Nickel-NHC-catalyzed α-arylation of acyclic ketones and amination of haloarenes and unexpected preferential N-arylation of 4-aminopropiophenone

Article abstract of DOI:10.1021/jo070313d

(Chemical Equation Presented) Arylation of both acyclic ketones and primary and secondary amines was achieved using a new, simple, stable, and easy-to-access nickel(II)-halide complex bearing mixed PPh₃/N- heterocyclic carbene ligands as a catalyst precursor. Acyclic ketones were first arylated at the α-position with the nickel catalyst. On the other hand, less basic amines, such as diphenylamine and 4-aminobenzophenone, were more favorable in the catalytic amination of haloarenes than basic amines, contrary to previous reports. N-Arylation of 4-aminopropiophenone was found to proceed selectively without causing α-arylation of the ketone group.

Full text of DOI:10.1021/jo070313d

Nickel-NHC-Catalyzed r-Arylation of Acyclic Ketones and
Amination of Haloarenes and Unexpected Preferential N-Arylation
of 4-Aminopropiophenone
Kouki Matsubara,*,† Keita Ueno,† Yuji Koga,† and Kenji Hara‡
Department of Chemistry, Faculty of Science, and School of Medicine, Fukuoka UniVersity,
8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
kmatsuba@fukuoka-u.ac.jp
ReceiVed February 15, 2007
Arylation of both acyclic ketones and primary and secondary amines was achieved using a new, simple,
stable, and easy-to-access nickel(II)-halide complex bearing mixed PPh3/N-heterocyclic carbene ligands
as a catalyst precursor. Acyclic ketones were first arylated at the R-position with the nickel catalyst. On
the other hand, less basic amines, such as diphenylamine and 4-aminobenzophenone, were more favorable
in the catalytic amination of haloarenes than basic amines, contrary to previous reports. N-Arylation of
4-aminopropiophenone was found to proceed selectively without causing R-arylation of the ketone group.
Introduction
Although Grignard coupling and Suzuki coupling have
proceeded smoothly under mild conditions using various nickel
catalysts, R-arylation of carbonyl compounds3 and amination
of haloarenes4 seem to need more activation energy and are
not popular in the nickel-catalyzed coupling reactions. In recent
reports, Buchwald et al.5a and Chan et al.5c showed asymmetric
versions of R-arylation of cyclic esters and cyclic ketones,
respectively, using chiral ligands in the presence of nickel(0)
precursors. However, as Chan commented, the achievement of
arylation of acyclic carbonyl compounds requires overcoming
some barrier. On the other hand, several efforts to aminate
haloarenes have been made using nickel catalysts bearing
Organonickel-catalyzed organic transformations, which are
wide and variable reactions similar to those catalyzed by
palladium catalysts, are now increasingly gaining attention as
tools using inexpensive metal sources.1 However, many useful
nickel catalysts are not well-known, and there are fewer useful
reactions with nickel catalysts in comparison with palladium
catalysts,2 since starting stable nickel(II) precursors are hardly
reduced to zerovalent nickel species, which are usually active
in the catalytic cycles. Moreover, active nickel(0) compounds
are hard to handle because of their toxicity and/or instability in
the air.
† Department of Chemistry, Faculty of Science.
(3) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234-245.
(b) Bolm, C.; Hildebrand, J. P.; Mun˜iz, K.; Hermanns, N. Angew. Chem.,
Int. Ed. 2001, 40, 3284-3308.
‡ School of Medicine.
(1) (a) Modern Organonickel Chemistry; Tamaru, Y., Ed.; Wiley-VCH:
Weinheim, Germany, 2005. (b) ComprehensiVe Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford,
1995; Vol. 12. (c) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. ReV. 2002, 102, 1359-1469. (d) Stanforth, S. P. Tetrahedron
1998, 54, 263-303. (e) Negishi, E. Acc. Chem. Res. 1982, 15, 340-348.
(2) (a) Palladium in Organic Synthesis; Tsuji, J., Ed.; Springer: Berlin,
2005. (b) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., De Meijere, A., Eds.; Wiley: New York, 2002. (c) PerspectiVes
in Organopalladium Chemistry for the XXI Century; Tsuji, J., Ed.; Elsevier
Science: Amsterdam, 1999.
(4) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067. (b)
Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675-703.
(5) (a) Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
3500-3501. (b) Spielvogel, D. J.; Davis, W. M.; Buchwald, S. L.
Organometallics 2002, 21, 3833-3836. (c) Chen, G.; Kwong, F. Y.; Chan,
H. O.; Yub, W.- Y.; Chan, A. S. C. Chem. Commun. 2006, 1413-1415.
(d) Cristau, H. J.; Vogel, R.; Taillefer, M.; Gadras, A. Tetrahedron. Lett.
2000, 41, 8457-8460. (e) Semmelhack, M. F.; Stauffer R. D.; Rogerson,
T. D. Tetrahedron Lett. 1973, 4519-4522. (f) Millard, A. A.; Rathke, M.
W. J. Am. Chem. Soc. 1977, 99, 4833-4835.
10.1021/jo070313d CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/09/2007
J. Org. Chem. 2007, 72, 5069-5076
5069

Matsubara et al.
SCHEME 1
Thus, in this study, we applied this nickel complex 1 to the
catalytic R-arylation of acyclic ketones as a catalyst, which has
not been reported to our knowledge, and obtained arylation
products efficiently. The arylation of ketones was carried out
in the presence of a sufficient amount of strong base which was
added for the purpose of enolization of ketones and reduction
of nickel(II) species, and further, N-arylation of primary and
secondary amines took place under the same conditions and is
reported in this paper. The amination of haloarenes proceeded
efficiently when primary and secondary arylamines, especially
sterically hindered amines and/or those substituted with electron-
withdrawing groups, were used, whereas a secondary donating
alkylamine, which was generally advantageous for the aryl
analogues in the previous N-arylation with Pd and Ni catalysts,
did not react efficiently. Interestingly, preferential arylation of
the amine moiety occurred when using 4-aminopropiophenone
as a substrate, even though arylation at the R-position of the
acyclic ketone moiety seems possible.
phosphines or carbenes.6a-c Recent studies showed that an in
situ-generated nickel(0) compound efficiently catalyzed the
arylation of amines under mild conditions in the presence of
bulky N-heterocyclic carbene (NHC) ligands, though neither
isolated NHC-nickel complexes nor divalent nickel compounds
were directly used.6b
Many chemists now use NHC, such as 1,3-dialkyl- or 1,3-
diarylimidazol-2-ylidenes, as sterically hindered 2-electron
σ-donor ligands in a number of catalytic organic reactions
instead of phosphines.7 Last year, Nolan et al. reported that an
easily synthesized, efficient, and versatile palladium(II) pre-
catalyst bearing an NHC ligand is useful for catalytic formation
of C-N and C-C bonds.8 In constructing a nickel version of
such a new, active, easy-to-prepare, and stable catalyst inducing
various catalytic reactions, we also employed NHC ligands and
fortunately found a new nickel(II) complex, NiX2(PPh3)(NHC)
(X ) Cl or Br, NHC ) 1,3-bis(2,6-diisopropylphenyl)imidazol-
2-yl), bearing mixed PPh3/NHC ligands, which was prepared
and structurally determined as reported in our latest paper.9 This
nickel complex demonstrated the highest catalytic activity in
Grignard cross-coupling of aryl halides among NiCl2(PPh3)2,
NiCl2(NHC)2, and the chloride version of the mixed PPh3/NHC
complex, NiCl2(PPh3)(NHC) (1), used as catalysts (Scheme 1).
One of the significant factors leading to this high activity in 1
may be the ability to eliminate triphenylphosphine under mild
conditions, forming a coordinatively unsaturated site in situ in
the nickel center. Thus, we considered that such a property in
1 may be significant in the catalytic R-arylation of carbonyl
compounds because, as Hartwig and Buchwald noted, the active
species of palladium in R-arylation should have only one
monodentate supporting ligand.10 In addition, our recent study
showed that two strongly binding NHC ligands in a palladium
complex deactivated the catalyst activity in the R-arylation of
ketones, while the reaction proceeded efficiently when one of
two NHC ligands was removed.11
Results and Discussion
Nickel-Catalyzed r-Arylation of Acyclic Ketones. The
R-arylation of cyclic ketones and esters and highly acidic
malononitrile by nickel catalysts was reportedly studied in
detail;5 however, the arylation of standard acyclic ketones, which
have already been established in organopalladium chemistry,
has never been reported.12 Thus, we conducted reactions of some
acyclic alkyl aryl ketones with haloarenes in the presence of
NaOtBu and a catalytic amount of the nickel complex 1. We
considered that facile reduction of the nickel(II) center may
make the reaction more efficient, using an appropriate base as
the reducing reagent. Sodium hydride was reported to be able
to reduce the nickel atom easily by way of transmetalation and
H2 evolution.6b However, employing NaH in our system instead
of NaOtBu caused no reaction. Our first attempt with acetophe-
none in toluene at 100 °C for 24 h, which is the simplest reagent
and easily reacts with haloarenes in the presence of palladium
catalysts,13 provided only aldol adducts by itself on adding any
aryl halides. After several attempts, using propiophenone as a
substrate, the reaction of 4-bromobenzophenone, an electrone-
gative aryl bromide, afforded an R-arylation product in 11%
isolated yield, with the rest of the starting materials being
recovered, when using 3 mol % 1. Methyl 4-bromobenzoate
was converted into both the R-arylation product and a Claisen
condensation product in a 1:1 ratio. The reactions of simple
haloarene derivatives, such as p-bromotoluene and p-bromoani-
sole, with propiophenone resulted in complete recovery of the
starting materials under this condition.
(6) (a) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6054-
6058. (b) Desmarets, C.; Schneider, R.; Fort, Y. J. Org. Chem. 2002, 67,
3029-3036 and references therein. (c) Bricout, H.; Carpentier, J. -F.;
Mortreux, A. Tetrahedron 1998, 54, 1073-1084. (d) Kelly, R. A., III; Scott,
N. M.; D´ıez-Gonza´lez, S.; Stevens, E. D.; Nolan, S. P. Organometallics
2005, 24, 3442-3447.
Under more severe conditions using 10 mol % 1, we finally
achieved the R-arylation of propiophenone with several ha-
loarenes in excellent yields (Table 1). This successfully led to
the efficient arylation of chlorobenzene, bromobenzene, 4-bro-
mobiphenyl, p-bromoanisole, and p-bromotoluene, which did
not react under the previous conditions (entries 2-5 and 7). In
the case of 4-bromobenzophenone, only 5 mol % 1 was required
to complete the coupling reaction (entry 8). These results
(7) (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
(b) Weskamp, T.; Bo¨hm, V. P. W.; Herrmann, W. A. J. Organomet. Chem.
2000, 600, 12-22. (c) Bourissou, D.; Guerret, O.; Gabba, F. P.; Bertrand,
G. Chem. ReV. 2000, 100, 39-91. (d) Herrmann, W. A.; Schu¨tz, J.; Frey,
G. D.; Herdtweck, E. Organometallics 2006, 25, 2437-2448. (e) Kantchev,
E. A. B.; O’ Brien, C. J.; Organ, M. G. Angew. Chem., Int. Ed. 2007, 46,
2768-2813.
(8) Marion, N.; Ecarnot, E. C.; Navarro, O.; Amoroso, D.; Bell, A.;
Nolan, S. P. J. Org. Chem. 2006, 71, 3816-3821.
(9) Matsubara, K.; Ueno, K.; Shibata, Y. Organometallics 2006, 25,
3422-3427.
(12) The reason for the low reactivity of acyclic ketones has not been
explained.5c We considered that the steric demand around the R-position
of the carbonyl group might induce such a low reactivity in comparison
with that of the cyclic analogues.
(13) (a) Ehrentraut, A.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2002,
344, 209-217. (b) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7996-8002.
(10) (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360-1370. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 1473-1478.
(11) Matsubara, K.; Senju, M.; Okazaki, H. J. Organomet. Chem. 2006,
691, 3693-3699.
5070 J. Org. Chem., Vol. 72, No. 14, 2007

Arylation of Ketones and Amination of Haloarenes
TABLE 1. r-Arylation of Ketones Catalyzed by [NiCl2(PPh3)(NHC)] (1)a
a Conditions: in toluene (0.3 mL), at 100 °C for 24 h, ketones (0.154 mmol), aryl halides (0.128 mmol), NaOtBu (0.192 mmol), and catalyst 1 (0.0128
mmol, 10 mol %). b Only the Aldol condensation product was obtained. c Each reaction was carried out more than two times, and the yield was determined
by column chromatography (SiO2). d The yield was determined by means of the 1H NMR spectrum of the crude mixture. e Catalyst 1 (6 µmol, 5 mol %) was
used.
indicated that the coupling reactions of aryl bromides did not
depend upon the substituents at the para position under these
conditions. With p-chloroanisole, the product was given in lower
yield than the others, the starting material was recovered, and
trace amounts of undetermined byproducts were detected in this
case (entry 6).14 Then, as listed in entries 9-11, we conducted
arylation of propiophenones having substituents at the para
position, such as 4-fluoropropiophenone, 4-methoxypropiophe-
none, and 4-(N,N-dimethylamino)propiophenone. These sub-
strates also reacted with 4-bromobenzophenone to form corre-
sponding products in good to moderate yields (entries 9-11),
indicating that the acidity of propiophenones due to the
substituents at the para position is low comparable to the
reaction rates, except for the propiophenone having the strongly
donating dimethylamino group. This was also pointed out in
the palladium-catalyzed R-arylation.3 As shown above, nickel-
catalyzed R-arylation of acyclic ketones was first achieved under
harder conditions than those with cyclic carbonyl compounds
using nickel(0) catalysts.
In considering the active catalyst in the reaction media, we
suspected that a metathesis reaction of compound 1 took place
to form bisphosphine and biscarbene complexes NiCl2(PPh3)2
and NiCl2(NHC)2 (NHC ) bis(2,6-diisopropylphenyl)imidazol-
2-yl),9 respectively, which could truly act in the R-arylation of
acyclic ketones.15 To exclude the above potential process, we
added a mixture of equal amounts (5 mol % each) of these
compounds, NiCl2(PPh3)2 and NiCl2(NHC)2, instead of 1 to the
solution of propiophenone and p-bromoanisole in the presence
of the base. As a result, the reaction gave an arylation product
1
(36% determined by means of H NMR) with a remarkable
amount of the reduced byproduct, anisole (31%), which was
not obtained in the arylation with 1. Generally, the formation
of anisole was attributed to the occurrence of â-elimination of
the metal C-enolate species due to the unhindered phosphine
(15) Although such a ligand exchange reaction of 1 was not detected at
room temperature,8 those of mixed NHC/PR3 palladium complexes were
reported; see: Herrmann, W. A.; Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.;
Grosche, M.; Reisinger, C. -P.; Weskamp, T. J. Organomet. Chem. 2001,
617-618, 616-628.
(14) The reduced product, anisole, did not form in the reaction. The C-O
bond activation of the anisole derivatives was also anticipated and is shown
in the following report on nickel-catalyzed Grignard coupling: Dankwardt,
J. W. Angew. Chem., Int. Ed. 2004, 43, 2428-2432.
J. Org. Chem, Vol. 72, No. 14, 2007 5071

Matsubara et al.
TABLE 2. Amination of Aryl Halides Catalyzed by [NiCl2(PPh3)(NHC)] (1)a
a Conditions: in toluene (0.3 mL), at 100 °C for 24 h, amines (0.154 mmol), aryl halides (0.128 mmol), NaOtBu (0.192 mmol), and catalyst 1 (0.0128
mmol, 10 mol %). Each reaction was carried out more than two times, and the yield was determined by column chromatography (SiO2).
ligands in the metal complex, such as MCl2(PPh3)2, strongly
suggesting that such a ligand exchange of 1, which formed
NiCl2(PPh3)2 and NiCl2(NHC)2, did not proceed under these
conditions.
Amination of Haloarenes. The coupling reaction of primary
and secondary amines with aryl halides was developed mainly
employing palladium catalysts,4 and in 1997, nickel-catalyzed
amination was first discovered.6a Recently, Fort et al. reported
that in situ-generated nickel(0) compounds in the presence of
bulky NHC ligands had high activity in regard to the arylation
of primary and secondary amines.6b Although the nickel center
in 1 is divalent, we attempted a reaction of morpholine with
aryl halides, such as p-chloroanisole and p-bromoanisole, under
similar conditions. However, the starting materials were com-
pletely recovered when the reaction was conducted at 65 °C
for 24 h using 5 mol % 1. At last, using 10 mol % 1 at 100 °C
for 24 h afforded amination products from aniline derivatives
in high yields without the primary nickel-reduction operation
from 1. As shown in Table 2, the reaction of several aryl halides,
including p-bromoanisole with secondary and primary amines,
5072 J. Org. Chem., Vol. 72, No. 14, 2007

Arylation of Ketones and Amination of Haloarenes
TABLE 3. Competing Reactions of 4-Aminopropiophenonea
proceeded to form corresponding amination products. Hartwig
et al. explained that secondary aliphatic amines, which are
sterically hindered and electron-donating, are suitable for
catalytic amination of haloarenes using Pd catalysts bearing
monodentate phosphorus ligands and that aromatic amines
can be coupled facilely by “second-generation” Pd catalysts
bearing bidentate phosphine ligands.4,17 Therefore, it was
unexpected that morpholine, which more facilely coupled
with haloarenes than anilines according to other reports,6 did
not react efficiently in our case (entries 1 and 2), whereas the
arylation of aniline (entry 10) gave a product in even
higher yield (79%) than that from morpholine. Moreover, the
reaction of diphenylamine with haloarene gave the tripheny-
lamine quantitatively, while, in contrast, it did not react at all
using Fort’s nickel catalyst,6b indicating that less basic ary-
lamines are more favorable to amination than basic alkylamines
when using nickel catalyst 1. We confirmed this by the
reaction of less basic 4-aminobenzophenone with p-bromoani-
sole to form the secondary arylamine in high yield (78%) (entry
15) without giving the diarylation product. On the other hand,
the arylation of rather bulky anilines, such as 2,4,6-trimethy-
laniline, also resulted in quantitative formation of the coupling
product (entry 3). Higher yields in the arylation of 2,4,6-
trimethylaniline than that of nonsubstituted aniline (entry 10)
revealed that the hindered amines are preferable, as Hartwig
suggested. However, lower yields in the coupling of bulkier
2,6-diisopropylaniline (entry 8) suggested that the appropriate
size and/or shape of amines is required for an efficient coupling
process. A yield of the amine (44%), lower than that from
4-bromobenzophenone (entry 10), was obtained after 24 h by
the reaction of its chloro analogue with aniline (entry 11).
Surprisingly, the reaction of reagents bearing the trifluoromethyl
moiety, 4-(trifluoromethyl)bromobenzene and 4-(trifluorom-
ethyl)aniline, only gave the starting materials dominantly (entries
6 and 13), while, reportedly, 4-(trifluoromethyl)chlorobenzene
efficiently gave amination products by a palladium catalyst.16
We now attribute this to an unknown catalyst-deactivation
process which should occur in the presence of such trifluorom-
ethyl-substituted arenes.
The reason for such preferable arylation of less basic
arylamines is unclear now. Tighter primary coordination of
arylamines to the nickel center than that of basic alkylamines
might make the catalytic reaction favorable. An alternative
explanation is that facile amide formation in situ from “acidic”
anilines by sodium tert-butoxide might increase the reaction rate,
while more basic amines were hardly deprotonated by the base.
This is discussed later in detail.
Although chemists have reported that the reduction of aryl
halides sometimes occurs to form arene derivatives in the
amination of aryl halides, as a result of â-elimination of the
palladium alkylamide species,18 our results showed that they
were not reduced by nickel catalyst 1 (entries 1 and 2). We
also could not detect diarylation products from primary anilines
in any reaction, which were sometimes yielded when using
electron-negative amines with palladium catalysts.4
yieldb (%)
entry
aryl halide
A
B
C
1
2
3
p-bromoanisole
p-bromotoluene
4-bromobenzophenone
0
0
trace
38
26
35
trace
trace
26
a Conditions: in toluene (0.5 mL), at 100 °C for 24 h, amines (0.15
mol/L), aryl halides (0.13 mol/L), NaOtBu (0.19 mol/L), and catalyst (0.013
mol/L). b Each reaction was carried out more than two times, and the yield
was determined by column chromatography (SiO2).
Fort et al. reported a nickel(0)-catalyzed efficient system using
monodentate NHC ligands.6b In our case, without the prior
nickel(II)-reduction system, an efficient amination process using
the NHC-bound nickel catalyst was successfully achieved.
Competing Reaction of 4-Aminopropiophenone. The above
results showed that nickel complex 1 catalyzed the arylation of
both acyclic ketones and amines to form coupling products in
good to excellent yields, so we were interested in how aryl
halides react with a substrate having both acyclic ketone and
primary arylamine groups. Arylation of ketones and amines can
be conducted under the same conditions; however, no one has
compared these reactions using such reagents to our knowledge.
In addition, our slow process may clarify the difference in the
rates between these couplings. At first, a simple reagent,
4-aminopropiophenone, was coupled with some aryl halides for
24 h. We expected that arylation of each ketone or amine group
would proceed in agreement with the above results. However,
surprisingly, R-arylation of the ketone moiety did not take place
after 24 h, in contrast to the formation of amination products at
the amine moiety in moderate yields. The other remaining
products were the starting materials recovered. As listed in Table
3, p-bromoanisole and p-bromotoluene were coupled with
4-aminopropiophenone to form secondary arylamines in 38%
and 26% yields (entries 1 and 2), respectively, but the R-ary-
lation products were not obtained at all. Highly reactive
4-bromobenzophenone also reacted mainly with the amine group
to give monoarylation and diarylation products in 35% and 26%
yields, respectively, while only a trace amount of arylation
product at the ketone group was detected in the crude 1H NMR
spectrum (entry 3). Diarylation of both the ketone and amine
groups in one molecule was not detected in any case.
Consideration of the Mechanism Using the Nickel Cata-
lyst. In the mechanism of these two coupling reactions,
R-arylation and amination, at first generation of the nickel(0)
species leads to the oxidative addition of the aryl halide, RX,
and then transmetalation of the nickel halide with an enolate or
amide occurs to form a nickel enolate or a nickel amide
intermediate (Scheme 2). The results employing several sub-
Bridging phosphine ligands in palladium had provided high
activity in the amination of haloarenes,19 whereas in contrast
(16) Ackermann, L.; Born, R. Angew. Chem., Int. Ed. 2005, 44, 2444-
2447.
(17) Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 11695-
11696.
(19) (a) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217-
7218. (b) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215-7216.
(18) Hartwig, J. F.; Richards, S.; Baran˜ano, D.; Paul, F. J. Am. Chem.
Soc. 1996, 118, 3626-3633.
J. Org. Chem, Vol. 72, No. 14, 2007 5073

Matsubara et al.
SCHEME 2
SCHEME 3
of the C- and O-bound nickel enolate species (Scheme 2). Such
a bidentate enolate form may stabilize the nickel enolate species
because as reported the formation of the nickel-oxygen bond
between the enolate and unsaturated nickel species is signifi-
cant.23 However, the assumption does not fit in our case because,
interestingly, a competing reaction of p-bromoanisole with equal
amounts of aniline and propiophenone gave an R-arylation
product in 29% yield, higher than that of an amination product
(23% yield) (Scheme 3). That is, in sharp contrast to the
coupling reactions of 4-aminopropiophenone, the R-arylation
product was given dominantly in the competing reaction,
suggesting that the existence of contaminating amines does not
prevent formation of the nickel enolate species. Thus, we
concluded that the result in Table 3 is attributable to the peculiar
property of 4-(aminoalkyl)phenones.
Thus, we speculated that the disadvantage to the R-arylation
of the ketone group in 4-aminopropiophenone may be due to
the powerful electron-donating amino moiety at the para
position. Indeed, the R-arylation result in Table 1, entry 11,
showed that a ketone, 4-(N,N-dimethylamino)propiophenone,
having a similar electron-donating substituent on the aryl moiety,
was coupled with 4-bromobenzophenone in moderate yield
(48%). It was one of the lowest yields of all arylation products,
indicating that the amino substituent at the para position is
indubitably an important factor for inhibiting the R-arylation
of 4-aminopropiophenone.
In addition, we assumed that the acyl-substituted arylamine
is acidic enough to compete with the acyl R-hydrogens which
have been rendered less acidic by the electron-donating amine
moiety for deprotonation by sodium tert-butoxide. Contrary to
the theory that less basic amines are unfavorable in catalytic
N-arylation,4 our N-arylation of less basic amines, such as
4-aminobenzophenone and diphenylamine, afforded amination
products in higher yields than by using the more basic amines.
We also conducted competing reactions of equivalent amounts
of 4-aminobenzophenone and aniline with p-bromoanisole,
resulting in the dominant formation of N-arylated aminoben-
zophenone (product ratio by NMR, 6.5:1.0, respectively)
(Scheme 4). Thus, we conclude that both the lower reactivity
strates, as shown in Tables 1 and 2, suggested the common
features of these nickel-catalyzed reactions, as noted above. That
is, it can be realized that the substituents in the aryl halides
little depended on the yields of the products in either R-arylation
or amination, except for inactive chloroarenes. This result
suggested that the oxidative addition with the active zerovalent
nickel species occurred rapidly and did not affect the overall
reaction because, in general, the nickel(0) species are highly
active and facilely form the nickel(II) species. In contrast to
palladium chemistry,20,21 some relationship between the acidity
of the ketones or amines and the yields of arylation products
can be pointed out. In particular, we found that less basic anilines
were coupled with haloarenes more favorably than basic
alkylamines by 1, indicating the significance of the transmeta-
lation process in the 1-catalyzed catalytic cycles.
The diarylation of amines by palladium catalysts has also
been studied,22 though nickel-catalyzed diarylation was not
reported; decreased steric hindrance between the ligand and
amine and/or the basicity of the generated arylamine frequently
induced diarylation. As shown in Table 3, in addition to using
less basic ketone-substituted aniline, only the most electron-
poor 4-bromobenzophenone among the para-substituted aryl
halides gave a diarylation product. After reductive elimination
of the arylamine in the first arylation process, a generated less
basic unhindered amine coordinated the nickel atom strongly,
maybe leading to the second arylation, as shown in Scheme
2,22 suggesting that using both unhindered and electron-negative
anilines and haloarenes with 1 only leads to the diarylation of
amines.
It is interesting to note that an arylamine having an alkyl
ketone moiety was easily arylated preferentially. The experi-
mental results with 1 indicated that the amine moiety may react
more easily than the enolate group in the transmetalation
process. First, we assumed that prior ligand exchange of
phosphine to amine may prevent formation of the nickel enolate
species because, in the case of the R-arylation of propiophenone,
facile elimination of PPh3 from the intermediary mixed PPh3/
NHC nickel compound was presumed to enhance the formation
SCHEME 4
(20) (a) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852-860. (b)
Yamashita, M.; Vicario, J. V. C.; Hartwig, J. F. J. Am. Chem. Soc. 2003,
125, 16347-16360.
(21) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816-
5817.
of the ketone moiety having the electron-donating amino group
and the higher reactivity of the acyl-substituted acidic amine
(22) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 3694-
3703.
5074 J. Org. Chem., Vol. 72, No. 14, 2007

Arylation of Ketones and Amination of Haloarenes
127.7, 115.9, 115.6, 47.8, 19.3. IR(νCO, cm-1): 1683 (vs), 1657
moiety in 4-aminopropiophenone may be the crucial factors in
yielding no R-arylation product.
(vs), 1598 (vs). EI-MS: m/z 332 [M+], 333 [M+ + 1], 334 [M+
+
2]. HRMS (m/z) for C22H17O2F: calcd 332.1213, found 332.1215.
Data for 2-(4-Benzoylphenyl)-1-(4-methoxyphenyl)-1-pro-
panone. 1H NMR (CDCl3, 400 MHz): δ 7.95 (d, J ) 8.8 Hz, 2H),
7.77-7.73 (m, 4H), 7.57 (t, J ) 6.0 Hz, 1H), 7.46 (t, J ) 8.0 Hz,
2H), 7.41 (d, J ) 8.0 Hz, 2H), 6.88 (d, J ) 8.2 Hz, 2H), 4.74 (q,
J ) 6.8 Hz, 1H), 3.83(s, 3H), 1.56 (d, J ) 6.8 Hz, 3H). 13C NMR
(CDCl3, 100 MHz): δ 198.1, 196.2, 163.4, 146.6, 137.5, 136.1,
132.3, 131.0, 130.8, 130.0, 129.1, 128.2, 127.7, 113.8, 55.4, 47.3,
19.4. IR(νCO, cm-1): 1673 (vs), 1657 (vs), 1599 (vs). EI-MS: m/z
344 [M+], 345 [M+ + 1], 346 [M+ + 2]. HRMS (m/z) for
C23H20O3: calcd 344.1412, found 344.1409
Conclusion
In summary, we first achieved efficient R-arylation of acyclic
ketones using the nickel complex 1, which, bearing both
triphenylphosphine and bulky NHC ligands, is significant as
an active, easy-to-access, simple, and air-stable nickel catalyst.
Propiophenone was arylated with several haloarenes, whereas
the arylation of acetophenone did not proceed. Using the bulky
donating NHC ligand and the easy-to-liberate phosphine ligand
in nickel(II) complex 1 may have contributed to these successful
results. In the presence of the same strong base, the amination
of haloarenes also occurred to form secondary or tertiary amines
from primary or secondary amines, respectively. Interestingly,
in contrast to earlier reports, the amination of less basic
arylamines proceeded more efficiently than that of basic
alkylamines. The yields of the amination products were highs
the same as those of the R-arylation products. The reaction of
4-aminopropiophenone, which is a special reagent leading
possibly to both R-arylation and amination, gave only amination
products, because of the low acidity of its R-protons and the
low basicity of the amine moiety. We are now investigating
these nickel-catalyzed reaction mechanisms, establishing an
efficient reduction process of 1, modifying 1, and applying the
modified compounds to other various catalytic reactions.
Data for 2-(4-Benzoylphenyl)-1-[4-(dimethylamino)phenyl]-
1
1-propanone. H NMR (CDCl3, 400 MHz): δ 7.90 (d, J ) 8.8
Hz, 2H), 7.77-7.72 (m, 4H), 7.57 (t, J ) 7.6 Hz, 1H), 7.47-7.42
(m, 4H), 6.64 (d, J ) 8.8 Hz, 2H), 4.73 (q, J ) 6.8 Hz, 1H), 3.03
(s, 6H), 1.55 (d, J ) 6.8 Hz, 3H). 13C NMR (CDCl3, 100 MHz):
δ 197.5, 196.3, 153.1, 147.3, 137.6, 135.9, 132.3, 131.0, 130.7,
130.0, 128.2, 127.7, 111.0, 46.8, 40.2, 19.4. IR (νCO, cm-1): 1654
(s), 1594 (vs). EI-MS: m/z 357 [M+], 358 [M+ + 1], 359 [M+
+
2]. HRMS (m/z) for C24H23NO2: calcd 357.1729, found 357.1738.
A Typical Procedure for Amination of Aryl Halides. To a
solution of 1 (10.0 mg, 12.8 µmol), NaOtBu (18.1 mg, 0.192 mmol),
and p-bromoanisole (16 µL, 0.128 mmol) in toluene (0.30 mL) was
added 2,4,6-trimethylaniline (0.021 mL, 0.154 mmol). The mixture
was stirred for 24 h at 100 °C. The reaction was quenched by adding
water. Then the mixture was extracted with dichloromethane. The
combined organic layers were dried over Na2SO4. After the solvent
was removed in vacuo, the residual mixture was purified by column
chromatography by elution with 7-10% ethyl acetate in hexane to
give an orange solid (27.5 mg, 0.114 mmol, 89%).
Experimental Section
General Procedures. All catalytic reactions were carried out
under an inert gas atmosphere using standard Schlenk techniques
and a glovebox, unless otherwise noted. Toluene and chloroform-d
were distilled from benzophenone ketyl and calcium hydride,
respectively, and stored under a nitrogen atmosphere. NaOtBu was
used as purchased. Organic reagents used for the coupling reactions
were dried and distilled just before use. Other reagents and solvents
were used as received. 4-(N,N-Dimethylamino)propiophenone, one
of the coupling substrates for N-arylation, was prepared referring
to the synthetic process of 4-(N,N-dimethylamino)acetophenone in
the literature, and the details are described in the Supporting
Information.24 The nickel complexes NiCl2(PPh3)(NHC) (1) and
NiCl2(NHC)2 were prepared according to the published methods.8
A Typical Procedure for r-Arylation of Ketones. To a solution
of 1 (5.2 mg, 6.7 µmol), NaOtBu (20.8 mg, 0.216 mmol), and
4-bromobenzophenone (34.4 mg, 0.132 mmol) in toluene (0.30 mL)
was added propiophenone (0.020 mL, 0.154 mmol). The mixture
was stirred for 24 h at 100 °C. The reaction was quenched by adding
water. Then the mixture was extracted with dichloromethane. The
combined organic layers were dried over Na2SO4. After the solvent
was removed in vacuo, the residual mixture was purified by column
chromatography by elution with 7-10% ethyl acetate in hexane to
give 2-(4-benzoylphenyl)-1-phenyl-1-propanone (25.3 mg, 0.120
mmol, 91%).
Data for N-(4-Benzoylphenyl)-N-(2,4,6-trimethylphenyl)-
aniline. 1H NMR (CDCl3, 400 MHz): δ 7.73-7.71 (m, 4H), 7.52
(t, J ) 7.6 Hz, 1H), 7.44 (t, J ) 8.0 Hz, 2H), 6.96 (s, 2H), 6.48 (d,
J ) 8.4 Hz, 2H), 2.32 (s, 3H), 2.18 (s, 6H). 13C NMR (CDCl3, 100
MHz): δ 195.1, 151.0, 139.0, 136.7, 136.4, 133.7, 133.0, 131.2,
129.5, 129.3, 128.0, 126.8, 111.8, 20.9, 18.2. IR (ν, cm-1): 3328
(NH, sh), 1590 (CO, vs). EI-MS: m/z 315 [M+], 316 [M+ + 1],
317 [M+ + 2]. HRMS (m/z) for C22H21NO: calcd 315.1623, found
315.1618.
Data for N-(4-Benzoylphenyl)-N-(2-isopropylphenyl)aniline.
1H NMR (CDCl3, 400 MHz): δ 7.76-7.73 (m, 4H), 7.54 (t, J )
6.4 Hz, 1H), 7.45 (t, J ) 7.2 Hz, 2H), 7.39-7.36 (m, 1H), 7.31-
7.29 (m, 1H), 7.24-7.21 (m, 2H), 6.77 (d, J ) 8.8 Hz, 2H), 3.18
(sept, J ) 6.8 Hz, 1H), 1.23 (t, J ) 7.2 Hz, 6H). 13C NMR (CDCl3,
100 MHz): δ 195.1, 150.5, 143.7, 138.8, 137.1, 132.8, 131.4, 129.5,
128.0, 127.7, 126.7, 126.5, 126.1, 125.5, 113.2, 27.9, 23.2. IR (ν,
cm-1): 3260 (NH, s), 1581 (CO, vs), 1569 (CO, vs). EI-MS: m/z
315 [M+], 316 [M+ + 1], 317 [M+ + 2]. HRMS (m/z) for C22H21-
NO: calcd 315.1623, found 315.1618.
Data for N-(4-Benzoylphenyl)-N-(2,6-diisopropylphenyl)-
aniline. 1H NMR (CDCl3, 400 MHz): δ 7.73 (d, J ) 8.0 Hz, 4H),
7.53 (t, J ) 6.8 Hz, 1H), 7.45 (t, J ) 7.6 Hz, 2H), 7.35 (t, J ) 7.6
Hz, 1H), 7.24 (d, J ) 7.2 Hz, 2H), 6.50 (br, 2H), 5.59 (br, 1H),
3.16 (sept, J ) 6.8 Hz, 2H), 1.16 (d, J ) 6.8 Hz, 12H). 13C NMR
(CDCl3, 100 MHz): δ 195.1, 152.2, 147.7, 139.0, 133.4, 133.0,
131.2, 129.5, 128.2, 128.0, 126.8, 124.1, 111.7, 28.3, 23.8. IR (ν,
cm-1): 3323 (NH, sh), 1598 (CO, vs), 1585 (CO, vs). EI-MS: m/z
357 [M+], 358 [M+ + 1], 359 [M+ + 2]. HRMS (m/z) for C25H27-
NO: calcd 357.2093, found 357.2088.
Data for N-(4-Benzoylphenyl)-N-(4-chlorophenyl)aniline. 1H
NMR (CDCl3, 400 MHz): δ 7.79-7.74 (m, 4H), 7.56 (t, J ) 6.0
Hz, 1H), 7.47 (t, J ) 7.2 Hz, 2H), 7.30 (d, J ) 8.8 Hz, 2H), 7.13
(d, J ) 8.8 Hz, 2H), 7.00 (d, J ) 8.8 Hz, 2H), 6.12 (br, 1H). 13C
NMR (CDCl3, 100 MHz): δ 195.2, 147.6, 139.3, 138.5, 132.7,
131.7, 129.6, 129.6, 129.1, 128.1, 121.7, 114.5. IR (ν, cm-1): 3310
(NH, vs), 1583 (CO, vs), 1564 (CO, vs). EI-MS: m/z 307 [M+],
Data for 2-(4-Benzoylphenyl)-1-(4-fluorophenyl)-1-propanone.
1H NMR(CDCl3, 400 MHz): δ 8.00-7.97 (m, 2H), 7.77-7.74 (m,
4H), 7.57 (t, J ) 5.6 Hz, 1H), 7.46 (t, J ) 7.6 Hz, 2H), 7.07 (t, J
) 8.4 Hz, 2H), 4.73 (q, J ) 6.8 Hz, 1H), 1.57 (d, J ) 6.8 Hz, 3H).
13C NMR (CDCl3, 100 MHz): δ 198.0, 196.1, 166.9, 164.3, 146.0,
137.4, 136.3, 132.5, 132.5, 132.4, 131.4, 131.3, 130.9, 130.0, 128.3,
(23) For examples of C- and O-bound nickel enolate complexes, see:
(a) Burkhardt, E. R.; Bergman, R. G.; Heathcock, C. H. Organometallics
1990, 9, 30-44. (b) Ca´mpora, J.; Maya, C. M.; Palma, P.; Carmona, E.;
Gutie´rrez-Puebla, E.; Ruiz, C. J. Am. Chem. Soc. 2003, 125, 1482-1483.
(24) Gupton, J. T.; Idoux, J. P.; Baker, G.; Colon, C.; Crews, A. D.;
Jurss, C. D.; Rampi, R. C. J. Org. Chem. 1983, 48, 2933-2936.
J. Org. Chem, Vol. 72, No. 14, 2007 5075

Matsubara et al.
308 [M+ + 1], 309 [M+ + 2]. HRMS (m/z) for C19H14NOCl: calcd
307.0764, found 307.0767.
(CDCl3, 100 MHz): δ 199.1, 195.2, 145.6, 145.6, 138.2, 132.5,
131.9, 130.7, 130.6, 130.1, 129.7, 128.2, 117.1, 116.7, 31.4, 8.5.
IR (ν, cm-1): 3308 (NH, s), 1587 (CO, s). EI-MS: m/z 329 [M+],
330 [M+ + 1], 331 [M+ + 2]. HRMS (m/z) for C22H19NO2: calcd
329.1416, found 329.1411.
Data for 4-[N,N-Bis(4-benzoylphenyl)amino]propiophenone.
1H NMR (CDCl3, 400 MHz): δ 7.94 (d, J ) 8.4 Hz, 2H), 7.82-
7.79 (m, 8H), 7.59 (t, J ) 7.2 Hz, 2H), 7.50 (t, J ) 7.2 Hz, 4H),
7.23-7.20 (m, 6H), 2.98 (q, J ) 7.2 Hz, 2H), 1.24 (t, J ) 7.2 Hz,
3H). 13C NMR (CDCl3, 100 MHz): 199.3, 195.3, 150.2, 150.0,
137.7, 133.0, 132.7, 132.3, 132.0, 129.8, 128.3, 124.1, 123.7, 31.6,
8.3. IR (νCO, cm-1): 1679 (s), 1651 (s), 1585 (vs). EI-MS: m/z
509 [M+], 510 [M+ + 1], 511 [M+ + 2]. HRMS (m/z) for C35H27-
NO3: calcd 509.1991, found 509.2002.
A Typical Procedure for the Reaction of 4-Aminopropiophe-
none. To a solution of 1 (5.0 mg, 6.4 µmol), NaOtBu (9.5 mg,
0.099 mmol), and 4-bromo-benzophenone (15.9 mg, 0.061 mmol)
in toluene (0.20 mL) was added 4-aminopropiophenone (10.9 mg,
0.073 mmol). The mixture was stirred for 24 h at 100 °C. The
reaction was quenched by adding water. Then the mixture was
extracted with dichloromethane. The combined organic layers were
dried over Na2SO4. After the solvent was removed in vacuo, the
residual mixture was purified by column chromatography to give
a yellow liquid (1.8 mg, 0.004 mmol, 26%) as a diamination product
and a pale yellow solid (7.0 mg, 0.021 mmol, 35%) as a
monoamination product by elution with 25-30% and 35-40%
ethyl acetate in hexane, respectively. The amount of the R-arylation
product was determined by means of the 1H NMR spectrum of the
crude mixture (5%).
Supporting Information Available: Experimental details of the
1
preparation of 4-(N,N-dimethylamino)propiophenone, H and 13C
Data for 4-[N-(4-Benzoylphenyl)amino]propiophenone. 1H
NMR (CDCl3, 400 MHz): δ 7.96 (d, J ) 8.8 Hz, 2H), 7.83 (d, J
) 8.4 Hz, 2H), 7.78 (d, J ) 8.2 Hz, 2H), 7.58 (t, J ) 7.2 Hz, 1H),
7.49 (t, J ) 7.2 Hz, 2H), 7.19 (d, J ) 8.8 Hz, 4H), 6.40 (br, 1H),
2.97 (q, J ) 7.2 Hz, 2H), 1.23 (t, J ) 7.6 Hz, 3H). 13C NMR
NMR spectra for new organic compounds, and the spectral data of
the other products. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO070313D
5076 J. Org. Chem., Vol. 72, No. 14, 2007