NICKEL-IN-CHARCOAL 1
Nickel-in-Charcoal uum for 3 h until the Ni/C fell from the frit into the collection
ć%
flask. The collection flask was then dried in vacuo at 100 C
for 18 h. Using these specific amounts, all of the nickel was
NiII/C
mounted in the support, which corresponds to 0.552 mmol
NiII/g catalyst, or 3.2% Ni/catalyst by weight. To achieve very
[7440-02-0] NiII/C
dry catalyst, two 50 ml portions of toluene can be distilled from
InChI = 1/C.Ni/q;+2
wet Ni/C following the H2O distillation to azeotropically dry
InChIKey = GAYXURBANYOVBS-UHFFFAOYAX
the reagent.
Handling, Storage, and Precautions: Ni/C is generally an air and
(a heterogeneous catalyst that has been applied to a number of
moisture stable solid. However, due the sensitivity of some of
group 10 transition metal mediated cross-coupling reactions)
the chemistry in which it can be used (e.g, Negishi couplings),
Ni/C is stored in a glass bottle within a dry, inert atmosphere.
Form Supplied in: not a commercially available substance.
Under these conditions, the lifetime of the catalyst is expected
Preparative Methods: Ni/C can be prepared using the follow-
R
to be several months.
ing procedure.3 Darco© KB (5.00 g, 100 mesh) activated car-
bon (25% H2O content) was added to a 100 ml round-bottom
flask along with a stir bar. A solution of Ni(NO3)2·6H2O
(727 mg, Aldrich, 24,407-4, Ni content by ICP determination:
92% of reagent purity; 2.30 mmol) in deionized H2O (35 ml)
was added to the activated carbon and more deionized H2O
Suzuki Couplings of Aryl Chlorides.4 A variety of function-
(40 ml) was added to wash down the sides of the flask. The
alized arylboronic acids and aryl chlorides (either partner being
flask was purged under argon and stirred vigorously for 1 min.
substituted by activating or deactivating substituents) can be cou-
The flask was submerged in an ultrasonication bath under a
pled to produce biaryl products in good to excellent yields (eq 1).
positive argon flow for 30 min. The flask was then attached
The active Ni0 complex is preformed by treating a Ni/C + Ph3P
to an argon purged distillation setup and placed in a preheated
mixture in dioxane with n-BuLi under an inert atmosphere, at
ć%
175 180 C sand bath atop a stir plate. As the distillation ended,
room temperature. Amounts of Ni/C as low as 2% relative to sub-
the sand bath temperature increased automatically but was held
strate are sufficient to mediate Suzuki couplings. Nonetheless, un-
ć%
below 210 C for an additional 15 min. Upon cooling to room
like precious metal-based catalysis, the amount of this base metal
temperature, the black solid was washed with H2O(2× 50 ml)
required is actually of no consequence, as it is of minimal cost
under argon into a predried 150 ml coarse fritted funnel
and easily recoverable. The reaction is refluxed and monitored
(Figure 1). The H2O (100 ml) used to wash the Ni/C was
for the disappearance of aryl chloride. Solvent studies have sug-
rotary evaporated and analyzed for recovered nickel
gested dry, deoxygenated 1,4-dioxane to be the ideal medium for
(ICP). The fritted funnel was turned upside down under vac- the catalysis. When complete, the reaction can be filtered through
R
a pad of Celite© to remove insoluble catalyst and the products
are purified by standard column chromatography. Results on the
majority of cases are competitive with those obtained under simi-
lar but homogeneous conditions.5
Ni/C, Ph3P, K3PO4
MeO Cl
+ HO
LiBr, dioxane, "
B
N
OH
MeO
(1)
N
85%
Activated aryl chlorides can be coupled with substituted boronic
acids in as little as 35 min using microwave irradiation (eq 2).6,7
Electron-rich chlorides, however, do not yield consistent and
reproducible results. Instead, successful Suzuki biaryls are to be
expected for this class of aromatic substrates using the equivalent
aryl bromide. These couplings are assisted by KF, suggesting the
possibility of a reactive potassium fluoroborate intermediate.8,9
Although not fully investigated, couplings are likely to be general
as well between aryl boronic acids and the heavier aryl halides
Figure 1 Glassware for filtration and drying of Ni/C
(Br, I) using heterogeneous Ni/C.
Avoid Skin Contact with All Reagents
2 NICKEL-IN-CHARCOAL
O
Kumada Couplings.10,13 A variety of electron-rich aryl chlo-
NC
rides can be efficiently coupled with both alkyl and aryl Grig-
+ O
nard reagents under the influence of Ni/C. Benzylic reagents are
HO
Cl
B especially amenable to transmetallation, affording unsymmetrical
diarylmethanes in as little as 9 h (eq 5). Other aliphatic and aro-
OH
matic reagents require slightly longer reaction times (10 20 h).
O
Ni/C, Ph3P, KF, LiOH
In general, as with most nickel-catalyzed cross-couplings, the
NC
(2)
dioxane, µW, 200 °C, 35 min
active oxidation state of metal must be Ni0, typically achieved
O
81% by addition of 2 equiv of n-BuLi. However, this oxidation state
can be more conveniently reached by simply employing an
excess of the Grignard species in the flask. Thus, by adding RMgX
(1.4 1.7 equiv versus substrate) to the 5% NiII/C dispersed in THF
Aromatic Aminations.10,11 Ni/C also allows for a wide in the presence of 20 mol % Ph3P at room temperature, Ni0/C is
variety of functionalized aryl halides, most notably aryl chlo- generated in situ within minutes.
rides, to be converted into their anilino derivatives (eq 3). The
OMe
catalyst, which is likely to be NiII oxide, is most effective to-
Ni/C, Ph3P, LiBr
ward aminations following prereduction to the Ni0 species with
+
THF, ", 9 h
n-BuLi. Aminations do proceed without the n-BuLi treatment, as
F Cl
MgCl
amines are known to mediate electron transfer to NiII.12 However,
the induction period for reduction produces a marked decrease in
OMe
overall reaction rate when the nickel is not first forcibly converted
(5)
to its active Ni0 oxidation state. Both activated and deactivated,
F
functionalized aryl chlorides, including sterically hindered ortho-
78%
substituted cases, react favorably in refluxing toluene with pri-
mary and secondary amines with a catalyst level of 10%. From a
The extent of functional-group tolerance in this methodology is
thorough ligand study, dppf was found to be the ligand of choice.
governed by the highly basic and nucleophilic character of Grig-
Isolated yields tend to be good to modest, ranging from 70 to 93%,
nard reagents, and hence, an electrophilic center present in the
with reaction times as short as 2.5 h. However, as the reaction rate
adduct is not typically tolerated. More recent studies have shown
is substrate dependent, other aminations can take as long as 48 h.
that Kumada couplings can be carried out at ambient tempera-
Upon completion, the catalyst can be filtered and reused with no
tures.14,15 Unfortunately, attempts to mimic these temperature
loss of activity.
conditions using Ni/C have so far met with little success.
O
Negishi Couplings.16 Negishi s original description of
Ni/C, dppf, LiO-t-Bu
HN
Pd- and Ni-catalyzed couplings focused on vinylzirconocenes,17
+
toluene, ", 16 h
which are prepared by traditional hydrozirconations of terminal
Cl
acetylenes. The use of transmetallation-derived organozinc com-
O
plexes (RZnX) has come to be better known as Negishi couplings,
and can be successfully affected by Ni/C using functionalized aryl
(3)
chlorides as reaction partners.18 A variety of organozinc halides
N
readily undergo coupling in refluxing THF with aryl chlorides
87%
bearing ketones, esters, nitriles, aldehydes, etc. Particularly note-
worthy is an example involving a diaryl sulfide (eq 6). Good
ć% to excellent yields of the cross-coupled products are commonly
Microwave irradiation at ca. 200 C has been shown, as
observed.
expected, to enhance reaction rates, leading to complete con-
version in under 1 h (eq 4).7 Electron-rich chlorides require the
O
longest reactions times; however, activated cases of chlorides, bro-
Cl
Ni/C, Ph3P, LiCl
mides, and iodides reach full conversion in only 10 15 min when
+
IZn CN
irradiated under controlled conditions.
THF, ", 20 h
S
O
OMe
(6)
CN
O Ni/C, dppf, LiO-t-Bu
+
HN
dioxane, µW, 200 °C, 40 min S
Cl
72%
MeO
As conventional heating of the heterogeneous mixtures can
N O
(4)
lead to elongated reaction times, microwave irradiation has been
found to greatly accelerate these couplings.7 Advantageously, this
86%
method negates prior n-BuLi-mediated reduction of the NiII/C
A list of General Abbreviations appears on the front Endpapers
NICKEL-IN-CHARCOAL 3
catalyst. Complete in as little as 15 min, the couplings involving complete and clean reduction, while being unreactive toward elec-
arylzinc halides retain high efficiencies and substrate compati- trophilic functionality present in the aryl chloride. Thus, esters, ke-
bility. Selected Negishi couplings of alkylzinc halides are limited tones, nitriles, etc. are all tolerated presumably due to the limited
ć%
due to decomposition of starting material at temperatures >70 C. Lewis acidity of the potassium salt ([Me2N·BH3]-K+) formed in
Nonetheless, high yielding reactions can still be effected in as situ. As with other Ni/C heterogeneous reactions, the catalyst can
little as 30 min under these restricted conditions (eq 7). be filtered away from the reaction and reused with negligible loss
of activity.
NC
O
Ni/C, Ph3P, dioxane/THF
O
+ IZn
µW, 70 °C, 30 min
OEt
Cl
1. K2CO3, Me2NH BH3
N
·
NC
H
Ph 2. Ni/C, Ph3P, CH3CN, ", 7 h
O
Cl
(7)
O
OEt
85%
N
(9)
H
Ph
More traditional Negishi coupling partners (vinyl zirconocenes
H
96%
and aryl chlorides) are also susceptible to Ni/C-catalyzed cou-
pling. Initially accomplished in refluxing THF, the Ni/C-catalyzed
Negishi coupling of an activated aryl iodide and a vinyl zir-
conocene required up to 24 h to reach a modest 70% conver- Coupling of Vinylalanes with Benzylic Chlorides.20 Effi-
sion. However, the reaction is markedly accelerated by microwave cient, room temperature coupling of various benzylic chlorides
ć%
assistance. At ca. 200 C in a sealed tube under microwave irra- with vinylalanes can be affected using 5% Ni/C as catalyst. Vinyl-
diation, the catalyst effects the complete conversion in 10 min alanes can be easily derived from terminal alkynes using standard
(eq 8).7 Chlorides require 30 40 min, while aryl bromides need Negishi carboalumination conditions. The versatility and prac-
only 15 20 min. Unfortunately, related substrates including aryl ticality of this reaction, which affords stereodefined allylic aro-
nonaflates, vinyl iodides, and benzylic chlorides led to limited suc- matics, is exemplified by its use en route to naturally occurring
cess, giving incomplete reactions that included multiple uniden- coenzyme Q10 (eq 10).
tifiable side products.
O
F3C
MeO
ClCp2Zr
+
C6H13 -n
I
MeO H
10
O
Ni/C, THF, ", 24 h
70% conversion F3C coenzyme Q10
MeO
(8)
Ni/C, THF
(10)
C6H13 -n
µW, 200 °C, 10 min MeO H
95% isolated yield
10
OTs
A fairly thorough ligand query was carried out which high-
The NiII catalyst is best used after in situ reduction by n-
lighted Ph3P as the most effective (and least costly) ligand for this
BuLi to form the active Ni0 species. Reactions go to completion
transformation. Less-effective ligands include Cy3P, dppe, dppf,
in reasonable times without resorting to unusually high concen-
and (Ä…)-BINAP. Similarly, Ph3P is an essential reaction compo-
trations (ca. 0.25 0.30 M). Both electron-rich and electron-poor
nent only when coupling aryl bromides and chlorides. Couplings
substrates react with all-hydrocarbon derived or É-functionalized
between aryl iodides and vinyl zirconocenes are actually retarded
vinylalanes at roughly comparable rates. Isolated yields tend to
by Ph3P, resulting in low conversions.
be good (78 94%). Preliminary investigations suggest that this
reaction is amenable to microwave assistance, leading to the same
Reductions of Aryl Halides.19 Aryl chlorides can effec-
ć%
aryl tosylate in 80% yield in only 20 min at ca. 200 C (eq 11).7
tively be reduced to the corresponding arenes using heterogeneous
Ni/C catalysis. Treatment of an aryl chloride with 1.1 equiv of
MeO
potassium dimethylamide-borane complex (generated prior to
Me2Al H
Cl +
the reduction by mixing commercially available Me2NH·BH3 MeO
9
and K2CO3) initiates reduction. Under the influence of 5%
OTs
Ni/C and 10% Ph3P in refluxing acetonitrile, the catalyst system
required only 5 10 h to affect complete reduction (eq 9). Prior MeO
Ni/C, Ph3P
conversion of NiII/C to the active Ni0 catalyst by n-BuLi is not
THF, rt, 14 h
(11)
necessary as a slight excess of Me2NH·BH3/K2CO3 (10 mol %)
85%
MeO H
Ni/C, Ph3P, THF
is capable of affording active Ni0/C. Additional hydride sources
10
OTs
(silanes, H2, etc.) were examined in the original publication.17
µW, 200 °C, 20 min
80%
Me2NH·BH3/K2CO3 proves to be most useful in affecting a
Avoid Skin Contact with All Reagents
4 NICKEL-IN-CHARCOAL
Related Reagents. Palladium-on-charcoal; Nickel-on- 9. Darses, S.; Genet, J.-P., Eur. J. Org. Chem. 2003, 4313.
graphite.6 10. Tasler, S.; Lipshutz, B. H., J. Org. Chem. 2003, 68, 1190.
11. Lipshutz, B. H.; Ueda, H., Angew. Chem., Int. Ed. 2000, 39, 4492.
12. Cramer, R.; Coulson, D. R., J. Org. Chem. 1975, 40, 2267.
13. Lipshutz, B. H.; Tomioka, T.; Blomgren, P. A.; Sclafani, J. A., Inorg.
1. Lipshutz, B. H., Adv. Synth. Catal. 2001, 343, 313.
Chim. Acta. 1999, 296, 164.
2. Lipshutz, B. H.; Tasler, S.; Chrisman, W.; Spliethoff, B.; Tesche, B., J.
14. Bohm, V. P. W.; Westkamp, T.; Gstottmayer, C. W. K.; Herrmann, W.
Org. Chem. 2003, 68, 1177.
A., Angew. Chem. Int. Ed. 2000, 39, 1602.
3. Frieman, B. A.; Taft, B. R.; Lee, C.-T.; Butler, T.; Lipshutz, B. H.,
15. Furstner, A.; Leitner, A., Angew. Chem. Int. Ed. 2002, 41, 609.
Synthesis 2005, 2989.
16. Lipshutz, B. H.; Frieman, B., Tetrahedron. 2004, 60, 1309.
4. Lipshutz, B. H.; Sclafani, J. A.; Blomgren, P. A., Tetrahedron 2000, 56,
17. Negishi, E.-i.; Van Horn, D. E., J. Am. Chem. Soc. 1977, 99, 3168.
2139.
18. Lipshutz, B. H.; Blomgren, P. A., J. Am Chem. Soc. 1999, 121, 5819.
5. Miyaura, N.; Saito, S.; Ohtani, S., J. Org. Chem. 1997, 62, 8024.
19. Lipshutz, B. H.; Tomioka, T.; Sato, K., Synlett 2001, 970.
6. Lipshutz, B. H.; Butler, T.; Frieman, B. A.; Kogan, V.; Lee, C.-T.; Lower,
A.; Nihan, D. M.; Taft, B. R.; Tomaso, A. E., Jr.; Pure Appl. Chem. 2006, 20. Lipshutz, B. H.; Frieman, B.; Pfeiffer, S. S., Synthesis 2002, 2110.
78, 377.
7. Lipshutz, B. H.; Frieman, B. A.; Lee, C.-T.; Lower, A.; Nihan, D. M.;
John B. Unger & Bruce H. Lipshutz
Taft, B. R., Chem. Asian J. 2006, 1, 417.
University of California, Santa Barbara, CA, USA
8. Molander, G. A.; Ito, T., Org. Lett. 2001, 3, 393.
A list of General Abbreviations appears on the front Endpapers