initial set of screening reactions using C3 as a preꢀcatalyst for the room
temperature crossꢀcoupling of cyclopropylamine, the amination of 3ꢀchloropyridine (1a)
proceeded in high conversion to afford 3a (Scheme 3). Conversely, the analogous crossꢀcoupling
using 4ꢀchloroanisole (1b) afforded only modest amounts of the target Nꢀarylcyclopropylamine
(3b) along with significant quantities (~80%) of unreacted 1b. It is plausible that the poor
performance of 1b can be attributed to the inability of catalytic species derived from C3 to
engage in oxidative addition to the rather electronꢀrich and thus deactivated 1b, and/or to
subsequent catalyst inhibition pathways (e.g., slow transmetallation or reductive elimination;
deleterious redox chemistry). In a preliminary examination of such phenomena, the otherwise
successful crossꢀcoupling of cyclopropylamine and 1a to give 3a by using C3 was monitored
over time in the presence of varying amounts of added 1b (Scheme 6 and Figure S1 in the
Supporting Information). Evaluation of the conversion to 3a after 40 minutes reaction time
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revealed that increasing the concentration of 1b diminished the ability of C3 to effect the
otherwise facile conversion of 1a to 3a, and throughout, negligible amounts of 3b were detected
by use of GC methods. These preliminary observations suggest that 1b engages with catalytic
species derived from C3 in such a way as to lead to suppression of catalytic activity.
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Scheme 6. Reaction monitoring of the formation of 3a using C3 with varying amounts of 1b.
a
General conditions: 1a (1.0 equiv) cyclopropylamine (1.5 equiv), NaO(tꢀBu) (1.5 equiv), in
toluene. Conversion to 3a determined on the basis of calibrated GC data. After 40 minutes
b
reaction time.
2.5. Nickel-Catalyzed N-Arylation of Cyclic Alkyl Ammonium Salts
The utility of C3 in the nickelꢀcatalyzed Nꢀarylation of cyclopropylamine prompted us to
explore its application in reactions involving other small, cyclic alkylamines. Like
cyclopropylamine, both cyclopropanemethylamine and cyclobutylamine have only seldom been
2
31
utilized in palladiumꢀ and copperꢀcatalyzed C(sp )ꢀN bondꢀforming processes, and analogous
nickelꢀcatalyzed transformations were unknown prior to our work herein. Given that both amines
are sensitive to air and moisture, we opted to employ the more conveniently handled and
commercially available hydrochloride salts of these substrates in our catalytic survey. Notably,
2
the use of alkyl ammonium salts in C(sp )ꢀN crossꢀcoupling chemistry is restricted to three
reports concerning transformations of methylamine or ethylamine hydrochloride exclusively,
32
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employing palladium or nickel
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Adapting the conditions employed for the Nꢀarylation of cyclopropylamine (Scheme 4),
we assessed the performance of C3 in the Nꢀarylation of cyclopropanemethylamine
hydrochloride and cyclobutylamine hydrochloride with some representative (hetero)aryl
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(
pseudo)halides (Scheme 7). Desired amination products derived from electrophiles featuring
orthoꢀsubstituents (5a, as well as 5b using C4), an electronꢀwithdrawing group (6a), or
heterocyclic frameworks (6b and 6c) were obtained successfully in this reaction, spanning
(hetero)aryl chloride, bromide, and tosylate coupling partners. Notably, these transformations
2
represent the first examples of the metalꢀcatalyzed C(sp )ꢀN crossꢀcoupling of alkyl ammonium
salts at room temperature.
Scheme 7. The nickelꢀcatalyzed Nꢀarylation of cyclopropanemethylamine hydrochloride and
cyclobutylamine hydrochloride. General conditions: (hetero)aryl (pseudo)halide (1.0 equiv),
a a
amine hydrochloride (1.1 equiv), NaO(tꢀBu) (2.5 equiv), in toluene. Isolated yields reported.
b
c
Conducted using 5 mol% C4. Yield estimated on the basis of calibrated GC data.
3
. Conclusion
2
In summary, we have developed the first nickelꢀcatalyzed C(sp )ꢀN crossꢀcouplings of
cyclopropylamine, cyclopropanemethylamine hydrochloride, and cyclobutylamine
hydrochloride, with an unprecedented scope of (hetero)aryl (pseudo)halides. Subtle electronic
modifications in the ancillary ligand framework were shown to be crucial for obtaining a highly
effective preꢀcatalyst for such challenging transformations. In this regard, the reported protocol
makes use of the new, airꢀstable CyPAdꢀDalPhos preꢀcatalyst C3, in the majority of cases under
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mild conditions (3 mol% Ni, 25 °C), with the demonstrated electrophile scope spanning a diverse
range of heteroaryl (pyridine, isoquinoline, quinoline, quinoxaline, pyrimidine, purine,
benzothiophene, and benzothiazole) and (pseudo)halide (chloride, bromide, mesylate, tosylate,
triflate, sulfamate, and carbamate) motifs. Whereas C3 was found to be less effective in
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combination with electronꢀrich aryl chlorides, preꢀcatalyst C4, featuring P(oꢀtolyl) and P(tꢀBu)2
2
donor pairings, proved to be useful in promoting crossꢀcouplings of these particular substrates.
This reactivity trend was found to be consistent with our observation of catalyst inhibition in the
otherwise efficient crossꢀcoupling of cyclopropylamine and 3ꢀchloropyridine using C3, upon
addition of 4ꢀchloroanisole. Competition studies involving C3 revealed a (pseudo)halide
reactivity preference (Cl > Br, OTs). Overall, this report highlights the utility of rationally
2
optimized ancillary ligand design for application in nickelꢀcatalyzed C(sp )ꢀN bond formation, as
a means of establishing new and synthetically useful base metalꢀcatalyzed amination reactions.
Our efforts to apply these and other ancillary ligand design strategies in the development of new
nickelꢀcatalyzed transformations will be the focus of future reports.
4. Experimental Section
General Considerations. Unless otherwise indicated, all experimental procedures were
conducted in a nitrogenꢀfilled, inert atmosphere glovebox using ovenꢀdried glassware, with
workꢀup procedures carried out on the benchtop in air. Toluene, and pentane used in the
synthesis of L5, were purged with nitrogen, passed through a double column purification system
containing alumina and copperꢀQ5 reactant, and stored over 4Å molecular sieves in bulbs with
Teflon taps prior to use. Diethyl ether, tetrahydrofuran (THF), and 1,4ꢀdioxane were dried over
Na/benzophenone, distilled under a nitrogen atmosphere, and stored in bulbs with Teflon taps
over 4Å molecular sieves. Dichloromethane (DCM) used in the synthesis of L5 was purged with
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nitrogen, and stored over 4Å molecular sieves in a bulb with a Teflon tap. C D Cl was freezeꢀ
2
2
4
pumpꢀthaw degassed three times and stored over 4Å molecular sieves in a bulb with a Teflon tap
in the glovebox. K PO was dried under vacuum at 180 °C for 24 h, and stored under nitrogen in
3
4
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the glovebox prior to use. (2ꢀbromophenyl)diꢀtertꢀbutylphosphine, L3, L4, C1, C2, 3ꢀ
3
4
34
methoxyphenyl 4ꢀmethylbenzenesulfonate, quinolinꢀ6ꢀyl methanesulfonate, naphthaleneꢀ1ꢀyl
3
5
36
trifluoromethanesulfonate,
3ꢀmethoxyphenyl dimethylsulfamate,
2ꢀmethylquinolinꢀ4ꢀyl
2
5b
37
diethylcarbamate,
and 9ꢀbenzylꢀ6ꢀchloropurine were prepared according to established
literature procedures. Otherwise, all other solvents, reagents, and materials were used as received
from commercial sources. For General Procedures and B, automated flash
A
chromatography was carried out on a Biotage Isolera One automated flash purification system
using 10 g Biotage SNAP KPꢀSIL (particle size 30ꢀ90 ꢀm) or 12 g Silicycle SiliaSep (particle
size 40–63 ꢀm, 230–400 mesh) silica flash cartridges with a typical gradient of 2ꢀ4ꢀ2 column
volumes and a flow rate of 10 mL/min. For General Procedure C, flash chromatography was
carried out on silica gel using Silicycle SiliaFlash 60 silica (particle size 40–63 ꢀm; 230–400
mesh). Unless otherwise indicated, NMR spectra were recorded on a Bruker AV 300 MHz or
Bruker AV 500 MHz spectrometer at 300 K, with chemical shifts (in ppm) referenced to residual
1
13
1
31
1
protio solvent peaks ( H), deuterated solvent peaks ( C{ H}), or external 85% H PO ( P{ H}).
3
4
Splitting patterns are indicated as follows: br, broad; app, apparent; s, singlet; d, doublet; t,
triplet; q, quartet; sept, septet; dd, doublet of doublets; td, triplet of doublets; m, multiplet, with
all coupling constants (J) reported in Hertz (Hz). In some cases, fewer than expected carbon
resonances were observed despite prolonged acquisition times. Elemental analyses were
performed by Galbraith Laboratories, Inc., Knoxville, TN. Mass spectra were obtained using ion
trap electrospray ionization (ESI) instruments operating in positive mode. Gas chromatography
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(
GC) data were obtained on an instrument equipped with a SGE BPꢀ5 column (30 m, 0.25 mm
i.d.).
Synthesis
of
di-tert-butyl(2-(dicyclohexyl)phosphino)phenyl)phosphine
(L5).
All
0
1
2
3
4
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manipulations, including work-up, were performed in an inert atmosphere glovebox. A glass vial
was charged with (2ꢀbromophenyl)diꢀtertꢀbutylphosphine (0.138 g, 0.458 mmol), Et O (2 mL),
2
and a magnetic stir bar, and the vial was placed in a –33 °C freezer for 20 min. After this time,
the vial was removed from the freezer, magnetic stirring was initiated, and nꢀBuLi (275 ꢀL of a
2
.5 M solution in hexanes, 0.687 mmol) was added dropwise to the cooled, stirring solution,
yielding a clear yellow solution. The solution was then allowed to stir at room temperature for 30
min., after which time a cold (–33 °C) solution of ClPCy (106 ꢀL, 0.481 mmol) in Et O (1 mL)
2
2
was added dropwise to the stirring solution, yielding a cloudy yellow mixture upon complete
addition. The mixture was allowed to stir at room temperature for 18 h (unoptimized), after
which time DCM (3 mL) was added, and the mixture was filtered through a Celite/silica plug
(~1:1), eluting with DCM (2 x 1 mL). The volatiles were removed from the clear, yellow filtrate
under reduced pressure yielding a yellowꢀorange oil, which solidified under vacuum after several
hours. The solid residue was then washed with cold (–33 °C) pentane (3 x 1 mL), and was dried
under reduced pressure to afford L5. Yield: 26.2 mg (14%). Additional L5 could be isolated by
removing the volatiles from the retained pentane washings, washing the resulting yellow solid
with cold (–33 °C) pentane (2 x 1 mL), and drying under reduced pressure. Yield: 33.5 mg
1
1
(17%). Combined Yield: 59.7 (31%). H NMR (500.1 MHz, CDCl ): δ H NMR (500.1 MHz,
3
CDCl ): δ 7.82ꢀ7.81 (m, 1H), 7.54 (br d, J = 5.8 Hz, 1H), 7.33ꢀ7.28 (m, 2H), 1.94ꢀ1.05 (m, 40H,
3
1
3
1
overlapping Cy and tꢀBu resonances, with the latter at 1.21, d, JPH = 11.4 Hz). C{ H} NMR
(125.8 MHz, CDCl ): δ 146.3ꢀ145.6 (overlapping m), 135.7, 133.1 (d, JPC = 6.9 Hz), 127.8,
3
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26.7, 35.9 (dd, J = 17.1, 5.0 Hz), 33.6 (dd, J = 26.6, 4.1), 31.1 (d, J = 14.7), 30.8 (d, J =
PC
PC
PC
PC
3
1
1
16.2 Hz), 29.7 (d, JPC = 9.4 Hz), 27.6ꢀ27.5 (overlapping d), 26.6. P{ H} NMR (202.5 MHz,
CDCl ): δ 17.9 (d, J = 156.0 Hz), ꢀ9.9 (d, JPP = 156.0 Hz). HRMSꢀESI (m/z): Calc’d for
3
PP
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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47
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53
54
55
56
57
58
59
60
+
C H P [M+H] : 419.2996. Found: 419.2991.
26
45 2
Synthesis of (L3)NiCl . A glass vial was charged with NiCl (DME) (85.7 mg, 0.390 mmol), L3
2
2
(
200.0 mg, 0.409 mmol), THF (2 mL), and a magnetic stir bar. Stirring was initiated, affording
initially a clear, dark orange solution. A redꢀbrown precipitate formed after several minutes. The
resulting mixture was stirred at room temperature for 2 hours, after which time the solid was
collected on a glass filter frit in air and washed with cold (~0 °C) pentane (2 x 2 mL). The
remaining solid was then dissolved off the frit using DCM (10 mL), and the clear, dark red
solution thus formed was collected. The volatiles were removed from the collected eluent
solution under reduced pressure, yielding the target complex as a dark redꢀbrown solid. Yield:
1
0.224 g (93%). H NMR (500.1 MHz, CDCl ): δ 8.32 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 7.2 Hz,
3
1
H), 7.68ꢀ7.62 (m, 2H), 4.02 (d, J = 13.5 Hz, 1H), 2.74ꢀ2.65 (m, 3H), 2.53 (d, J = 13.4 Hz, 1H),
1
3
1
2
.31 (d, J = 14.0 Hz, 1H), 2.00ꢀ1.93 (m, 1H), 1.87ꢀ1.11 (overlapping m, 31H). C{ H} NMR
(
125.8 MHz, CDCl ): δ 141.2, 139.0, 134.9, 132.4 (two signals), 131.8, 97.1 (d, JPC = 64.7 Hz),
3
7
4.7, 53.6, 41.1, 40.2, 38.5, 37.3, 29.9 (d, J = 13.6 Hz), 29.5, 28.9 (d, J = 7.9 Hz), 27.6, 27.3ꢀ
PC PC
3
1
1
27.1 (m, overlapping signals), 26.8, 26.4, 25.8 (d, JPC = 6.1 Hz). P{ H} NMR (202.5 MHz,
CDCl ): δ 75.8 (br s), 46.4 (br s). Anal. Calc’d. for C H Cl NiO P : C, 54.40; H, 6.85; N, 0.
3
28 42
2
3 2
Found: C, 54.76; H, 6.72; N, <0.5.
Synthesis of (L3)NiCl(o-tolyl), C3. A glass vial was charged with (L3)NiCl (150.0 mg, 0.243
2
mmol), THF (2.5 mL), and a magnetic stir bar, yielding a clear, dark orange solution. Stirring
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2
2
2
2
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3
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3
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3
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4
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was initiated, then (oꢀtolyl)MgCl (277 ꢀL of a 0.920 M solution in THF, 0.255 mmol) was
added dropwise (~30 s/drop) to the stirring solution over ~1ꢀ2 min., yielding a hazy, orange
mixture upon complete addition. The mixture was allowed to stir at room temperature for 2 h,
after which time the reaction mixture was quenched with MeOH (2 mL) in air. The volatiles
were removed from the clear, orange solution under reduced pressure, yielding a paleꢀorange
solid, which was dried under reduced pressure for ~1 h (unoptimized). The solid was then
dissolved in DCM (5 mL), cooled to ~0 °C, then filtered through Celite, eluting with cold (~0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
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7
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0
°
C) DCM (2 x 3 mL). The volatiles were removed from the clear, orange filtrate under reduced
pressure yielding the target complex as an orange solid. Yield: 0.153 g (93%). Anal. Calc’d. for
C H ClNiO P : C, 62.38; H, 7.33; N, 0. Found: C, 62.71; H, 7.47; N, <0.5. A single crystal
35
49
3 2
suitable for Xꢀray diffraction was obtained by slow evaporation of pentane into a toluene
solution of C3 at ~4 °C. As outlined in the text (Figure 3), complex C3 (as prepared above)
exists as four diastereomers in solution, whereas recrystallized samples, when dissolved in
1
solution, initially feature only two of these diastereomers. Even in the latter case, the solution H
1
3
1
and C{ H} NMR spectra for C3 are sufficiently complex so as to preclude meaningful
assignment, given the C ꢀsymmetric nature of each diastereomer of C3; these and related spectra
1
31
1
are provided for reference in the Supporting Information. Bulk C3: P{ H} NMR (202.5 MHz,
CDCl ): δ 53.0 (d, J = 10.6 Hz), 52.0 (d, J = 10.5 Hz), 49.55 (d, J = 20.3 Hz), 49.47 (d, J
3
PP
PP
PP
PP
=
20.6 Hz), 34.9 (d, J = 20.8 Hz), 34.5 (d, J = 20.3 Hz), 20.4 (d, J = 10.6 Hz), 19.1 (d, J =
PP PP PP PP
31
1
1
0.5 Hz). Recrystallized C3: P{ H} NMR (202.5 MHz, CDCl ): δ 53.0 (d, J = 10.4 Hz), 52.0
3
PP
(d, JPP = 10.2 Hz), 20.4 (d, JPP = 10.4 Hz), 19.1 (d, JPP = 10.3 Hz). Further spectroscopic
31
1
31
1
experiments conducted on C3 include: P{ H}ꢀ P{ H} COSY (Figure S12), timeꢀlapsed
3
1
1
31
1
P{ H} NMR spectra of recrystallized C3 (Figure S13), elevatedꢀtemperature P{ H} NMR (in
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C D Cl , Figure S14), and P{ H} NMR saturation transfer experiments (Figure S15), which are
2
2
4
discussed in the Results and Discussion section.
Synthesis of (L4)NiCl . A glass vial was charged with THF (2.6 mL), NiCl (DME) (57.8 mg,
2
2
10
11
12
13
14
15
16
17
18
19
20
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49
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52
53
54
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56
57
58
59
60
0
.263 mmol), L4 (200.0 mg, 0.276 mmol), and a magnetic stir bar, yielding a cloudy, purple
mixture. The mixture was then stirred magnetically at room temperature for 2 hours, after which
time the purple solid was collected on a glass filter frit in air and washed with cold (~0 °C)
pentane (2 x 2 mL). The solid was dissolved off the frit using DCM (15 mL), and was collected.
The volatiles were removed from the clear, dark purple solution under reduced pressure, yielding
1
the target complex a dark purple solid. Yield: 0.132 g (89%). H NMR (500.1 MHz, CDCl ): δ
3
8
.03 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.0 Hz, 1H), 7.56ꢀ7.53 (m, 1H), 7.47 (d, J = 7.0 Hz, 1H),
7.41ꢀ7.37 (m, 2H), 7.34 (d, J = 7.3 Hz, 1H), 7.24 (s, 1H), 7.21ꢀ7.18 (m, 1H), 7.15 (d, J = 7.4 Hz,
H), 7.01 (t, J = 6.8 Hz, 1H), 6.31 (d, J = 6.1 Hz, 1H), 3.62 (br s, 3H), 2.55 (br s, 3H), 1.77 (br s,
1
1
3
1
9H), 1.30 (br s, 9H). C{ H} NMR (125.8 MHz, CDCl ): δ 145.6, 142.9, 137.7, 136.0, 135.8,
3
133.8, 133.3, 132.6, 132.2, 131.94, 131.87, 131.7, 128.5, 126.7, 126.3, 126.0, 41.4, 39.7, 31.8,
3
1
1
31.0, 27.0, 23.9. P{ H} NMR (202.5 MHz, CDCl ): δ 126.6 (br s), 90.7 (br s). Anal. Calc’d. for
3
C H Cl NiP : C, 59.61; H, 6.43; N, 0. Found: C, 59.76; H, 6.01; N, <0.5.
28
36
2
2
Synthesis of (L4)NiCl(o-tolyl), C4. A glass vial was charged with (L4)NiCl (40.0 mg, 0.0709
2
mmol), THF (2 mL), and a magnetic stir bar, yielding a cloudy, purple mixture. Stirring was
initiated, then (oꢀtolyl)MgCl (92.5 ꢀL of a 0.920 M solution in THF, 0.0851 mmol) was added
dropwise (~30 s/drop) to the stirring mixture, affording a clear, brownꢀorange solution upon
complete addition. The solution was then allowed to stir at room temperature for 18 h
(unoptimized), after which time the now darkerꢀcolored solution was quenched with MeOH (1.5
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2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
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mL) in air. The volatiles were removed under reduced pressure, yielding a brownꢀorange solid
residue, which was dried further under reduced pressure for ~1 h (unoptimized). DCM (5 mL)
was then added, and the cloudy, orange mixture was cooled to ~0 °C, and filtered through Celite,
eluting with cold (~0 °C) DCM (3 x 2 mL). The volatiles were removed from the clear, orangeꢀ
brown filtrate under reduced pressure, yielding a brownꢀorange solid. The solid was washed with
cold (~0 °C) pentane (2 x 1 mL) and dried under reduced pressure to afford the target complex.
Yield: 0.040 g (91%). Anal. Calc’d. for C H ClNiP : C, 67.82; H, 6.99; N, 0. Found: C, 67.58;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
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43
2
H, 7.04; N, <0.5. A single crystal suitable for Xꢀray diffraction was obtained by slow evaporation
of pentane into a DCM solution of C4 at ~4 °C. As outlined in the text, complex C4 exists in
solution as two diastereomers, where temperatureꢀdependent line broadening due to hindered
rotation and/or dynamic equilibria involving tetrahedral and square planar species, is also
1
13
1
apparent. As such, the solution H and C{ H} NMR spectra for C4 are sufficiently complex so
3
1
1
as to preclude meaningful assignment; these spectra, as well as variableꢀtemperature P{ H}
3
1
1
NMR for C4 (Figure S22), are provided for reference in the Supporting Information. P{ H}
NMR (202.5 MHz, CDCl ): δ 69.9 (s), 66.9 (d, J = 8.9 Hz), 55.4 (br s), 49.2 (br s).
3
PP
Synthesis of (L5)NiCl . A glass vial was charged with NiCl (DME) (30.0 mg, 0.137 mmol), L5
2
2
(60.0 mg, 0.143 mmol), THF (1.5 mL), and a magnetic stir bar. Stirring was initiated, yielding a
cloudy, redꢀorange mixture after several minutes. The mixture was allowed to stir at room
temperature for 2 h, after which time the mixture was filtered onto a glass filter frit in air, and the
collected orange solid was washed with cold (~0 °C) pentane (2 x 1 mL). The solid was washed
off the frit using DCM (10 mL), and the volatiles were removed from the slightly hazy, redꢀ
orange filtrate yielding an orange solid residue. The solid residue was dissolved in a minimal
amount of DCM and filtered through a short Celite plug. The volatiles were removed from the
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clear, red filtrate yielding the target complex as an orange solid. Yield 0.044 g (56%). H NMR
(500.1 MHz, CDCl ): δ 7.95 (br d, J = 6.7 Hz, 1H), 7.70 (br d, J = 6.3 Hz, 1H), 7.61ꢀ7.57 (m,
3
2
H), 2.64ꢀ2.57 (overlapping m, 4H), 1.86ꢀ1.77 (overlapping m, 8H), 1.70ꢀ1.67 (m, 2H), 1.63 (d,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
1
J = 13.1 Hz, 18H), 1.57 (br s, 2H), 1.36ꢀ1.18 (overlapping m, 6H). C{ H} NMR (125.8 MHz,
PH
CDCl ): δ 135.0, 132.2, 131.2, 130.7, 39.6 (d, J = 13.2 Hz), 38.4 (d, J = 26.7 Hz), 31.8, 30.7,
3
PC
PC
3
1
1
2
9.6, 27.5, 26.0. P{ H} NMR (202.5 MHz, CDCl ): δ 91.9 (br s), 64.4 (br s). Anal. Calc’d. for
3
C H Cl NiP : C, 56.97; H, 8.09; N, 0. Found: C, 56.69; H, 7.83; N, <0.5.
26
44
2
2
Synthesis of (L5)NiCl(o-tolyl), C5. A glass vial was charged with (L5)NiCl (35.0 mg, 0.0638
2
mmol), THF (1 mL), and a magnetic stir bar, yielding a cloudy, redꢀorange mixture. Stirring was
initiated and (oꢀtolyl)MgCl (72.9 ꢀL of a 0.920 M solution in THF, 0.0670 mmol) was then
added dropwise (~30 s/drop) to the stirring solution, yielding a clear, orange solution upon
complete addition. After several minutes, a yellow precipitate formed. The resulting cloudy,
yellow mixture was then stirred at room temperature for 18 h (unoptimized), after which time the
reaction was quenched with MeOH (2 mL) in air. The volatiles were removed under reduced
pressure, yielding a yellow solid residue, which was dried further under vacuum for ~1.5 h. To
the residue was added DCM (5 mL), and the hazy, yellow mixture was cooled to ~0 °C, and
filtered through Celite, eluting with cold (~0 °C) DCM (2 x 3 mL). The volatiles were removed
from the clear, orangeꢀyellow filtrate, yielding the target complex as an orangeꢀyellow solid.
Yield: 0.034 g (87%). A single crystal suitable for Xꢀray diffraction was obtained by slow
1
evaporation of a THF solution of C5 at room temperature. H NMR (500.1 MHz, CDCl ): δ
3
8
.05ꢀ8.03 (m, 1H), 7.66ꢀ7.64 (m, 1H), 7.55ꢀ7.52 (m, 2H), 7.27ꢀ7.25 (overlapping m with CHCl3,
H), 6.87ꢀ6.85 (m, 1H), 6.79ꢀ6.75 (m, 2H), 3.13ꢀ3.11 (m, 1H), 3.05 (s, 3H), 2.65ꢀ2.58 (m, 1H),
1
2.22ꢀ2.14 (m, 1H), 1.86ꢀ1.77 (m, 3H), 1.72ꢀ1.69 (m, 2H), 1.64ꢀ1.58 (m, 10H), 1.53ꢀ1.49 (m,
29
ACS Paragon Plus Environment