Development of an air-stable, broadly applicable nickel source for nickel-catalyzed cross-coupling

Article abstract of DOI:10.1021/acscatal.5b00498

The synthesis of NiCl(o-tolyl)(TMEDA) (3; TMEDA = tetramethylethylenediamine) and its application in coupling reactions is described. In combination with a suitable ligand, precatalyst 3 was applied to a wide range of transformations, such as Suzuki, amination, Kumada, Negishi, Heck, borylation, and reductive coupling. Yields of products obtained with 3 are equal or superior to those obtained with common Ni sources such as Ni(cod)₂ (1) and NiCl₂(dme) (2). Importantly, and unlike 1, complex 3 is stable for months in air as a solid, which eliminates the need for a glovebox and greatly facilitates the reaction setup. Thus, complex 3 is the first highly versatile Ni source that combines the broad applicability of 1 with the air stability of 2.

Full text of DOI:10.1021/acscatal.5b00498

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Letter
Development of an Air-Stable, Broadly Applicable
Nickel Source for Nickel-Catalyzed Cross-Coupling
Javier Magano, and Sebastien Monfette
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b00498 • Publication Date (Web): 17 Apr 2015
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Development of an Air-Stable, Broadly Applicable Nickel
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Javier Magano and Sebastien Monfette*
Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
KEYWORDS: cross-coupling, Nickel, precatalyst, air stability, homogeneous catalysis.
ABSTRACT: The synthesis of NiCl(o-tolyl)(TMEDA) (3) and its application in coupling reactions is described. In combination
with a suitable ligand, precatalyst 3 was applied to a wide range of transformations, such as Suzuki, amination, Kumada, Negishi,
Heck, borylation and reductive coupling. Yields of products obtained with 3 are equal or superior to those obtained with common
Ni sources such as Ni(cod)2 (1) and NiCl2(dme) (2). Importantly, and unlike 1, complex 3 is stable for months in air as a solid,
which eliminates the need for a glovebox and greatly facilitates the reaction setup. Thus, complex 3 is the first highly versatile Ni
source that combines the broad applicability of 1 with the air stability of 2.
Transition metal-catalyzed cross-coupling reactions are now
well established methods for C–C and C–heteroatom bond
formation.1 Palladium is by far the most prevalent transition
metal in cross-coupling chemistry due to its ability to catalyze
a broad range of transformations. However, some of the cave-
ats associated with the use of this metal are its high cost,2 tox-
icity (which requires stringent controls to minimize its levels
in drug manufacturing),3 and questionable long-term supply.4
As a result, research on the application of first row metals (Fe,
Ni, Cu) in cross-coupling has received considerable attention
in recent years. In particular, Ni has been applied to a broad
range of transformations5 and shows great promise as a viable
alternative to Pd.5,6
catalyze several types of coupling reactions (Chart 1).11 While
these precatalysts show good substrate scope, they are not
suitable Ni sources for HTE since the built-in phosphine will
inevitably compete with an added external ligand for the Ni
center, thereby leading to questionable screening results.
Chart 1. Recently reported well-defined Ni precatalysts
The broad application of cross-coupling chemistry, especial-
ly in industrial settings,7 has been facilitated by the availability
of automated equipment. Thus, high-throughput experimenta-
tion (HTE) has received increasing attention as a means to
solve specific problems by carrying out a very large number of
microscale reactions to cover a broad reaction space.8 Critical
for accomplishing this goal is the need for metal sources that,
in combination with a large number of ligands, can test a com-
prehensive set of reaction conditions. Ideally, the metal source
should be air, moisture, and thermally stable and readily avail-
able from commercial sources. Pd(OAc)2 and Ni(cod)2 (1; cod
= 1,5-cyclooctadiene) are typically the “go-to” metal sources
for cross-coupling screening. However, the high air and ther-
mal sensitivities of 1 are significant drawbacks that limit its
With the intention of facilitating the incorporation of Ni ca-
talysis in the complex cross-couplings prevalent in the phar-
maceutical industry, we set out to develop a stable Ni source
amenable to HTE that would combine the advantages of com-
plexes 1 and 2. We set a number of desirable properties for
this new Ni source: a) easy to prepare on multi-gram quanti-
ties; b) air and moisture stable; c) highly soluble and stable in
solution over several hours to allow stock solution preparation
and dispensing; d) inexpensive. The recently published precat-
alysts by the Jamison and Buchwald groups both showcase the
“NiCl(o-
use outside of
a glovebox environment. In contrast,
NiCl2(dme) (2) is an air-stable, non-hygroscopic solid that has
been used extensively by Fu and co-workers,9 amongst oth-
ers.10 Nevertheless, the low solubility of 2 in many organic
solvents, which dramatically slows down its handling by ro-
botic equipment, the necessity to add external reductants in,
e.g., amination and Heck reactions, and the uncertainty regard-
ing the extent and timeframe of complexation with an external
ligand (given its low solubility) makes 2 unattractive for HTE.
Recently the groups of Hartwig, Buchwald, and Jamison have
described a series of air-stable Ni-phosphine complexes that
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Table 1. Coupling yieldsa using Ni sources 1, 2 and 3.
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a
Yields determined by ultra-performance liquid chromatography (UPLC) analysis or NMR spectroscopy.
tolyl)” structural element. We therefore sought to conserve
these anionic ligands and complete the coordination sphere of
the metal by a placeholder ligand that would be readily dis-
placed upon addition of a second ligand, such as a phosphine.
Here we report the synthesis and application of NiCl(o-
tolyl)(TMEDA) (3; TMEDA = tetramethylethylenediamine) to
a variety of cross-coupling reactions of relevance to the phar-
maceutical industry. Complex 3 is the first well-defined Ni
precatalyst that combines the broad applicability of Ni(0) 1
with the air and moisture stability of Ni(II) 2.
months as a solid under air at RT (vide infra). Importantly, and
in sharp contrast to the related NiCl(Ph)(TMEDA)12 for which
we observed rapid decomposition and formation of biphenyl
(see Supporting Information), complex 3 is stable as a solution
in a variety of common organic solvents under nitrogen, in-
cluding methylene chloride, at RT for at least 24 hours, which
is critical to its application in HTE, as noted above.
We next tested the applicability of complex 3 as a metal
source in a variety of different coupling reactions (Table 1)
and compared the performance of 3 against the established
complexes 1 and 2. We purposely chose unoptimized reactions
conditions that do not provide quantitative yield of the desired
product to elicit any differences between Ni sources 1–3. As-
suming that all three precatalysts should funnel toward the
same active species during catalysis and that the stabilizing
ligand (cod, dme or TMEDA) acts as a spectator, the yields of
coupling product should be identical, within experimental
error, for complexes 1–3.5a,14 All reactions were carried out in
a N2-filled glovebox given the high air/moisture sensitivity of
complex 1 and the reaction yields were assessed by ultra-
performance liquid chromatography (UPLC) analysis or NMR
spectroscopy.
Scheme 1. Synthesis of complex 3
Complex 3 was prepared in a manner analogous to that re-
ported by Grushin and coworkers (Scheme 1).12 Specifically, a
suspension of Ni(cod)2 and TMEDA in 2-chlorotoluene was
stirred at RT for 3 days under nitrogen over which time the
color of the suspension changed to dark orange. Addition of
hexanes followed by filtration in air allowed for the isolation
of complex 3 in 91% yield as a dark orange, fluffy powder.
Importantly, complex 3 will shortly be commercially availa-
ble.13 The structure of diamagnetic 3 is supported by NMR and
combustion analyses. Complex 3 is indefinitely stable as a
solid under a dinitrogen atmosphere at RT and for over six
Suzuki-Miyaura coupling involving sp2 (entry 1)15 and sp3
(entry 2)16 halides as well as activated phenols as electrophiles
(entry 3)17 afforded the desired product in equal or superior
yields to those reported with either 1 or 2. The nearly identical
yields between 1 and 3 suggests that both phosphine and phe-
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nanthroline ligands readily replace the TMEDA ligand within nificantly lower yield (27%) was observed with 1. Interesting-
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3. Importantly, dichloride 2 provided substantially lower yield
of the desired biphenyl product (entry 1) and was totally inef-
fective in the sp2-sp3 Suzuki coupling of entry 2. This under-
scores the dramatic impact of selecting an appropriate Ni
source for a given reaction and reinforces the need for a highly
versatile Ni source. Precatalyst 3 proved effective for the Su-
zuki coupling of important pharma-relevant heterocycles such
as the unprotected indole and 2-aminopyridine in entries 4 and
5 (75% and 70% yield, respectively). Buchwald-Hartwig cou-
pling (entry 6) afforded the expected product in excellent
yield. Importantly, the use of dichloride 2 as an air stable Ni
source proved effective only when N-heterocyclic carbenes
were used as ligands (see Supporting Information, Figure S6).
Only trace amounts of product, if any, was detected with this
Ni source when phosphine ligands were employed whereas
several phosphines proved effective with either 1 or 3. In
HTE, this implies that several “hits” could be missed if an
inappropriate Ni source (such as dichloride 2) is employed.
Heck coupling as reported by Jamison and co-workers18
proceeded smoothly (entry 7). The isolated yield as well as the
isomeric ratio of the desired styrenyl product matched very
well with the reported values (84%; >99:1 branched/linear).
Despite complete consumption of chlorobenzene, no product
could be detected using dichloride 2. Jamison showed that the
isomeric ratio for this reaction is very sensitive to the phos-
phine used. We were thus pleased to find that the
branched:linear product ratio obtained upon substitution of
dcppb for dppb afforded the same isomeric ratio of products
(>99:1 and 4:1 branched:linear for dcppb and dppb, respec-
tively), with both Ni sources 1 and 3. This shows that the same
active species is formed in solution irrespective of the source
of Ni used.
ly, this is the only time that dichloride 2 proved marginally
superior to 3. For all three Ni sources investigated, increasing
the stoichiometry of phenylacetylene from 1.1 to 2 equiv led
to a 10–15% drop in yield of cross-coupled product, possibly
due to sequestration of the Ni center by the acetylene moiety.
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1 mol% [Ni], catalyst stored under N
1% N2
1 mol% [Ni], catalyst exposed to air
1% air
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0
5 mol% [Ni], catalyst stored under N
5% N2
5% air
5 mol% [Ni], catalyst exposed to air
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12
time (h)
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Figure 1. Yield of 4-methoxybiphenyl over time. Conditions: 1 or
5 mol% [Ni], 2 or 10 mol% PPh3, 0.7 M 4-chloroanisole, 1.2
equiv of phenylboronic acid, 3 equiv K3PO4·H2O, THF, 65 ºC, N2
atmosphere. ±3% in replicate runs.
Having established the applicability of 3 to a variety of cross-
coupling reactions, we wished to examine the air stability of
this new precatalyst. Thus, we exposed a solid sample of com-
plex 3 to air for 2 months. No color or appearance change was
observed over this time, providing qualitative evidence for the
air stability of complex 3. In sharp contrast, the notoriously
sensitive complex 1 turns black from yellow in less than 30
min when exposed to air, and the resulting solid was totally
ineffective in the Suzuki cross-coupling of 4-chloroanisole
with phenylboronic acid. To detect any decomposition of 3
upon exposure to air, we obtained the conversion profile for
this same reaction (Figure 1). If precatalyst 3 had undergone
even partial decomposition in air, we would have expected the
conversion profile to be slower relative to a sample of 3 that
was kept under an inert atmosphere. We were thus pleased to
find identical conversion profiles, within experimental error,
with the catalyst generated in situ by combination of 3 and
PPh3 even after the precatalyst was exposed to air for two
months. This provides strong evidence for the stability of 3 to
air, implying that it can be safely handled outside of a glove-
box.
Kumada coupling of 4-trifluoromethylchlorobenzene with
PhMgBr provided near quantitative yield of the desired bi-
phenyl product with both 1 and 3 (entry 8). The yield is re-
duced by nearly 50% when complex 2 is used instead. Similar-
ly, sp2-sp3 Negishi coupling (entry 9) with 1 and 3 and PPh3 as
the ligand afforded good yields (60–62%, respectively) of
product after 18 hours at RT; a reduced yield (47%) was again
observed employing 2 as the Ni source. Benzene accounts for
the mass balance with all three Ni sources.
Boronic acids are an extremely valuable commodity in the
pharmaceutical industry. We were thus keen to apply 3 in the
borylation reaction between an aryl halide and B2(OH)4 as
reported by Molander and co-workers.19 To our delight, the
reaction afforded the desired boronic acid in 71% yield after
two hours at 80 °C using only 1 mol% of 3 (entry 10). Interest-
ingly, the yields with Ni(0) 1 are consistently ca. 20% lower
relative to 3. We hypothesize that the instability of 1 in ethanol
may be the cause for the reduced yield of boronic acid.
The foregoing describes the synthesis and application of
precatalyst 3 in coupling reactions. Complex 3 is the first Ni
complex that combines the broad applicability of Ni(cod)2 (1)
with the air and moisture stabilities characteristic of Ni(II)
complexes such as NiCl2(dme) (2). Precatalyst 3 was success-
fully employed to mediate twelve different cross-coupling
reactions with reaction yields matching or exceeding those
obtained with the alternative Ni complexes 1 and 2. Important-
ly, drastically higher yields are observed when complex 3 is
used over dichloride 2 in sp2-sp3 Suzuki, Buchwald-Hartwig
amination, and Heck couplings. This highlights the importance
of choosing an appropriate Ni source for reaction screening
and the value of an alternative, air-stable Ni source to replace
dichloride 2. The reason(s) why precatalyst 3 outperforms 2 in
Cross-electrophile coupling20 is a powerful methodology
that avoids the need for a nucleophile. Using conditions re-
ported by Weix and coworkers,21 the coupling between 4-
trifluoromethylchlorobenzene and ethyl 4-bromobutanoate
was carried out in the presence of Zn as the stoichiometric
reductant (entry 11). The reaction provided the desired cou-
pling product in 53% yield with 1 and 3, matching the reported
yield.21 The two different homocoupling products account for
the mass balance of material.
Lastly, Sonogashira coupling (entry 12) using 3 with dppf as
ligand afforded the desired product in 56% yield while a sig-
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C.; Nantermet, P.; Liu, Y.; Helmy, R.; Welch, C. J.; Vachal, P.; Da-
several cases remains unclear, however. Given the rapidly
expanding area of Ni-catalyzed cross-coupling in both aca-
demic and industrial settings and the upcoming commercial
availability of 3,13 we expect that this novel precatalyst will
see rapid uptake and further accelerate the development of the
field.
vies, I. W.; Cernak, T.; Dreher, S. D. Science 2015, 347, 49–53.
9 (a) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264–1266.
(b) Choi, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 9102–9105.
10 Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.;
MacMillan, D. W. C. Science 2014, 345, 437–440.
11 (a) Park, N. H.; Teverovskiy, G.; Buchwald, S. L. Org. Lett.
2014, 16, 220–223. (b) Ge, S.; Hartwig, J. F. Angew. Chem., Int. Ed.
2012, 51, 12837–12841. (c) Standley, E. A.; Smith, S. J.; Müller, P.;
Jamison, T. F. Organometallics 2014, 33, 2012–2018.
12 Marshall, W. J.; Grushin, V. V. Can. J. Chem. 2005, 83, 640–
645.
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ASSOCIATED CONTENT
Supporting Information
9
Text, figures, and tables with experimental protocols for the syn-
thesis of 3 and catalytic experiments. This material is available
free of charge via the Internet at http://pubs.acs.org.
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13 Precatalyst 3 will be available from Strem Chemicals Inc. (cat.
no. 28-0165).
14 (a) Cornella, J.; Gómez-Bengoa, E.; Martin, R. J. Am. Chem.
Soc. 2013, 135, 1997–2009. (b) Standley, E. A.; Jamison, T. F. J. Am.
Chem. Soc. 2013, 135, 1585–1592.
15 Tang, Z.-Y.; Hu, Q.-S. J. Org. Chem. 2006, 71, 2167–2169.
16 Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340–1341.
17 Quasdorf, K. W.; Riener, M.; Petrova, K. V.; Garg, N. K. J. Am.
Chem. Soc. 2009, 131, 17748–17749.
18 Tasker, S. Z.; Gutierrez, A. C.; Jamison, T. F. Angew. Chem.,
Int. Ed. 2014, 53, 1858–1861.
19 Molander, G. A.; Cavalcanti, L. N.; García-García, C. J. Org.
Chem. 2013, 78, 6427–6439.
20 (a) Moragas, T.; Correa, A.; Martin, R. Chem. Eur. J. 2014, 20,
8242–8258. (b) Everson, D. A.; Weix, D. J. J. Org. Chem. 2014, 79,
4793–4798.
21 Everson, D. A.; Jones, B. A.; Weix, D. J. J. Am. Chem. Soc.
2012, 134, 6146–6159.
AUTHOR INFORMATION
Corresponding Author
*Email for S.M: sebastien.monfette@pfizer.com
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors acknowledge Stephane Caron, Joel Hawkins, Chris
McWilliams, and Nicholas Thompson for helpful discussions, and
Angel Diaz for analytical support. This work has been influenced
through the ongoing efforts of the Non-Precious Metal Catalysis
Alliance between Pfizer, Boehringer-Ingelheim, Abbvie, and
GlaxoSmithKline.
ABBREVIATIONS
PPh3 = triphenylphosphine; PCy3 = tricyclohexylphosphine; dppp
=
1,3-bis(diphenylphosphino)propane;
dppf
=
1,1’-
1,3-bis(2,6-
1,4-bis-
(dicyclopentylphosphino)butane tetrafluoroborate; TESOTf
bis(diphenylphosphino)ferrocene; SiPr•HCl
diisopropylphenyl)imidazolinium chloride; dcppb
=
=
=
triethylsilyl triflate; DIPEA = diisopropylethylamine; MeObpy =
4,4’-dimethoxybipyridine; CPME = cyclopentylmethyl ether.
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