Evaluating 1,1′-Bis(phosphino)ferrocene Ancillary Ligand Variants in the Nickel-Catalyzed C-N Cross-Coupling of (Hetero)aryl Chlorides

Article abstract of DOI:10.1021/acs.organomet.6b00885

Previous reports in the literature have established the utility of 1,1′-bis(diphenylphosphino)ferrocene (DPPF, L^Ph) in the nickel-catalyzed cross-coupling of (hetero)aryl electrophiles with primary or secondary amines. In an effort to evaluate

Full text of DOI:10.1021/acs.organomet.6b00885

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Evaluating 1,1′-Bis(phosphino)ferrocene Ancillary Ligand Variants in
the Nickel-Catalyzed C−N Cross-Coupling of (Hetero)aryl Chlorides
Jillian S. K. Clark,† Christopher N. Voth,† 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: Previous reports in the literature have established
the utility of 1,1′-bis(diphenylphosphino)ferrocene (DPPF, LPh) in
the nickel-catalyzed cross-coupling of (hetero)aryl electrophiles
with primary or secondary amines. In an effort to evaluate the
effect of varying the PR2-donor groups on catalytic performance in
such transformations, a series of 10 structurally varied 1,1′-
bis(bis(alkyl/aryl)phosphino)ferrocene ancillary ligands (LX) were
systematically examined in selected competitive test cross-
couplings of (hetero)aryl halides with furfurylamine, morpholine,
and indole employing Ni(COD)2/LX catalyst mixtures. In addition
to the excellent performance observed for the parent ligand LPh in a number of the test transformations explored, selected
dialkylphosphino (e.g., DiPPF, LiPr) and meta-disubstituted diarylphosphino variants of LPh also proved highly effective. In
particular, the electron-deficient ligand variant LCF3 featuring 3,5-bis(trifluoromethyl)phenyl groups on phosphorus was found to
exhibit superior catalytic performance relative to LPh in most of the test transformations involving the N-arylation of indole. Our
efforts to prepare Ni(II) precatalysts of the type (LX)Ni(o-tolyl)Cl, in analogy with known (LPh)Ni(o-tolyl)Cl, by employing
several literature methods met with mixed results. Whereas (LiPr)Ni(o-tolyl)Cl was prepared straightforwardly and was
crystallographically characterized, the use of LCF3 or ligands featuring tert-butyl (LtBu), o-tolyl (Lo‑tol), or 4-methoxy-3,5-
dimethylphenyl (LOMe) groups on phosphorus under similar conditions resulted in poor conversion to product and/or the
formation of poorly soluble materials, highlighting the limitations of this commonly used precatalyst design.
Recent efforts to develop base-metal catalysts that offer
competitive reactivity profiles versus palladium has contributed
to the renaissance in nickel C(sp2)−N cross-coupling
chemistry,12 due in part to the lower cost, greater natural
abundance, and desirable catalytic properties of nickel,
including with (hetero)aryl chlorides and phenol-derived
electrophiles.13 The pioneering report on such reactivity by
Wolfe and Buchwald14 documented the cross-coupling of
(hetero)aryl chlorides with selected primary or secondary alkyl/
aryl amines in the presence of Ni(COD)2/LPh mixtures. In the
ensuing 20 years, LPh has remained one of the most effective
ligands for use in nickel-catalyzed C(sp2)−N cross-couplings of
secondary alkylamines or anilines (Scheme 1).15 In keeping
with this ancillary ligand design theme, alternatively configured
bis(phosphine)-ligated nickel catalysts have also been identified
that are particularly effective for the cross-coupling of primary
alkylamines,16 ammonia,16c,17 primary amides/lactams,18 and
beyond.19
1. INTRODUCTION
The ubiquitous nature of substituted (hetero)anilines, within
both biologically active compounds and conjugated materials,
provides motivation for the development of efficient catalytic
C(sp2)−N bond-forming protocols.1 As a complement to
Ullmann cross-couplings employing copper,2 the palladium-
catalyzed cross-coupling of NH substrates and (hetero)aryl
(pseudo)halides (i.e., Buchwald−Hartwig amination,3 BHA)
has emerged as a broadly useful C(sp2)−N bond-forming
methodology.4 Collectively, state of the art catalysts for BHA
accommodate a broad substrate scope, including, but not
restricted to, transformations involving primary and secondary
amines and amides, azoles, and ammonia.4 The successful
development of BHA methods can be attributed in part to the
design of ancillary ligands5 that give rise to suitably reactive and
selective palladium catalytic species. Whereas tris(o-tolyl)-
phosphine,3 racemic 2,2′-bis(diphenylphosphino)-1,1′-bi-
naphthyl (rac-BINAP),6 and 1,1′-bis(diphenylphosphino)-
ferrocene (DPPF, LPh)7 were used as ancillary ligands in the
early development of BHA, in the ensuing years palladium
catalysts supported by more strongly electron donating and
sterically demanding ancillary ligands (e.g., biaryl mono-
phosphines8 and N-heterocyclic carbenes9) have proven to be
particularly effective,4b,10 especially in combination with less
reactive (hetero)aryl chlorides.11
In contrast to palladium-catalyzed BHA chemistry, for which
overarching ancillary ligand design prerequisites are known
(vide supra),4b guiding principles for the steric and electronic
design of ancillary ligands for use in analogous nickel chemistry
Received: November 28, 2016
© XXXX American Chemical Society
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Scheme 1. Prior Nickel-Catalyzed C(sp2)−N Cross-
Coupling Employing DPPF (LPh) and the Competitive
Reactivity Survey Herein
featuring the following (Scheme 1): electron-rich alkylphos-
phines of varying steric bulk (DiPPF, LiPr; DCPF, LCy; DTBPF,
LtBu), a relatively electron rich arylphosphine (LOMe); electron-
poor arylphosphines (LCF3 and HiersoPHOS-3, Lfur), an
electron-neutral meta-disubstituted arylphosphine (LMe), and
bulky ortho-substituted arylphosphines (Lo‑tol and L1‑nap).
Encouraged by the established utility of LPh in the nickel-
catalyzed C(sp2)−N cross-coupling of alkylamines, we opted to
include furfurylamine and morpholine as test substrates.14,15
Whereas (NHC)Ni catalysts have proven to be particularly
effective in the cross-coupling of a range of (hetero)aryl
chlorides and indole derivatives,19i the application of LPh-ligated
nickel catalysts in analogous transformations of aryl chlorides is
limited to the cross-coupling of 4-chlorobenzotrifluoride and
carbazole at 110 °C;15e indeed, to the best of our knowledge no
examples of nickel-catalyzed indole N-arylation at room
temperature are known. In this context, indole was selected
as a potentially more challenging nucleophile for our reactivity
survey. 1-Chloronaphthalene, 4-chlorobenzonitrile, 3-chloroa-
nisole, and 5-chlorobenzo[b]thiophene were employed initially
as representative ortho-disubstituted, para-substituted electron
poor, meta-disubstituted electron poor, and heterocyclic test
electrophiles, respectively. A selection of successful LX variants
was then carried forward in potentially more challenging cross-
couplings involving 4-chloroquinaldine (at room temperature),
1-bromo-4-tert-butylbenzene, hindered 2-chloro-1,4-dimethyl-
benzene, and/or electron-rich 4-chloroanisole. Throughout, our
focus remained on efficiently identifying LX variants that
afforded high conversion to the target monoarylation product
of interest. While for the most part low yields of the target
compound were accompanied by substantial quantities of
unreacted starting materials, in some cases non-negligible
amounts of byproducts possibly arising from hydrodehaloge-
nation, diarylation, and/or aryl transfer from the LX ligand20
were observed but were neither identified nor quantified. To
expedite our catalytic screen, we opted to employ Ni(COD)2/
LX catalyst mixtures, which mandated the use of inert-
atmosphere conditions owing to the air-sensitive nature of
Ni(COD)2. While the requirement of inert-atmosphere
instrumentation has in the past represented a barrier to the
implementation of protocols that make use of Ni(COD)2, Garg
and co-workers22 have recently demonstrated that employing
paraffin-coated Ni(COD)2 capsules allows for the use of more
simple benchtop techniques.
have not yet been firmly established. To contribute toward this
understanding, we became interested in evaluating the
performance of structurally varied 1,1′-bis(bis(alkyl/aryl)-
phosphino)ferrocene ancillary ligand variants of LPh in nickel-
catalyzed C(sp2)−N cross-coupling chemistry, owing to the
privileged nature of this ligand in such transformations (vide
supra). A conceptually related study involving the palladium-
catalyzed amination of aryl bromides with selected primary
alkylamines appeared nearly 20 years ago;20 nonetheless, we
envisioned that the influence of 1,1′-bis(bis(alkyl/aryl)-
phosphino)ferrocene ligation on the performance of nickel in
C(sp2)−N cross-couplings would be distinct from analogous
transformations involving palladium, given the differing sizes,
electronegativities, and redox properties of these metals.13c,21
To the best of our knowledge, the comparison of LPh analogues
in nickel-catalyzed C(sp2)−N cross-couplings is limited to a
single report by Stewart and co-workers15g involving a relatively
small number of DPPF variants in the cross-coupling of 4-
chloroanisole and p-toluidine. We report herein on the results
of our competitive reactivity survey involving 10 variants of LPh
in the nickel-catalyzed C(sp2)−N cross-coupling of the test
nucleophiles furfurylamine, morpholine, and indole in combi-
nation with structurally varied (hetero)aryl chlorides (Scheme
1).
2.2. Nickel-Catalyzed Monoarylation of Furfuryl-
amine. The relative ability of the LX ancillary ligand variants
in Scheme 1 to promote the nickel-catalyzed monoarylation of
furfurylamine was explored initially (Scheme 2). In cross-
couplings with 1-chloronaphthalene or 4-chlorobenzonitrile,
the use of LiPr, LCy, LPh, LCF3, LOMe, or LMe in each case
afforded high conversion to the target products 1a,b.
Conversely, the application of LtBu, Lo‑tol, L1‑nap, or Lfur in all
of the furfurylamine cross-couplings examined gave minimal
conversion to product. The superiority of the diarylphosphino
variants LPh, LCF3, LOMe, and LMe, relative to the dialkylphos-
phino derivatives LiPr and LCy, was apparent in transformations
involving 3-chloroanisole and 5-chlorobenzo[b]thiophene
leading to 1c,d. Collectively, these observations suggest that,
for the nickel-catalyzed monoarylation of primary alkylamines, a
range of electronically diverse LX variants are competent,
including dialkylphosphino (LiPr and LCy), electron-neutral
2. RESULTS AND DISCUSSION
2.1. Selection of Ancillary Ligand Variants and Test
Substrates. While definitive mechanistic data pertaining to
nickel-catalyzed C(sp2)−N cross-couplings employing LPh and
related variants are lacking, we envisioned that the use of
relatively electron rich ancillary ligands might promote
(hetero)aryl chloride oxidative addition; conversely, relatively
electron-poor ancillary ligands may facilitate product-forming
C−N reductive elimination. Furthermore, sterically demanding
ancillary ligands may enhance catalytic performance both by
driving C−N reductive elimination and by discouraging the
formation of putative off-cycle (LX)2Ni-type intermediates.16a
In this context, and in viewing DPPF (LPh) as the parent
ancillary ligand prototype, we targeted the use of variants
(LPh and LMe), electron-poor (LCF3), and electron-rich (LOMe
)
diarylphosphino derivatives. However, LX derivatives featuring
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To place our observations in the context of some related
palladium-catalyzed C(sp2)−N cross-coupling chemistry in-
volving primary alkylamines, Hamann and Hartwig20,23 noted
that while the use of Lo‑tol in place of LPh in some instances
improved selectivity for monoarylation over diarylation,
increased hydrodehalogenation also occurred. These workers
also established that electronic perturbations arising from
arylphosphine substitution in variants of LPh are less
pronounced than in simple monodentate triarylphosphines, in
Scheme 2. Comparative Catalytic Screening in the Nickel-
Catalyzed Monoarylation of Furfurylamine
a
keeping both with the observation that electron-poor (LCF3
)
and electron-rich (LOMe) diarylphosphino derivatives per-
formed similarly to the parent ligand LPh in palladium-catalyzed
amination chemistry20 and with our observations with nickel
herein. Conversely, whereas the use of LtBu afforded negligible
conversion in our survey of nickel-catalyzed cross-couplings of
furfurylamine with (hetero)aryl chlorides (Scheme 2), Hamann
and Hartwig23 found LtBu to be highly effective in analogous
palladium-catalyzed arylations of primary anilines and alkyl-
amines, as well as secondary cyclic dialkylamines such as
morpholine. This latter observation further underscores the
concept that the application of ancillary ligands that perform
well in palladium-catalyzed BHA chemistry is not a universally
effective strategy for the development of effective nickel-
catalyzed C(sp2)−N cross-couplings.16c,17a
2.3. Nickel-Catalyzed N-Arylation of Morpholine.
Morpholine was employed subsequently, under established
literature conditions,15e as a prototypical secondary dialkyl-
amine test substrate in our survey of LX variants in nickel-
catalyzed amine arylation (Scheme 3). Whereas in trans-
formations involving 1-chloronaphthalene leading to 2a the
relatively unhindered diarylphosphino derivatives LPh, LCF3
,
LOMe, and LMe proved most effective, a much larger collection
of the LX ancillary ligands surveyed performed well in cross-
couplings of 4-chlorobenzonitrile leading to 2b. Indeed, the
cross-coupling of morpholine and 4-chlorobenzonitrile repre-
sents the only substrate pairing throughout our entire study in
which LtBu, Lo‑tol, and L1‑nap perform in a competitive manner
relative to other effective LX variants. When 3-chloroanisole was
used, a different collection of ligands afforded ≥80% conversion
to 2c (LiPr, LCy, LPh, and LMe), with LCF3 and LOMe proving
somewhat less effective. A similar trend was observed in the
cross-coupling of 5-chlorobenzo[b]thiophene to give 2d, with
the exception that LOMe, but not LCF3, proved competitive with
LiPr, LCy, LPh, and LMe.
a
Estimated conversion to product after 16 h (unoptimized) on the
basis of calibrated GC data, with isolated yields in parentheses (unless
b
c
otherwise indicated). Conducted at 25 °C. Using 10 mol % Ni/LX.
d
1
Calculated yield on the basis of H NMR data.
A selection of effective LX variants were then carried forward
and applied in nickel-catalyzed cross-couplings of morpholine
with more challenging electrophiles, leading to products 2e−h
(Scheme 3). While in all cases LPh and/or LMe provided
optimal catalytic performance, it worth noting that the hindered
and modestly electron rich 2-chloro-1,4-dimethylbenzene
proved particularly challenging (≤50% conversion to 2g for
all LX variants).
2.4. Nickel-Catalyzed N-Arylation of Indole. The nickel-
catalyzed N-arylation of indoles and related derivatives
continues to represent a particularly challenging transforma-
tion.12 The most broadly effective nickel catalyst for such
reactions is (IPr)Ni(styrene)2 (5−10 mol % of Ni, 110 °C),
which has been shown to accommodate a range of (hetero)aryl
chlorides.19i Conversely, the feasibility of conducting such aryl
chloride aminations employing LX ancillary ligands is restricted
to a single entry involving the cross-coupling of the unhindered
and electronically activated electrophile 4-chlorobenzotrifluor-
ide with carbazole using LPh at elevated temperatures.15e As
sterically demanding phosphorus donor groups (e.g., LtBu, Lo‑tol
,
and L1‑nap), are incompatible with such transformations. Similar
trends were observed by Stewart and co-workers15g in their
study of LPh variants in the nickel-catalyzed cross-coupling of 4-
chloroanisole and p-toluidine. The poor performance of LtBu
and Lo‑tol may be related to difficulty in accessing putative
(LX)Ni(aryl)Cl intermediates, in keeping with our inability to
synthesize (LX)Ni(o-tolyl)Cl precatalysts derived from these
ancillary ligands (see section 2.5).
We then turned our attention to what we envisioned were
potentially more challenging nickel-catalyzed cross-couplings of
4-chloroquinaldine (at room temperature), or ortho-disubsti-
tuted 2-chloro-1,4-dimethylbenzene, with furfurylamine leading
to 1e,f, employing LX variants that performed well in the
formation of 1a−d (Scheme 2). Whereas LiPr gave low
conversion to products 1e,f, the arylphosphine derivatives
LPh, LCF3, LOMe, and LMe in general performed well (>80%);
modest deviation from this trend was observed in the lower
conversion to 1f (60%) that was achieved by use of LOMe
.
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Scheme 3. Comparative Catalytic Screening in the Nickel-
Catalyzed N-Arylation of Morpholine
Scheme 4. Comparative Catalytic Screening in the Nickel-
Catalyzed N-Arylation of Indole
a
a
a
a
Estimated conversion to product after 16 h (unoptimized) on the
Estimated conversion to product after 16 h (unoptimized) on the
basis of calibrated GC data, with isolated yields in parentheses.
basis of calibrated GC data, with isolated yields in parentheses.
b
c
b
c
d
Conducted at 25 °C. From the aryl bromide.
Conducted at 25 °C. From the aryl bromide. Using 2.5 mol % of
e
f
Ni/LX. Using 10 mol % of Ni/LX. Using 5 mol % of Ni/LX.
such, we viewed the nickel-catalyzed cross-coupling of indole
with sterically and electronically varied (hetero)aryl chlorides
leading to 3a−f as offering an intriguing context in which to
compare the catalytic utility of LX variants (Scheme 4).
The remarkable utility of the electron-poor ancillary ligand
LCF3 in the nickel-catalyzed N-arylation of indole was apparent
in reactions involving 1-chloronaphthalene, whereby only this
variant afforded the target product 3a in high yield. In contrast,
cross-couplings employing less challenging 4-chlorobenzo-
nitrile, leading to 3b, proceeded effectively with several LX
variants, including LiPr, LCy, LPh, LCF3, LOMe, and LMe. In
keeping with our previous reaction surveys involving furfuryl-
amine and morpholine (vide supra), consistently inferior
performance was noted for LtBu, Lo‑tol, L1‑nap, and Lfur in each
of the indole cross-couplings examined.
nature of these ligands relative to LPh and LCF3 in the formation
of 3b. Formation of 3d, derived from 5-chlorobenzo[b]-
thiophene, in ≥90% yield was achieved by use of LPh, LCF3
LOMe, or LMe exclusively.
,
We then employed a focused set of ancillary ligands (i.e., LiPr,
LPh, LCF3, LOMe, and LMe) in subsequent reactivity studies
involving more challenging transformations of 4-chloroquinal-
dine, 1-bromo-4-tert-butylbenzene, 4-chloroanisole, and 2-
chloro-1,4-dimethylbenzene, leading to 3e−h, respectively.
The parent ligand LPh proved superior in the formation of
3e; to the best of our knowledge, this transformation represents
the first room-temperature N-arylation of indole employing an
aryl chloride electrophile by any catalyst (i.e., Cu, Pd, Ni, or
other). With the exception of transformations employing LCF3
or LMe in the formation of 3g, and LCF3 or LOMe in the
formation of 3h, modest conversion to 3f−h (≤60%) was
achieved throughout. The successful nickel-catalyzed cross-
coupling leading to 3g observed herein warrants further
Amination of 3-chloroanisole to form 3c was brought about
most successfully by use of LCF3, followed by LPh and the two
dialkylphosphine derivatives LiPr and LCy; the observation that
LOMe and LMe afforded comparatively lower conversion to 3c
was somewhat surprising, given the otherwise competitive
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commentary. The only analogous C(sp2)−N cross-coupling
reaction leading to 3g of which we are aware was claimed by
Buchwald and co-workers,24 whereby 2-bromo-1,4-dimethyl-
benzene was employed in the presence of a Pd2(dba)3/
binaphthylmonophosphine catalyst system (5 mol % of Pd, 120
°C, 87% isolated yield 3g). In this regard, the first high-yielding
formation of 3g from an aryl chloride by use of Ni(COD)2/
LCF3 (10 mol % Ni, 110 °C) is noteworthy.
survey (vide supra), may arise due to the poor ligating
properties of these sterically demanding ligands with nickel
and/or their inability to support putative (LX)Ni0 species that
undergo oxidative addition of (hetero)aryl chlorides. The
problematic nature of preparing alternative (bisphosphine)Ni-
(o-tolyl)Cl complexes featuring sterically demanding P(o-tolyl)2
or P(tBu)2 donor fragments has been described.25
Difficulties were also encountered in our efforts to prepare
(LX)Ni(o-tolyl)Cl precatalysts using LCF3 or LOMe. Our most
promising, albeit low-yielding (<30%), results were obtained by
treatment of LCF3 with (TMEDA)Ni(o-tolyl)Cl or via
formation of the putative intermediate (LOMe)NiCl2 followed
by exposure to (o-tolyl)MgCl. In both cases, yellow-orange
solids were obtained that proved competent in a selection of
the C(sp2)−N cross-couplings presented herein. Nonetheless,
the remarkably poor solubility of these presumed (LX)Ni(o-
tolyl)Cl complexes derived from LCF3 or LOMe in a range of
solvents thwarted our efforts to properly characterize these
materials.
2.5. Attempted Precatalyst Syntheses. Interest in the
application of well-characterized LnNi(aryl)X precatalysts in
place of Ni(COD)2/Ln mixtures arises from the fact that such
nickel(II) species are typically air stable and can be reduced
directly under catalytic conditions;25 moreover, the potentially
inhibiting effect of COD is also avoided.26 In the context of our
ancillary ligand survey herein, Buchwald and co-workers15e have
demonstrated that (LPh)Ni(o-tolyl)Cl is particularly effective in
nickel C(sp2)−N cross-couplings. In this vein, we sought to
prepare new (LX)Ni(o-tolyl)Cl variants so as to compare
directly their catalytic abilities. The synthetic methods that we
envisioned might be effective in this regard included the
following: formation of (LX)NiCl2 followed by treatment with
(o-tolyl)MgCl,25 ligand displacement by LX starting from
(TMEDA)Ni(o-tolyl)Cl15h,19l or (PPh3)2Ni(o-tolyl)Cl,15e and
exposure of LX to Ni(COD)2 followed by addition of 2-
chlorotoluene. We were pleased to find that our preliminary
attempt employing the first of these methods proved suitable
for the synthesis of diamagnetic (LiPr)Ni(o-tolyl)Cl, which was
obtained as an air-stable analytically pure solid. The single-
crystal X-ray structure of (LiPr)Ni(o-tolyl)Cl is presented in
Figure 1 and features what is best described as a distorted-
3. CONCLUSIONS
In summary, our comparative reactivity survey involving 10
structurally varied 1,1′-bis(bis(alkyl/aryl)phosphino)ferrocene
ancillary ligands (LX) in the nickel-catalyzed C(sp2)−N cross-
coupling of furfurylamine, morpholine, or indole with various
(hetero)aryl halides using Ni(COD)2 revealed some informa-
tive structure−reactivity trends. Whereas ortho-disubstituted
diarylphosphino (Lo‑tol and L1‑nap), sterically demanding
dialkylphosphino (LtBu), and difuranylphosphino (Lfur) variants
proved ineffective, the parent ligand LPh, less sterically
demanding dialkylphosphino (LiPr and LCy), and meta-
disubstituted diarylphosphino (LCF3, LOMe, and LMe) ancillary
ligands proved competent in several of the test reactions
employed. Particularly challenging cross-couplings such as the
room-temperature amination of 4-chloroquinaldine, or reac-
tions involving ortho-disubstituted electrophiles revealed the
superiority of the diarylphosphino ancillary ligand subclass
(LPh, LCF3, LOMe, and LMe); in the case of indole N-arylation,
the electron-poor variant LCF3 proved particularly effective. The
comparable catalytic performance of LPh, LCF3, and LOMe in
several of the nickel-catalyzed C(sp2)−N cross-couplings
examined herein suggests that any electronic perturbations
arising from arylphosphine substitution do not markedly
influence the behavior of nickel in this chemistry, in keeping
with prior observations in related metal-catalyzed aminations.
However, the poor performance of LtBu in the nickel-catalyzed
transformations reported herein contrasts the outstanding
ability of this ancillary ligand in enabling palladium-catalyzed
arylations of primary anilines and alkylamines, highlighting the
sometimes divergent ancillary ligand preferences of nickel and
palladium in C(sp2)−N cross-couplings.
Figure 1. Single-crystal X-ray structure of (LiPr)Ni(o-tolyl)Cl, shown
with 30% thermal ellipsoids and with hydrogen atoms omitted for
clarity. Selected interatomic distances (Å) and angles (deg): Ni−P1
2.1888(4), Ni−P2 2.1927(4), Ni−Cl 2.2462(4), Ni−C(aryl)
1.8993(13),; P1−Ni−P2 144.863(16), P1−Ni−C(aryl) 91.99(4),
P2−Ni−Cl 90.57(4), Cl−Ni−C(aryl) 166.54(4).
Whereas the synthesis of (LPh)Ni(o-tolyl)Cl and related
nickel(II) compounds has been described previously in the
literature, our efforts to prepare analogous LX ancillary ligand
derivatives met with limited success. Whereas (LiPr)Ni(o-tolyl)
Cl was prepared straightforwardly and crystallographically
characterized, the use of LCF3, LtBu, Lo‑tol, or LOMe under
similar conditions resulted in poor conversion to product and/
or the formation of highly insoluble materials. Notwithstanding
the utility of LnNi(aryl)X precatalysts, these results bring to
light practical limitations of this design strategy.
square-planar geometry, involving a trans-spanning LiPr ligand;
the trans coordination of LiPr is consistent with the observation
of a single 31P NMR resonance. Whereas the structural features
of (LiPr)Ni(o-tolyl)Cl mirror those in (LCy)Ni(o-tolyl)Cl,25
(LPh)Ni(o-tolyl)Cl15e features cis-ligated bis(phosphine) liga-
tion. Unfortunately, we were unsuccessful in preparing
analogous complexes featuring LtBu and Lo‑tol, despite
exhaustive efforts employing the synthetic protocols outlined
above. Our inability to synthesize (LX)Ni(o-tolyl)Cl complexes
of LtBu and Lo‑tol, and their poor performance in our catalytic
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product was isolated in 35% yield (221 mg, 0.30 mmol) as a light
4. EXPERIMENTAL SECTION
1
orange solid. H NMR (500 MHz, CDCl3): δ 6.97−6.94 (m, 12H),
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,
hexanes, 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 cyclopentyl methyl ether (CPME)
was sparged with nitrogen gas 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. With the exception of
bis(3,5-dimethyl-4-methoxyphenyl)chlorophosphine, which was pre-
pared as per literature methods,27 all chlorophosphines as well as LPh,
LiPr, LCy, LtBu, and Lfur were obtained from Strem Chemicals. The
4.27−4.26 (m, 4H), 4.04−4.03 (m, 4H), 2.27 (s, 24H). 13C{1H} NMR
(125.8 MHz, CDCl3): δ 138.7 (d, J = 7.6 Hz), 137.8 (d, J = 6.3 Hz),
131.7, 131.5, 130.7, 74.0 (d, J = 13.8 Hz), 72.8, 21.8. 31P{1H} NMR
(202.5 MHz, CDCl3): δ −16.9. HRMS: m/z ESI+ found 667.2340 [M
+ H]+, calculated for C42H45FeP2 667.2346.
4.4. Synthesis of (LiPr)Ni(o-tolyl)Cl. Within a glovebox, a vial
containing a magnetic stir bar was charged with NiCl2(DME) (0.088 g,
0.4 mmol) and 1,1′-(bis(diisopropylphenyl)phosphino)ferrocene
(0.176 g, 0.42 mmol). To the solid mixture was added tetrahydrofuran
(4 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 pentane (4 mL), thereby generating a precipitate. The solid was
isolated via suction filtration, washed with pentane (5 × 2 mL), and
dried in vacuo to afford the presumptive intermediate product
(DiPPF)NiCl2 as a dark green solid (0.18 g, 0.34 mmol, 83%), which
was used without further purification. Within an inert-atmosphere
glovebox, the isolated (DiPPF)NiCl2 (0.18 g, 0.34 mmol) was
transferred to a vial containing a magnetic stir bar, followed by the
addition of THF (3.4 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; 0.41 mL); the mixture was warmed
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 (∼ −90 °C; 0.5 mL)
and cold pentane (∼−90 °C; 2 mL), thereby generating a precipitate.
The solid was isolated via suction filtration and washed with cold
methanol (∼−90 °C; 4 × 1 mL) followed by cold pentane (∼−90 °C;
5 × 2 mL). The resulting material was dried in vacuo to afford the
product as a dark red-orange solid (0.12 g, 0.2 mmol, 57%). A single
crystal suitable for X-ray diffraction was obtained via vapor diffusion of
diethyl ether into a dichloromethane solution of the target complex.
1H NMR (500 MHz; CDCl3): δ 7.17 (m, 1H), 6.74−6.70 (m, 3H),
4.64−4.36 (m, 8H), 3.61 (s, 3H), 3.09 (m, 2H), 1.69 (m, 2H), 1.50−
1.48 (m, 6H), 1.10−0.97 (m, 12H), 0.38−0.36 (m, 6H). 13C{1H}
NMR (125.8 MHz; CDCl3; quaternary carbons not observed despite
prolonged acquisition times): δ 136.0, 125.9, 124.0, 122.0, 72.8, 71.7,
70.8, 69.7, 27.0, 25.1−24.9 (overlapping), 24.0, 21.1, 19.6, 17.5.
31P{1H} NMR (202.5 MHz; CDCl3): δ 0.26 (s). Anal. Calcd for
20
20
28
known ligands Lo‑tol
,
LCF3
,
and L1‑nap
,
were synthesized in a
manner analogous to that described below for LOMe and LMe, via
quenching of dilithiated ferrocene prepared in situ using literature
methods28 with 2 equiv of the appropriate ClPR2 reagent, employing
modified literature protocols.20 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).
1H 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, broad; s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet. Mass spectra were
obtained using ion trap (ESI) instruments operating in positive mode.
4.2. Synthesis of 1,1′-(Bis(bis(3,5-dimethyl-4-
methoxyphenyl))phosphino)ferrocene (LOMe). Within a glovebox,
a vial containing a magnetic stir bar was charged with ferrocene (167
mg, 0.9 mmol), tetramethylethylenediamine (283 μL, 1.89 mmol), and
hexanes (3.74 mL), and magnetic stirring was initiated. To the vial was
added dropwise n-butyllithium (2.5 M in hexanes, 756 μL, 1.89
mmol), and the resulting mixture was stirred at ambient temperature
for 12 h. In a separate vial, bis(3,5-dimethyl-4-methoxyphenyl)-
chlorophosphine (637 mg, 1.89 mmol) was treated with tetrahy-
drofuran (1.2 mL); we found this chlorophosphine to be poorly
soluble in this and other common solvents. Both the chlorophosphine
mixture and the dilithioferrocene mixture were cooled to −33 °C. To
the stirring dilithioferrocene mixture was added the chlorophosphine
mixture dropwise, and the resulting mixture was then stirred until full
consumption of the chlorophosphine was confirmed on the basis of
31P{1H} NMR data obtained from a reaction aliquot (ca. 2 h). The
reaction mixture was then concentrated in vacuo and purified by flash
column chromatography on silica gel using a gradient eluent: starting
with hexanes (∼200 mL), 49/1 hexanes/ethyl acetate (∼200 mL), 24/
1 hexanes/ethyl acetate (∼400 mL) and finishing with 15.7/1
hexanes/ethyl acetate. The product was isolated in 30% yield (210
mg, 0.27 mmol) as a light orange solid. 1H NMR (500 MHz, CDCl3):
δ 6.97−6.96 (m, 8H), 4.20 (m, 4H), 4.03 (m, 4H), 3.71 (s, 12H), 2.22
(s, 24H). 13C{1H} NMR (125.8 MHz, CDCl3): δ 157.6, 134.1 (d, J =
20.1 Hz), 135.5, 130.7, 130.6, 73.6 (d, J = 13.8 Hz), 72.3, 59.8, 16.3.
31P{1H} NMR (202.5 MHz; CDCl3): δ −19.1. HRMS: m/z ESI+
C29H43Cl1Fe1Ni1P2: C, 57.71; H, 7.18; N, 0. Found: C, 57.33; H, 6.80;
N, <0.5.
4.5. General Procedure for the Monoarylation of Furfuryl-
amine with Aryl Halides (GP1). Within a glovebox, bis-
(cyclooctadiene)nickel(0) (0.05 equiv), LX (0.05 equiv), NaOtBu
(2.0 equiv), aryl halide (1.0 equiv), and toluene (0.12 M of aryl halide)
were placed in a screw-capped vial containing a magnetic stir bar,
followed by the addition of furfurylamine (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 the mixtures were
cooled to room temperature, reactions were monitored using both
TLC and calibrated GC methods. The product was isolated or
analyzed by using Workup Method A or Workup Method B.
4.6. General Procedure for the Arylation of Morpholine with
Aryl Halides (GP2). Within a glovebox, bis(cyclooctadiene)nickel(0)
(0.05 equiv), LX (0.05 equiv), LiOtBu (1.5 equiv), aryl halide (1.0
equiv), and cyclopentyl methyl ether (0.5 M of aryl halide) were
placed in 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 25
or 100 °C for 16 h. After the mixtures were cooled to room
temperature, reactions were monitored using both TLC and calibrated
GC methods. The product was isolated or analyzed by using Workup
Method A or Workup Method B.
found 787.2763 [M + H]+, calculated for C46H53FeO4P2 787.2769.
4.3. Synthesis of 1,1′-(Bis(3,5-dimethylphenyl)phosphino)-
ferrocene (LMe). A protocol directly analogous to that described for
the synthesis of LOMe was employed, using ferrocene (148 mg, 0.85
mmol), tetramethylethylenediamine (268 μL, 1.79 mmol), n-
butyllithium (2.5 M in hexanes, 714 μL, 1.79 mmol), and bis(3,5-
dimethylphenyl)chlorophosphine (494 mg, 1.79 mmol). The reaction
mixture was then concentrated in vacuo and purified by flash column
chromatography on silica gel using a gradient eluent: starting with
hexanes (∼200 mL), 99/1 hexanes/ethyl acetate (∼200 mL), 49/1
hexanes/ethyl acetate (∼200 mL), 32.3/1 hexanes/ethyl acetate
(∼200 mL), and finishing with 24/1 hexanes/ethyl acetate. The
4.7. General Procedure for the Arylation of Indole with Aryl
halides (GP3). Within a glovebox, bis(cyclooctadiene)nickel(0) (0.05
equiv), LX (0.05 equiv), LiOtBu (1.5 equiv), aryl halide (1.0 equiv),
F
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Organometallics
Article
and toluene (0.12 M of aryl halide) were placed in a screw-capped vial
containing a magnetic stir bar, followed by the addition of indole (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 25 or 110 °C for 16 h. After the
mixtures were cooled to room temperature, reactions were monitored
using both TLC and calibrated GC methods. The product was isolated
or analyzed by using Workup Method A or Workup Method B.
4.8. Workup Method A (Purification by Chromatography).
Following GP1, GP2, or GP3 (employing between 0.6 and 1.0 mmol
of aryl halide), after it was cooled to room temperature, the reaction
mixture was diluted with ethyl acetate (ca. 30 mL) and washed with
brine (3 × ca. 30 mL) and the organic layer was dried over sodium
sulfate. The solvent was removed in vacuo, and the compound was
purified by flash column chromatography on silica gel.
ACKNOWLEDGMENTS
■
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. C.N.V. acknowledges
NSERC-CREATE Sustainable Synthesis for supporting an
internship in the Stradiotto group. Dr. Michael Lumsden
(NMR-3, Dalhousie) is thanked for ongoing technical
assistance in the acquisition of NMR data, and Mr. Xiao
Feng (Maritime Mass Spectrometry Laboratories, Dalhousie) is
thanked for technical assistance in the acquisition of mass
spectrometric data.
4.9. Workup Method B (Procedure for the Preparation of GC
Samples). Following GP1, GP2, or GP3 (employing 0.12 mmol of
aryl halide), after it was cooled to room temperature, the reaction
mixture was diluted using ethyl acetate and was passed through a
Kimwipe filter containing a Celite/silica gel pad into a GC vial.
Calibrated GC estimates are given by comparison to authentic
samples.
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Corresponding Author
*E-mail for M.S.: mark.stradiotto@dal.ca.
ORCID
Michael J. Ferguson: 0000-0002-5221-4401
Mark Stradiotto: 0000-0002-6913-5160
Notes
The authors declare no competing financial interest.
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