PAd2-DalPhos Enables the Nickel-Catalyzed C?N Cross-Coupling of Primary Heteroarylamines and (Hetero)aryl Chlorides

Article abstract of DOI:10.1002/anie.201900095

Base-metal catalysts capable of enabling the assembly of heteroatom-dense molecules by cross-coupling of primary heteroarylamines and (hetero)aryl chlorides, while sought-after given the ubiquity of unsymmetrical di(hetero)arylamino fragments in pharmacophores, are unknown. Herein, we disclose the new “double cage” bisphosphine PAd2-DalPhos (L2). The derived air-stable Ni^II pre-catalyst C2 functions well at low loadings in challenging test C?N cross-couplings with established substrates, and facilitates the first Ni-catalyzed C?N cross-couplings of primary five- or six-membered ring heteroarylamines and activated (hetero)aryl chlorides, with synthetically useful scope that is competitive with Pd catalysis.

Full text of DOI:10.1002/anie.201900095

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Accepted Article
Title: PAd2-DalPhos Enables the Nickel-Catalyzed C-N Cross-
Coupling of Primary Heteroarylamines and (Hetero)aryl Chlorides
Authors: Jillian Clark, Michael Ferguson, Robert McDonald, and Mark
Stradiotto
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900095
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10.1002/anie.201900095
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COMMUNICATION
PAd2-DalPhos Enables the Nickel-Catalyzed C-N Cross-Coupling of
Primary Heteroarylamines and (Hetero)aryl Chlorides
Jillian S. K. Clark,[a] Michael J. Ferguson,[b] Robert McDonald,[b] and Mark Stradiotto*,[a]
Abstract: Base-metal catalysts capable of enabling the assembly of
heteroatom-dense molecules via cross-coupling of primary
heteroarylamines and (hetero)aryl chlorides, while sought-after given
the ubiquity of unsymmetrical di(hetero)arylamino fragments in
pharmacophores, are unknown. Herein, we disclose the new ‘double
cage’ bisphosphine PAd2-DalPhos (L2). The derived air-stable Ni(II)
pre-catalyst C2 functions well at low loadings in challenging test C-N
cross-couplings with established substrates, and facilitates the first Ni-
catalyzed C-N cross-couplings of primary five- or six-membered ring
heteroarylamines and activated (hetero)aryl chlorides, with
synthetically useful scope that is competitive with Pd catalysis.
However, there is growing interest in the use of Ni-based
catalysts in place of Pd for C-N cross-coupling,[5] not only from an
environmental and economic standpoint (although costing of Pd
vs Ni catalysts varies based on the precursor and ligands
involved),[6] but also given the innate propensity of Ni species to
engage electrophilic reaction partners where C-X oxidative
addition is typically challenging (e.g., C-Cl in (hetero)aryl
chlorides[7]). The repurposing of ligands from the early days of
BHA, including bisphosphines[8] such as DPPF[9] and BINAP,[10] is
a commonly employed approach that has enabled the Ni-
catalyzed C-N cross-coupling of some substrate classes.
However, this strategy has proven insufficient in the quest to
match or exceed the performance of state-of-the-art BHA
catalysts. Furthermore, the use of superlative BHA ligands,
including decorated biaryl monophosphines,[3] has in general
proven unsuccessful in facilitating Ni-catalyzed C-N cross-
coupling chemistry.[8]
Given the absence of reports focusing on the rational
development of new ancillary ligands specifically for use in Ni-
catalyzed C-N and related cross-couplings, we envisioned that
sterically demanding and moderately electron-donating
bisphosphines[8] might prove useful in enabling presumptively
challenging C-N reductive elimination within a putative Ni(0)/Ni(II)
cycle.[11] In 2016 we disclosed the new ligand PAd-DalPhos (L1,
Scheme 1B), featuring trioxaphosphaadamantane (PCg) and
di(o-tolyl)phosphino donor fragments spanned by an o-phenylene
bridge.[12] The derived Ni(II) pre-catalyst (L1)Ni(o-tol)Cl has
proven effective in a diversity of C-N cross-coupling applications,
including the monoarylation of ammonia,[12] unhindered primary
alkylamines,[12] primary amides,[13] and lactams,[13] with a wide
range of (hetero)aryl electrophiles. Variation of the PR2 group in
PAd-DalPhos has enabled other challenging C-N cross-couplings,
including the N-arylation of cyclopropylamine[14] and hindered
primary alkylamines[15] (Scheme 1B). We have also demonstrated
that replacing the phenylene backbone of L1 with a 3,4-
thiophenylene linker (i.e., ThioPAd-DaPhos) affords Ni catalysts
for the C-N cross-coupling of unhindered primary alkylamines that
operate under mild conditions (25 ⁰C, <1 mol% Ni), in a manner
that is competitive with BHA.[16]
Over the past 20 years, the Pd-catalyzed cross-coupling of NH
nucleophiles with (hetero)aryl (pseudo)halide electrophiles (i.e.,
Buchwald Hartwig Amination, BHA) has evolved into a first-choice
synthetic protocol for the synthesis of (hetero)anilines.[1] The
development of such protocols can be attributed in part to the use
of sophisticated ancillary ligands[2] (e.g., Buchwald biaryl
monophosphines[3] and others[4]) designed to accommodate
challenging reaction partners, including those featuring extensive
heteroatom substitution, thereby providing access to target
(hetero)anilines possessing useful biological activity (Scheme
1A).[1]
Scheme 1. A. Metal-catalyzed C-N cross-coupling of primary
heteroarylamines and (hetero)aryl chlorides. B. Previously reported
DalPhos ligands for Ni-catalyzed C-N cross-coupling, and the new ‘double
cage’ ligand PAd2-DalPhos (L2) reported in this work.
Despite recent advances in Ni-catalyzed C-N cross-
coupling, the identification of new ancillary ligands/catalysts that
are capable of addressing unmet reactivity challenges remains an
important goal. Encouraged by the success of our PCg-containing
PAd-DalPhos ligands (vide supra), we became interested in
exploring the utility of analogous chelating bisphosphines
featuring two bulky and moderately electron-donating PCg donor
groups. Herein we report on the synthesis and characterization of
such new ‘double cage’ ancillary ligands, including PAd2-DalPhos
(L2, Scheme 1B). Application of air-stable (L2)Ni(o-tol)Cl allows
for previously unknown and sought-after Ni-catalyzed cross-
couplings of primary five- and six-membered ring
heteroarylamines and (hetero)aryl chlorides (Scheme 1A) to be
achieved with synthetically useful scope.
[a]
J. S. K. Clark, Prof. Dr. M. Stradiotto
Department of Chemistry
Dalhousie University
Halifax, Nova Scotia B3H 4R2 (Canada)
E-mail: mark.stradiotto@dal.ca
[b]
Dr. M. J. Ferguson, Dr. R. McDonald
X-ray Crystallography Laboratory, Department of Chemistry
University of Alberta
Edmonton, Alberta T6G 2G2 (Canada)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201YXXXXX.
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New double cage (PCg)2(hetero)arene variants of L1 based
on phenyl (L2), pyridyl (L3), or quinoxalyl (L4) linking fragments
were prepared in synthetically useful yield (Scheme 2A). Owing
to the chiral (racemic) nature of the HPCg starting material, ~1:1
diastereomeric mixtures of air-stable meso (RS,SR) and rac
(RR,SS) L2-L4 were obtained when using the sequential P-C
cross-coupling approach outlined in Scheme 2A; in the case of L2
and L3, the meso and rac diastereomers could be separated in
air by use of column chromatography.[17] The isolated
diastereomers of L2 and L3, and the meso/rac mixture of L4, were
characterized on the basis of solution NMR spectroscopic data
and high-resolution mass spectrometric analysis. Furthermore,
single-crystal X-ray data were successfully obtained for each of
the meso and rac isomers of L2-L4 (see Figures S1-S6). The
synthesis of variants of L2-L4, starting from 3,4-
dibromothiophene under otherwise analogous conditions, proved
to be low-yielding and thus unsuitable for further investigation.
The catalytic competence of the new complexes C2-C4,
versus C1, was assessed initially in challenging room
temperature Ni-catalyzed C-N cross-couplings of the heteroaryl-
containing substrate furfurylamine with aryl chlorides at low
catalyst loadings, leading to the known products 1a-c[16] (Scheme
3). Employing 1.75 mol% C1-C4 with 4-chlorobenzonitrile to give
1a revealed the superiority of C2-C4 (>88% yield) versus C1 (26%
yield) in this reaction. In cross-couplings of 1-chloronaphthalene
using 0.25 mol% Ni, the exceptionally high conversion to 1b
achieved when using C2 or C3 (>93% yield) was contrasted by
the lower productivity of C1 and C4 (61% and 66% yield,
respectively). These entries involving C2 and C3 represent the
first examples of such high-yielding (> 90%), Ni-catalyzed C-N
cross-couplings of aryl chlorides conducted at room temperature
using only 0.25 mol% Ni. Similar trends were noted in cross-
couplings involving 4-chloroanisole using 0.5 mol% catalyst,
whereby C2 and C3 (>95% yield of 1c) outperformed C1 (24%).
Having established C2 and C3 as offering comparably high
catalytic efficiency, for simplicity we narrowed our subsequent
examination of (PCg)2(hetero)arene-based pre-catalysts to the
use of C2. In examining further cross-couplings leading to 1a
using only 0.5 mol% C1 or C2, excellent productivity was attained
with C2 (78% yield), whereas no turnover was achieved using C1.
Collectively, this survey establishes C2 (and C3) as having the
potential to offer superior catalytic performance in these
transformations versus otherwise best-in-class Ni pre-catalysts,
such as C1 and related variants.
Scheme 2. A: Synthesis of L2-L4 using sequential Pd-catalyzed P-C
cross-coupling protocols, as well as C2-C4. B: Single-crystal X-ray
structures of meso-C2 and rac-C2, each represented with thermal
ellipsoids at the 30% probability level, and with hydrogen atoms omitted for
clarity. Selected interatomic distances (Å) and angles (°): for meso-C2: Ni-
P1 2.1791(7), Ni-P2 2.2458(7), Ni-Cl1 2.2177(8), Ni-C31 1.925(3), P1-Ni-
P2 87.99(2), P2-Ni-Cl1 96.33(3), P1-Ni-C31 92.77(8), Cl1-Ni-C31
85.44(8); for rac-C2: Ni-P1 2.1679(10), Ni-P2 2.2402(10), Ni-Cl1
2.1893(11), Ni-C31 1.923(3), P1-Ni-P2 87.34(4), P2-Ni-Cl1 96.22(4), P1-
Ni-C31 93.96(11), Cl1-Ni-C31 84.94(11).
Pre-catalyst complexes of the type (L)Ni(o-tol)Cl often
exhibit improved performance relative to catalytic mixtures formed
in situ from the combination of a metal source (e.g. Ni(COD)2) and
ligand.[18] As such, complexes of this type featuring L2-L4 were
prepared via treatment with NiCl2(DME), followed by
transmetallation of the putative intermediates (L)NiCl2 with (o-
tol)MgCl, to afford C2-C4 as analytically pure, air-stable solids
(Scheme 2A). In addition to the solution NMR spectroscopic
characterization of these complexes, single-crystal X-ray
diffraction data were obtained for meso-C2 and rac-C2 (Scheme
2B), as well as meso-C3 and meso-C4 (see Figures S9 and S10).
In each case, a distorted square planar geometry is observed at
Ni, with the Ni-P distance trans to chloride being shorter than the
Ni-P distance opposite to the more strongly trans-directing o-tolyl
group.
[a]
Scheme 3. Pre-catalyst screening. Estimated conversion to the target
product after 16 h (unoptimized time) on the basis of calibrated GC data
using dodecane and authentic samples of the known products 1a-c as
standards; mass balance corresponds to unreacted starting material;
NaOtBu (2 equiv), toluene (0.12M ArCl), 25 °C; NaOPh (1.2 equiv), 2-
[b]
[c]
MeTHF (0.25M ArCl), 80 °C.
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Encouraged by the outstanding catalytic performance of C2
in known transformations leading to 1a-c, we sought to apply this
pre-catalyst in a desirable class of C-N cross-couplings for which
no broadly effective base-metal catalyst is known. In this regard,
the base-metal cross-coupling of primary five- or six-membered
ring heteroarylamines with (hetero)aryl chlorides to afford
unsymmetrical di(hetero)arylamines represents an attractive
route to heteroatom-dense, biologically active compounds that
exploit relatively inexpensive starting materials (Scheme 1).[19]
Heteroaromatic rings are found commonly in active
pharmaceutical ingredients, owing to their roles as bioisosteres[20]
and enhanced binding affinity with polar functional groups of
proteins. The di(hetero)arylamine motif in particular, formally
derived from primary five-membered ring heteroarylamines, is
featured in a number of commercialized pharmaceuticals,
including dasatanib (leukemia). However, metal-catalyzed C-N
cross-coupling involving such NH nucleophiles has proven to be
significantly more challenging than transformations involving
alkylamines or simple anilines, due in part to the increased acidity
of the amine as a result of adjacent heteroatoms, which can lead
to poor substrate binding and/or slow C-N reductive elimination.[21]
Prior to our work herein, no base-metal catalyst capable of
effecting the cross-coupling of primary five-membered ring
heteroarylamines and (hetero)aryl chlorides with synthetically
useful scope had been disclosed in the literature. In the context
of Pd catalysis, a 2017 report from Buchwald and co-workers[22]
describing the C-N cross-coupling of (hetero)aryl chlorides and
bromides with 2-aminooxazole and 4-aminothiazole using a
Pd/EPhos catalyst (2.0-7.5 mol% Pd; 100 °C) represents the
state-of-the-art for this type of transformation. In light of these
considerations, we compared the performance of C1 and C2, as
well as related pre-catalysts featuring JosiPhos CyPF-Cy,[23]
DPPF,[9a] or XantPhos,[24] which have each been employed
successfully in alternative C-N cross-coupling applications, in the
cross-coupling of 2-aminooxazole and 4-chlorobenzophenone to
give 2a (2.5 mol% Ni, 80 °C; Scheme 3). Under these conditions,
C1 and C2 afforded quantitative conversion to 2a, whereas
negligible catalytic turnover was achieved by use of the other Ni
pre-catalysts. In lowering the loading to 1.5 mol% Ni, 92% yield of
2a was achieved with C2, whereas use of C1 afforded only 30%
yield of 2a. A significant drop-off in conversion was noted upon
lowering the catalyst loading to 1 mol% Ni, whereby negligible
conversion of the starting materials was achieved with C1, and
33% yield of 2a was observed when using C2. Notably, further
screening of this C-N cross-coupling reaction leading to 2a
employing diastereomerically pure meso-C2 or rac-C2 (1 mol%
Ni) revealed the former to be more effective than the latter (with
both being superior to C1) in this particular transformation.
containing ketone (2a) and cyano (2e) functionality proved to be
suitable reaction partners, as did electrophiles featuring extended
or linked aromatic hydrocarbon groups (2j, 2k). Heteroaryl
chlorides based on quinoxaline (2b, 2d), quinoline (2c, 2h),
benzothiazole (2g), and quinaldine (2f, 2i) core structures proved
to be suitable reaction partners, and the successful cross-
coupling of 2-bromo-4-phenylthiazole leading to 2l confirmed the
compatibility of heteroaryl bromides in this chemistry. In keeping
with the trends in Scheme 3, inferior catalytic performance was
observed for C1 versus C2 under analogous conditions in cross-
couplings leading to 2b or 2l. For convenience, the experimental
setup employed in the cross-coupling reactions leading to 2a-2l
involved handling of the air-stable pre-catalyst C2 on the
benchtop, followed by reaction setup within an inert-atmosphere
glovebox. To evaluate the chemoselectivity of C2, and to establish
that glovebox/Schlenk methods are not required for the chemistry
reported
herein,
the
cross-coupling
of
4-chloro-N-
methylpicolinamide and aminopyrazine was conducted under
nitrogen using benchtop-only protocols. The targeted
unsymmetrical di(hetero)arylamino product 2m was obtained in
83% isolated yield.
Scheme 4. Scope of the Ni-catalyzed C-N cross-coupling of primary
[a]
heteroarylamines with (hetero)aryl electrophiles using C2.
Reaction
Encouraged by the utility of C2 in the cross-coupling of 2-
aminooxazole leading to 2a, we turned our attention toward
exploring the scope of reactivity with other heteroarylamines and
(hetero)aryl chlorides (Scheme 4). To avoid substrate-specific
optimization, the diastereomeric mixture of C2 (meso and rac)
was employed at 5 mol% (i.e., the mid-point loading of the
Pd/EPhos catalyst employed by Buchwald and co-workers[22]). 2-
conditions: C2 (5 mol%), electrophile (1 equiv), amine (1.2 equiv), NaOPh
(1.2 equiv), 2-MeTHF (0.25M ArX), 80 °C, 16 h (unoptimized time). Isolated
[b]
yields are reported, unless otherwise indicated.
NMR integrated yield
[c]
using ferrocene as an internal standard in DMSO-d6.
THF used as
solvent, mixture of NaOtBu/PhOH (1.2 equiv each) used as base. [d] NMR
[e]
integrated yield using dodecane as an internal standard in CDCl3.
Starting from the corresponding heteroaryl bromide. [f] In THF.
Some substrate scope limitations were encountered,
Aminooxazole,
2-aminothiazole,
5-amino-1,3-dimethyl-1H-
including
unsuccessful
cross-couplings
of
5-amino-3-
pyrazole, and 2-aminopyridine were each employed successfully
as nucleophiles in combination with our C2 pre-catalyst, affording
products 2a-2l in synthetically useful isolated yield. Aryl chlorides
methylisoxazole with 4-halobenzonitrile (X = Cl or Br), or 3-
chloropyridine with 4-aminopyridine, under conditions outlined in
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Scheme 4. Our efforts to accommodate more complex diamine
substrates, including the cross-coupling of 2,3-diaminopyrazine or
3,4-diaminopyridine with 4,6-dichloro-2-methylaniline, as well as
electrophiles lacking activating groups (i.e., 4-chlorobiphenyl or 4-
chloroanisole with 2-aminothiazole), were similarly unsuccessful.
We independently confirmed via control experiments that
the transformations reported herein proceed negligibly in the
absence of C2 under the conditions employed. For the reaction
leading to 2g, exclusion of C2 resulted in the formation of
substantial quantities of the C-O coupled product arising from
reactivity with the phenoxide base. These results notwithstanding,
our observation that ethyl 2-chlorooxazole carboxylate, 2-
Keywords: amination • bisphosphines • cross-coupling • ligand
design • nickel
[1]
[2]
P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016, 116, 12564.
M. Stradiotto, R. J. Lundgren, Ligand Design in Metal Chemistry:
Reactivity and Catalysis, John Wiley & Sons, Ltd, Chichester, West
Sussex, UK, 2016.
[3]
[4]
D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 6338.
a) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534; b) C. Valente, M.
Pompeo, M. Sayah, M. G. Organ, Org. Process Res. Dev. 2014, 18,
180.
[5]
[6]
M. Marín, R. J. Rama, M. C. Nicasio, Chem. Rec. 2016, 16, 1819.
a) J. D. Hayler, D. K. Leahy, E. M. Simmons, Organometallics 2019, 38,
36; b) S. Z. Tasker, E. A. Standley, T. F. Jamison, Nature 2014, 509,
299.
chlorobenzoxazole,
2-chlorobenzothiazole,
2-chloro-4,6-
dimethoxypyrimidine, and 4-chloro-6,7-dimethoxyquinazoline
afforded C-N coupled (and other) products in selected reactions
with 2-aminothiazole, 2-aminooxazole, and 2-aminopyridine
under the conditions in Scheme 4, but in the absence of C2,
underscores the importance of conducting control experiments in
developing metal-catalyzed cross-coupling methodologies.
In summary, a new class of double cage bisphosphine
ligands, including PAd2-DalPhos (L2), have been developed for
use in addressing outstanding challenges in Ni-catalyzed C-N
cross-coupling. Building on our observation that L2 systematically
outperformed the state-of-the-art parent PAd-DalPhos (L1) in
selected challenging test cross-couplings involving furfurylamine
and 2-aminooxazole as nucleophiles, the L2-derived Ni pre-
catalyst C2 was employed successfully in establishing the first
base-metal cross-coupling of (hetero)aryl chlorides and primary
five- or six-membered ring heteroarylamines, with synthetically
useful scope. Notably, the catalytic performance of the Ni pre-
catalyst C2 in enabling the assembly of sought-after heteroatom-
dense, unsymmetrical di(hetero)arylamines is competitive with
state-of-the-art Pd catalysis, in terms of catalyst loading and
substrate scope, while operating effectively at more milder
reaction temperatures. We are currently exploring the application
of L2 and related ancillary ligands in addressing other outstanding
reactivity challenges in base-metal catalysis, and will disclose our
progress in this regard in future reports.
[7]
[8]
[9]
V. V. Grushin, H. Alper, Chem. Rev. 1994, 94, 1047.
C. M. Lavoie, M. Stradiotto, ACS Catal. 2018, 8, 7228.
a) N. H. Park, G. Teverovskiy, S. L. Buchwald, Org. Lett. 2014, 16, 220;
b) J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 6054.
[10] S. Z. Ge, R. A. Green, J. F. Hartwig, J. Am. Chem. Soc. 2014, 136,
1617.
[11] a) C. M. Lavoie, R. McDonald, E. R. Johnson, M. Stradiotto, Adv.
Synth. Catal. 2017, 359, 2972; b) S. G. Rull, I. Funes-Ardoiz, C. Maya,
F. Maseras, M. R. Fructos, T. R. Belderrain, M. C. Nicasio, ACS Catal.
2018, 8, 3733.
[12] C. M. Lavoie, P. M. MacQueen, N. L. Rotta-Loria, R. S. Sawatzky, A.
Borzenko, A. J. Chisholm, B. K. V. Hargreaves, R. McDonald, M. J.
Ferguson, M. Stradiotto, Nat. Commun. 2016, 7, 11073.
[13] C. M. Lavoie, P. M. MacQueen, M. Stradiotto, Chem. Eur. J. 2016, 22,
18752.
[14] J. P. Tassone, P. M. MacQueen, C. M. Lavoie, M. J. Ferguson, R.
McDonald, M. Stradiotto, ACS Catal. 2017, 7, 6048.
[15] J. P. Tassone, E. V. England, P. M. MacQueen, M. J. Ferguson, M.
Stradiotto, Angew. Chem. Int. Ed. 2019, 58, 2485.
[16] J. S. K. Clark, R. T. McGuire, C. M. Lavoie, M. J. Ferguson, M.
Stradiotto, Organometallics 2019, 38, 167.
[17] We employ 'meso' (RS/SR) and 'rac' (RR/SS) in reference to the
relative handedness of the PCg fragments within the ligands L2-L4.
Complete experimental details and characterization data are provided
in the Supporting Information, and CCDC 1883505-1883514 contain
the supplementary data for the crystallographic characterization of
meso-L2, rac-L2, meso-L3, rac-L3, meso-L4, rac-L4, meso-C2, rac-C2,
meso-C3, and meso-C4.
[18] N. Hazari, P. R. Melvin, M. M. Beromi, Nat. Rev. Chem. 2017, 1, 0025.
[19] D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W. Thomas, D.
M. Wilson, A. Wood, Nat Chem 2018, 10, 383.
Acknowledgements
[20] N. A. Meanwell, J. Med. Chem. 2011, 54, 2529.
[21] M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1997, 119, 8232.
[22] E. P. K. Olsen, P. L. Arrechea, S. L. Buchwald, Angew. Chem. Int. Ed.
2017, 56, 10569.
We are grateful to NSERC of Canada (Discovery Grant for M.S.;
PGS-D for J.S.K.C.), the Killam Trusts, and Dalhousie University
for their support of this work. Cytec/Solvay is thanked for the
donation of HPCg. Repare Therapeutics is thanked for providing
chemicals and instrumentation time during the revision phase of
this manuscript. We also thank M. Yue Shen and Joseph Tassone
for contributions to catalyst screening, as well as Dr. Michael
Lumsden and Mr. Xiao Feng (Dalhousie) for technical assistance
in the acquisition of NMR and MS data.
[23] a) J. S. K. Clark, C. M. Lavoie, P. M. MacQueen, M. J. Ferguson, M.
Stradiotto, Organometallics 2016, 35, 3248; b) P. M. MacQueen, M.
Stradiotto, Synlett 2017, 28, 1652; c) A. Borzenko, N. L. Rotta-Loria, P.
M. MacQueen, C. M. Lavoie, R. McDonald, M. Stradiotto, Angew.
Chem. Int. Ed. 2015, 54, 3773.
[24] E. A. Standley, S. J. Smith, P. Muller, T. F. Jamison, Organometallics
2014, 33, 2012.
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Entry for the Table of Contents
COMMUNICATION
Jillian S. K. Clark, Michael J. Ferguson,
Robert McDonald, and Mark Stradiotto*
Page No. – Page No.
PAd2-DalPhos Enables the Nickel-
Catalyzed C-N Cross-Coupling of
Primary Heteroarylamines and
(Hetero)aryl Chlorides
Cage match: A nickel(II) pre-catalyst featuring the new double cage PAd2-DalPhos
ancillary ligand enables the first examples of Ni-catalyzed C-N cross-couplings of
primary five- or six-membered ring heteroarylamines and (hetero)aryl chlorides with
synthetically useful scope.
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