Nickel(0)/dihydroimidazol-2-ylidene complex catalyzed coupling of aryl chlorides and amines

Article abstract of DOI:10.1021/jo016352l

A general and simple nickel-catalyzed coupling of aryl chlorides and amines is reported. The scope and limitations of the coupling process using Ni(0), 1,3-bis(2,6-diisopropylphenyl)dihydroimidazol-2-ylidene, and NaO-t-Bu as base were investigated. Secondary cyclic and acyclic amines and anilines provided the arylamine coupling products in good to excellent yields. Compared to palladium-catalyzed aminations, this procedure offers an alternative route to N-substituted anilines starting from readily available aryl chlorides.

Full text of DOI:10.1021/jo016352l

J . Org. Chem. 2002, 67, 3029-3036
3029
Nick el(0)/Dih yd r oim id a zol-2-ylid en e Com p lex Ca ta lyzed Cou p lin g
of Ar yl Ch lor id es a n d Am in es
Christophe Desmarets, Raphae¨l Schneider, and Yves Fort*
Synthe`se Organique et Re´activite´, UMR 7565, Universite´ Henri Poincare´, Nancy I,
Faculte´ des Sciences, BP 239, 54506 Vandoeuvre les Nancy Cedex, France
Yves.Fort@sor.uhp-nancy.fr
Received December 6, 2001
A general and simple nickel-catalyzed coupling of aryl chlorides and amines is reported. The scope
and limitations of the coupling process using Ni(0), 1,3-bis(2,6-diisopropylphenyl)dihydroimidazol-
2-ylidene, and NaO-t-Bu as base were investigated. Secondary cyclic and acyclic amines and anilines
provided the arylamine coupling products in good to excellent yields. Compared to palladium-
catalyzed aminations, this procedure offers an alternative route to N-substituted anilines starting
from readily available aryl chlorides.
Aromatic amines are attractive targets for chemical
synthesis because of their prevalence and wide utility as
pharmacological agents, fine chemicals, dyes, and poly-
mers.1 There is thus a considerable interest in developing
efficient synthetic protocols for the construction of aryl-
nitrogen bonds.
recently developed by Lipshutz.9 For our part, we have
reported the use of a catalyst combination of in situ
generated colloidal Ni(0) associated with 2,2′-bipyridine
and NaO-t-Am-activated sodium hydride, which provided
an efficient route to substituted anilines.10 Some advan-
tages of this nickel-catalyzed approach were that the
coupling reactions occurred under fairly mild conditions
and were effective with inexpensive and readily available
aryl chlorides. In addition, the Ni/2,2′-bipyridine catalyst
The palladium-catalyzed carbon-nitrogen bond forma-
tion using aryl halides has been an area of intense
research in recent literature.2,3 The groups of Buchwald
and Hartwig have detailed the palladium-catalyzed
formation of aryl-nitrogen bonds using primary and
secondary amines, hydrazines, anilines, imines, and ni-
trogen-containing heterocycles. General, reliable, and
practical N-arylations using both electron-rich and elec-
tron-deficient aryl halides have thus been achieved.
These studies have all shown that a well-tailored metal-
ligand catalyst system is crucial for successful aryl
carbon-nitrogen bond formation. In the search for ligands
that provide highly active catalysts, improvements have
been made using bidentate phosphines,4 aminophos-
phines,5 and bulky electron-rich phosphines.6
By contrast, nickel-catalyzed amination reactions have
received less attention. Buchwald first reported the use
of Ni(cod)2 (cod ) cyclooctadiene) associated with 1,1′-
bis(diphenylphosphino)ferrocene (dppf) or 1,10-phenan-
throline for the synthesis of arylamines.7 Bolm extended
this N-arylation method for the coupling of sulfoximines
with aryl tosylates using Ni(cod)2 liganded with 2,2′-bis-
(diphenylphosphino)-1,1′-binaphthyl (BINAP).8 A hetero-
geneous Ni(0)/C catalyst liganded with dppf was also
(3) For recent reports, see: (a) Ali, M. H.; Buchwald, S. L. J . Org.
Chem. 2001, 66, 2560. (b) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40,
1513. (c) Arterburn, J . B.; Rao, K. V.; Ramdas, R.; Dible, B. R. Org.
Lett. 2001, 3, 1351. (d) Cui, W.; Loeppky, R. N. Tetrahedron 2001, 57,
2953. (e) Song, J . J .; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937. (f)
Madar, D. J .; Kopecka, H.; Pireh, D.; Pease, J .; Pliushchev, M.; Sciotti,
R. J .; Wiedeman, P. E.; Djuric, S. W. Tetrahedron Lett. 2001, 42, 3681.
(g) Parrish, C. A.; Buchwald, S. L. J . Org. Chem. 2001, 66, 3820. (h)
Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron Lett.
2001, 42, 4381.(i) Beletskaya, I. P.; Averin, A. D.; Bessmertnykh, A.
G.; Guilard, R. Tetrahedron Lett. 2001, 42, 4983. (j) Beletskaya, I. P.;
Averin, A. D.; Bessmertnykh, A. G.; Guilard, R. Tetrahedron Lett. 2001,
42, 4987. (k) J onckers, T. H. M.; Maes, B. U. W.; Lemie`re, G. L. F.;
Dommisse, R. Tetrahedron 2001, 57, 7027. (l) Wong, K.-T.; Wang, Z.-
J .; Chien, Y.-Y.; Wang, C.-L. Org. Lett. 2001, 3, 2285. (m) Cacchi, S.;
Fabrizi, G.; Goggiamani, A.; Zappia, G. Org. Lett. 2001, 3, 2539. (n)
Rivas, F. M.; Riaz, U.; Giessert, A.; Smulik, J . A.; Diver, S. T. Org.
Lett. 2001, 3, 2673. (o) Lee, S.; J orgensen, M.; Hartwig, J . F. Org. Lett.
2001, 3, 2729. (p) Wong, K.-T.; Hung, T. H.; Kao, S. C.; Chou, C. H.;
Su, Y. O. Chem. Commun. 2001, 1628. (q) Klapars, A.; Antilla, J . C.;
Huang, X.; Buchwald, S. L. J . Am. Chem. Soc. 2001, 123, 7727. (r)
Catenalli, M.; Catucci, C.; Celentano, G.; Ferraccioli, R. Synlett 2001,
803. (s) Brill, W. K.-D.; Riva-Toniolo, C.; Mu¨ller, S. Synlett 2001, 1097.
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Waibel, R.; Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40, 1283. (v)
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* To whom correspondence should be addressed.
(4) (a) Haman, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1998, 120,
7369. (b) Sadighi, J . P.; Harris, M. C.; Buchwald, S. L. Tetrahedron
Lett. 1998, 39, 5327.
(5) (a) Old, D. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 9722. (b) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 2000,
65, 1144.
(6) (a) Hartwig, J . F.; Kawatsura, M.; Hauck, S. I.; Saughnessy, K.
H.; Alcazar-Roman, L. M. J . Org. Chem. 1999, 64, 5575. (b) Wolfe, J .
P.; Buchwald, S. L. J . Org. Chem. 2000, 65, 1157. (c) Wolfe, J . P.;
Tomori, H.; Sadighi, J . P.; Yin, J .; Buchwald, S. L. J . Org. Chem. 2000,
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S., Ed.; Interscience: New York, 1968; p 61. (b) Negwer, M. Or-
ganic Drugs and their Synonyms, 7th ed.; Akademie Verlag
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10.1021/jo016352l CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/29/2002

3030 J . Org. Chem., Vol. 67, No. 9, 2002
Sch em e 1. Ca r ben e P r ecu r sor s
Desmarets et al.
has also been shown to be effective for a wide variety of
carbon-nitrogen bond forming processes including N-
monoarylation of piperazine11 and polyamination or
selective monoamination of aryl di- and trichlorides.12
However, the scope of our Ni/2,2′-bipyridine was some-
what limited. Indeed, fast and clean amination reactions
could only be achieved in the presence of a stoichiometric
amount of sodium hydride. The strong basicity of the
catalytic system limits the functional group tolerance of
the process and the nature of the amine which could be
used as coupling partner. For example, primary amines
and anilines were readily deprotonated by NaO-t-Am- or
NaO-t-Bu-activated NaH and the aryl amination prod-
ucts were obtained as mixtures of regioisomers resulting
from a competing benzyne pathway.
nickel-catalyzed aryl amination processes performed
without NaH demonstrating that the scope of the reaction
could be extended to aromatic and primary alkylamines
with this catalyst combination.
Resu lts a n d Discu ssion
In flu en ce of th e Ca r ben e Liga n d . To select the most
effective ligand, chlorobenzene and morpholine were
considered as appropriate substrates for the aryl ami-
nation coupling, and this combination was tested with
various mono- and bidentate imidazolium or dihydroimi-
dazolium salts (Scheme 1) associated with Ni(0) to
(11) Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2000, 41,
2881.
Considering the major effect of the ligands in pal-
ladium-catalyzed carbon-nitrogen bond forming pro-
cesses, we wondered whether the scope of our nickel-
catalyzed amination reactions could be improved and
extended to primary amines and anilines by the help of
a judiciously selected ligand, yielding a catalyst combina-
tion which does not require sodium hydride.
(12) (a) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett.
2000, 41, 2875. (b) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron
Lett. 2001, 42, 247. (c) Desmarets, C.; Schneider, R.; Fort, Y. Tetra-
hedron 2001, 57, 7657.
(13) Gardiner, M. G.; Herrmann, W. A.; Reisinger, C.-P.; Schwartz,
J .; Spiegler, M. J . Organomet. Chem. 1999, 572, 239.
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J . Am. Chem. Soc. 2001, 123, 8878. (b) Hillier, A. C.; Lee, H. M.;
Stevens, E. D.; Nolan, S. P. Organometallics 2001, 20, 4246.
(15) (a) Randl, S.; Connon, S. J .; Blechert, S. Chem. Commun. 2001,
1796. (b) Seiders, T. J .; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3,
3225. (c) Choi, T.-L.; Lee, C. W.; Chatterjee, A. K.; Grubbs, R. H. J .
Am. Chem. Soc. 2001, 123, 10417. (d) Schramm, M. P.; Reddy, D. S.;
Kozmin, S. A. Angew. Chem., Int. Ed. 2001, 40, 4274.
(16) (a) Huang, J .; Nolan, S. P. J . Am. Chem. Soc. 1999, 121, 9889.
(b) Zhang, C.; Huang, J .; Trudell, M. L. Nolan, S. P. J . Org. Chem.
1999, 64, 3804. (c) Zhang, C.; Trudell, M. L. Tetrahedron Lett. 2000,
41, 595. (d) Furstner, A.; Leitner, A. Synlett 2001, 290. (e) Grasa, G.
A.; Nolan, S. P. Org. Lett. 2001, 3, 119. (f) Magill, A. M.; McGuinness,
D. S.; Cavell, K. J .; Britovsek, G. J . P.; Gibson, V. C.; White, A. J . P.;
Williams, D. J .; White, A. H.; Skelton, B. W. J . Organomet. Chem. 2001,
617-618, 546. (g) Peris, E.; Loch, J . A.; Mata, J .; Crabtree, R. H. Chem.
Commun. 2001, 201. (h) Andrus, M. B.; Song, C. Org. Lett. 2001, 3,
3791.
(17) (a) Huang, J .; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307.
(b) Stauffer, S. R.; Sunwoo, L.; Stambuli, J . P.; Hauck, S. I.; Hartwig,
J . F. Org. Lett. 2000, 2, 1423. (c) Caddick, S.; Cloke, F. G. N.;
Clensmith, G. K. B.; Hitchcock, P. B.; McKerrecher, D.; Titcomb, L.
R.; Williams, M. R. V. J . Organomet. Chem. 2001, 617-618, 635. (d)
Cheng, J .; Trudell, M. L. Org. Lett. 2001, 3, 1371. (e) Titcomb, L. R.;
Caddick, S.; Cloke, F. G. N.; Wilson, D. J .; McKerrecher, D. Chem.
Commun. 2001, 1388. (g) Grasa, G. A.; Viciu, M. S.; Huang, J .; Nolan,
S. P. J . Org. Chem. 2001, 66, 7729.
In recent years, it has become clear that N-heterocyclic
carbenes (NHCs) can offer an interesting alternative class
of ligands to the ubiquitous phosphines for catalytic
applications. Various reactions involving imidazolium
salts as precursors to NHCs have recently been reported.
These include copolymerization of ethylene and CO,13
hydrogenation,14 and alkene metathesis.15 Palladium-
catalyzed protocols using NHCs have also been shown
to offer a significant advantage for a range of syntheti-
cally valuable coupling processes such as carbon-
carbon16 or carbon-nitrogen17 bond forming reactions.
These reports have all demonstrated that such thermally
stable and strong electron-donating ligands can be in-
corporated into the catalysts and that an excess of ligand
is not required to prevent aggregation of the metal.
A preliminary account of nickel-catalyzed amination
reactions performed with Ni(0)/NHC catalysts associated
with NaO-t-Bu-activated NaH has appeared.18 Herein,
we disclose the results of a detailed study of NHCs in
(18) Gradel, B.; Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron Lett.
2001, 42, 5689.

Coupling of Aryl Chlorides and Amines
J . Org. Chem., Vol. 67, No. 9, 2002 3031
Ta ble 1. Eva lu a tion of Im id a zoliu m Sa lts for
Nick el-Ca ta lyzed Cou p lin g of Ch lor oben zen e w ith
Mor p h olin ea ,b
formation of moderately active catalysts and allowed low
conversion of the starting materials (entries 4, 5, and
7-12), while the use of IPr‚HCl (1) led to N-phenylmor-
pholine in 90% yield. The differences in activity displayed
by the ligands might be attributed to the effectiveness
of NaO-t-Bu in the imidazolium salt deprotonation step
or, once the carbene is generated, to steric and electronic
effects affecting the performances of the nickel species
in the course of the aryl amination process. However, one
general feature needs to be noted. Dihydroimidazolium
carbenes, more σ-donating than imidazolium-based car-
benes,19 increased the activity of the catalysts, and
N-phenylmorpholine was obtained in substantial in-
creased yields using these ligands (compare entries 3-5
to entries 6-8, respectively).
In addition, a number of Ni(II) precursors were screened
in the coupling between morpholine and chlorobenzene
in refluxing THF using 1,3-bis(2,6-diisopropylphenyl)-
dihydroimidazol-2-ylidene as supporting ligand. Ni(acac)2
was found to be the best Ni(0) source. Ni(OAc)2 can also
be used (81% yield after 6 h of reaction time), while the
reaction proceeded, respectively, in only 53% and 35%
yield using NiCl2 and NiBr2. A variety of reaction con-
ditions were also examined, and we found that the base
NaO-t-Bu gave significantly higher isolated yields than
either the lithium or potassium analogue (respectively,
19% and 4%). Finally, either THF or dioxane at reflux
appeared suitable as solvent, while the use of a nonpolar
solvent such as toluene resulted in a slower conversion
(43% after 15 h) and significant reduction of chloroben-
zene to benzene via â-hydride elimination followed by
reductive elimination from the intermediate nickel-
amido complex.
Ar yla tion of Secon d a r y Cyclic a n d Acyclic Alk yl-
a m in es. To further investigate the scope of this new
method, we studied the nickel-catalyzed coupling of
secondary cyclic and acyclic amines with aryl chlorides
using 4 as carbene precursor and NaO-t-Bu as base.
Table 2 describes the results of these couplings using
structurally and electronically diverse aryl chlorides.
Using the optimal conditions described above (5 mol %
Ni, 5 mol % SIPr‚HCl, NaO-t-Bu (1.5 equiv relative to
the aryl chloride), THF, 65 °C), the Ni-catalyzed couplings
of aryl or heteroaryl chlorides with secondary amines
provided a general route to the corresponding arylamines.
The only side product observed was the arene resulting
from reduction of the starting aryl chloride. Electron-poor
aryl chlorides generally gave the amination product in
good to excellent yields (entries 7-13, 20-23, and 25,
Table 2), while lower yields were obtained with electron-
rich aryl chlorides (entries 14 and 15).
entry
ligand
yield (%) entry
ligand
yield (%)
1
2
3
4
5
6
0
25c
90
12
5
7
8
9
10
11
12
SIMes‚HCl, 5
20
8
2,2-bipyridine
IPr‚HCl, 1
IMes‚HCl, 2
ITol‚HCl, 3
SIPr‚HCl, 4
SITol‚HCl, 6
7
8
9
10
44d
0
27
14
94
a
Reaction conditions: 10 mmol of chlorobenzene, 15 mmol of
morpholine, 0.5 mmol of Ni(0), 0.5 mmol of imidazolium salt, 18
b
mmol of t-BuONa, 12 mL of THF, 65 °C. Yields were determined
by GC and are the average of two runs. c Reaction performed using
d
2 equiv of 2,2′-bipyridine relative to Ni(0). Reaction performed
using 4 equiv of imidazolium chloride relative to Ni(0).
determine the optimal conditions for the catalytic N-
arylation.
A variation on the preparation of the Ni(0) complex
was first investigated. Instead of employing stoichiomet-
ric amounts of NaH for the cross-coupling of amines with
aryl chlorides, the aryl amination reactions were per-
formed in the presence of NaO-t-Bu. The amount of NaH
used for the preparation of the catalyst was therefore
exactly adjusted to reduce the starting Ni(II) to Ni(0) and
to convert t-BuOH into NaO-t-Bu. This variation was
found to be effective, and a slight excess of NaH was not
necessary to maintain the Ni(0) catalyst in the lowest
oxidation state. The catalysts were all in situ generated
by stirring a mixture of Ni(acac)2 (5 mol %), the imida-
zolium carbene precursor, and NaH in refluxing THF
followed by the addition of t-BuOH and morpholine.
These Ni/carbene catalysts were used after 1/2 h at 65
°C for the amination of chlorobenzene.
The role of the in situ generated NaO-t-Bu is 2-fold
during the preparation of the starting NHC liganded
Ni(0) complex: (i) it initially activates sodium hydride
used to reduce the Ni(II) salt to Ni(0) ; (ii) it deprotonates
the imidazolium salt to form the carbene ligand which
coordinates to the metal.
As expected, the coupling without using ligand resulted
in no detectable reaction products (entry 1, Table 1). It
was also of interest to run a control reaction with 2,2′-
bipyridine, which has led to good results when the
reactions were performed with stoichiometric amounts
of NaH.10-12 Using the new protocol, this ligand af-
forded only a moderately active catalyst, and N-phenyl-
morpholine was obtained in a modest 25% yield (entry
2, Table 1).
A screening of representative NHC ligands is sum-
marized in Table 1. After some experimentation, we first
found that with monodentate carbenes 1-6 and 10,
biscarbene 9, or tridentate ligand 8, a 1/1 ratio of carbene
to Ni gave the best catalyst combination. Using 1,3-di-
(tert-butyl)imidazolium 7, a Ni/ligand ratio of 1/4 gave
improved yields of N-phenylmorpholine (10% when Ni/L
) 1/1 compared to 44% when Ni/L )1/4).
The bulky 1,3-bis(2,6-diisopropylphenyl)dihydroimi-
dazol-2-ylidene, generated from SIPr‚HCl (4), was found
to be the most effective NHC precursor, leading to
N-phenylmorpholine in a 94% yield (entry 6). 1,3-Disub-
stituted imidazolium salts 2, 3, and 5-10 led to the
Surprisingly, while morpholine and pyrrolidine were
efficiently coupled with 3-chloroanisole in high yields
(entries 7 and 9), the reaction with piperidine gave a large
amount of reduced side product, and N-phenylpiperidine
was obtained in a modest 55% yield. Such a limitation
was previously observed with the Pd/BINAP20 catalyst
and is, for the moment, difficult to explain.
(19) (a) Huang, J .; Nolan, S. P. J . Am. Chem. Soc. 1999, 121, 9889.
(b) Zhang, C.; Huang, J .; Trudell, M. L. Nolan, S. P. J . Org. Chem.
1999, 64, 3804. (c) Zhang, C.; Trudell, M. L. Tetrahedron Lett. 2000,
41, 595. (d) Furstner, A.; Leitner, A. Synlett 2001, 290. (e) Grasa, G.
A.; Nolan, S. P. Org. Lett. 2001, 3, 119. (f) Maggill, A. M.; McGuiness,
D. S.; Cavell, K. J .; Britovsek, G. J . P.; Gibson, V. C.; White, A. J . P.;
Williams, D. J .; White, A. H.; Skelton, B. W. J . Organomet. Chem. 2001,
617-618, 546. (g) Peris, E.; Loch, J . A.; Mata, J .; Crabtree, R. H. Chem.
Commun. 2001, 201.

3032 J . Org. Chem., Vol. 67, No. 9, 2002
Ta ble 2. Nick el-Ca ta lyzed Cou p lin g of Secon d a r y Am in es w ith Ar yl Ch lor id esa
Desmarets et al.
a
Reaction conditions: 10 mmol of aryl halide, 15 mmol of amine, 18 mmol of NaO-t-Bu, 0.5 mmol of Ni(0), 0.5 mmol of SIPr‚HCl, 12
mL of THF, 65 °C, 5-10 h (reaction times have not been minimized). All products were characterized by 1H and 13C NMR, IR, and
b
GC/MS spectroscopy methods. c Yields are for isolated compounds estimated to be >95% pure by 1H and 13C NMR, GC, and EA and are
d
an average of two runs. A 1 mmol sample of Ni(0), a 1 mmol sample of SIPr‚HCl, and a 20 mmol sample of amine were used, and
dioxane was used as solvent. e A 20 mmol sample of piperazine was used, and dioxane was used as solvent. f A 30 mmol sample of chloro-
g
h
benzene and a 10 mmol sample of piperazine were used. A 28 mmol sample of NaO-t-Bu was used. A 10 mmol sample of aryl halide,
a 30 mmol sample of amine, a 36 mmol sample of NaO-t-Bu, a 1 mmol sample of Ni(0), and a 1 mmol sample of SIPr‚HCl were used.
The Ni(0)/SIPr‚HCl catalyst was only slightly sensitive
to an ortho-substitution of the aryl chloride. 2-Chloro-
toluene reacted with morpholine in 69% yield (entry 4,
Table 2), while 3- and 4-chlorotoluene reacted with the
amine without difficulty (entries 5 and 6). Contrary to
other Ni(0) catalysts,21 nitriles (entry 11) and noneno-
lizable ketone groups (entry 12) were well tolerated.
Moreover, substrates containing functional groups that
might be problematic in a palladium-catalyzed methodol-
ogy such as a primary aromatic (entry 13) or an alkene
(entry 15) were transformed in good yields.
The reaction of acyclic secondary amines occurred in
refluxing dioxane using 10 mol % catalyst with rates that
were comparable to those of cyclic secondary amines.
N-Methylbenzylamine and N-methylaminoacetaldehyde
dimethyl acetal reacted with chlorobenzene to give the
desired arylamines in, respectively, 92% and 81% yield
(entries 16 and 17), and even the sterically hindered
dibenzylamine reacted with 3-chloropyridine to give the
coupled product in 54% yield (entry 22).
in dioxane, chlorobenzene coupled with piperazine to
form the N-arylated product in 79% yield (entry 18, Table
2). Higher temperatures than those used for secondary
cyclic monoamines were however necessary. It must also
be underlined that the formation of the bisarylated
product was observed in less than 7% yield. Using an
excess of chlorobenzene (3 equiv) relative to piperazine,
the symmetrically N,N′-biphenyl substituted diamine
could be isolated in 83% yield (entry 19).
Amination of aryl dichlorides was finally investigated.
Diaminated products were formed exclusively and in good
yields when 1,3-dichlorobenzene or 4,4′-dichloroben-
zophenone was treated with morpholine using 5 mol %
Ni(0)/SIPr‚HCl catalyst combination per carbon-chlorine
functionality (entries 24 and 25, Table 2).
Ar yla t ion of An ilin es. Given the success of the
Ni(0)/SIPr‚HCl combination for the arylation of secondary
cyclic and acyclic amines, we were interested to extend
the scope and generality of this system to the arylation
of anilines.
The Ni(0)/SIPr‚HCl catalyst was also effective for the
arylation of piperazine. Using a 2-fold excess of amine
relative to the aryl chloride and performing the reaction
Under standard conditions using typically 5 mol %
nickel and 5 mol % SIPr‚HCl and preparing the Ni(0)
catalyst in the presence of the amine, aniline was coupled
in a poor 21% yield with chlorobenzene even after
extended reaction times. Initial studies revealed first that
premixing the aryl chloride and the amine and adding
(20) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 2000, 65, 1144.
(21) (a) Garcia, J . J .; J ones, W. D. Organometallics 2000, 19, 5544.
(b) Miller, A. J . Tetrahedron Lett. 2001, 42, 6991.

Coupling of Aryl Chlorides and Amines
J . Org. Chem., Vol. 67, No. 9, 2002 3033
Ta ble 3. Nick el-Ca ta lyzed Cou p lin g of An ilin es w ith Ar yl Ch lor id esa
a
Reaction conditions: 10 mmol of aryl halide, 15 mmol of amine, 18 mmol of NaO-t-Bu, 1 mmol of SIPr‚HCl, 0.5 mmol of Ni(0), 12 mL
of dioxane, 100 °C, 5-10 h (reaction times have not been minimized). All products were characterized by 1H and 13C NMR, IR, and
b
GC/MS spectroscopy methods. c Yields are for isolated compounds estimated to be >95% pure by 1H and 13C NMR, GC, and EA and are
d
e
an average of two runs. A 2 mmol sample of SIPr‚HCl and a 1 mmol sample of Ni(0) were used. A 10 mmol sample of aryl dihalide,
a 30 mmol sample of amine, a 36 mmol sample of NaO-t-Bu, a 2 mmolsample of Ni(0), and a 4 mmol sample of SIPr‚HCl were used.
these reagents simultaneously to the liganded Ni(0)
catalyst was essential for a high catalytic activity. These
results support the fact that these nickel-catalyzed aryl
aminations proceed via intermediates in which the
nitrogen-nickel interaction is important. Presumably,
adding simultaneously the aryl chloride and the amine
to the catalyst allowed the coordination of aniline toward
the nickel center to be avoided, thereby permitting the
oxidative addition of the aryl chloride.
We also reevaluated the relative importance of the
ligand/metal ratio and solvent on the reaction yields
using diphenylamine as a model substrate. Reaction rates
were markedly increased using a 2/1 ratio of ligand to
metal and using dioxane as solvent. A slight excess of
the amine was also necessary.
scope for arylation of anilines was similar to that for
reactions performed with secondary cyclic or acyclic
amines. Excellent results for the arylations of aniline,
p-toluidine, or p-anisidine with aryl chloride were ob-
tained using the Ni(0)/SIPr‚HCl catalyst. For example,
the reaction of p-toluidine with chlorobenzene proceeded
to completion in 5 h to afford the desired product in 99%
yield (entry 2, Table 3). Using ortho (entry 7), meta
(entries 6 and 8), or para (entries 9 and 20) substituted
aryl halides, the corresponding amines were obtained in
good to excellent yields. Even ortho,ortho disubstituted
substrates such as 2,6-dimethylchlorobenzene reacted
with p-anisidine to give the diarylamine in 86% yield
(entry 10), indicating that a high degree of steric hin-
drance on the aryl chloride does not impede the reaction.
The scope of the reaction of anilines with aryl chlorides
is presented in Table 3. An excess of aniline (1.5 equiv
relative to the aryl chloride) was used in all these
couplings to ensure short reaction times. However, we
found that reactions could also be performed using 1.2
equiv of the amine without a significant decrease of
reaction yields. It is also worth noting that no double
arylation products were observed using either 1.5 or 1.2
equiv of amine relative to the aryl chloride.
We next screened a variety of anilines to determine
the effect of the substitution pattern on the reaction yield.
Ortho substitution of the aniline was well tolerated
(entries 11, 16, and 17, Table 3). Reactions performed
with sterically hindered anilines afforded the desired
products in moderate to good yields. Chlorobenzene
reacted with 2,4,6-trimethylaniline (entry 12) in 91%
yield, and even 2,6-diisopropylaniline provided the di-
arylamine product in 55% yield when combined with
chlorobenzene (entry 13). However, the Ni(0)/SIPr‚HCl
catalyst system was found to be less effective for the
arylation of anilines bearing electron-withdrawing sub-
The amination technology based on the Ni(0)/SIPr‚HCl
combination is applicable to a wide range of anilines and
aryl or heteroaryl chlorides. In general, the substrate

3034 J . Org. Chem., Vol. 67, No. 9, 2002
Desmarets et al.
Sch em e 2
stituents (entries 14-16, Table 3). For example, the
coupling between chlorobenzene and 3-fluoroaniline gave
only 59% N-(3-fluorophenyl)-N-phenylamine (entry 15),
while aniline reacted with 3-fluorochlorobenzene to give
the desired arylamine in 83% yield (entry 6). Using such
substrates, reaction times were increased and aryl ami-
nation was depressed. Arylations of anilines substituted
by electron-withdrawing substituents were possible, al-
though fairly high catalyst loadings (10 mol % Ni) were
required (entries 14-16). This may be a consequence of
the reduced nucleophilicity of these amines, which in-
hibits the coordination to the nickel(II) center, which is
necessary for their deprotonation. An alternative expla-
nation is that their reduced nucleophilicity inhibits the
substitution of the chlorine atom on the intermediate
aryl nickel(II) complex, which is necessary for the tran-
samination step. This relative drawback can however
easily be overcome by inverting the substitution pattern
of the aniline and the aryl chloride (compare entries 6
and 15).
Surprisingly, the introduction of an o-methoxy group
on the aromatic ring resulted in an incomplete reaction
even after extended reaction times (24 h), and the
coupling between chlorobenzene and o-anisidine afforded
N-(2-methoxyphenyl)-N-phenylamine in only 63% yield
(entry 17, Table 3). We speculate that the decrease of
efficiency of the Ni(0)/SIPr‚HCl catalyst might result
from a coordination of the nickel center at the nitrogen
and oxygen atoms of o-anisidine.
N-Methylaniline was also efficient in cross-coupling
with various aryl chlorides (entries 18-20 and 22). As
shown in Table 3, the reaction proceeded to completion
in less than 10 h, affording the desired products in yields
ranging from 84% with chlorobenzene (entry 18) to 99%
with the activated 4-chlorobenzophenone (entry 20).
Changing the substitution on the nitrogen atom from Me
to a simple Et group provided the diarylamine in a
modest 47% yield (entry 21). This experiment demon-
strates that the steric bulk on the nitrogen atom plays
an important role in the outcome of the reaction using
the Ni(0)/SIPr‚HCl catalyst and explains why diaryl-
amines were obtained selectively without formation of
the corresponding triarylamines.
alkylamines relative to other amines used in this study
may be due to the formation of catalytically inactive
nickel species such as bis-amido-bridged complexes or bis-
(amine) complexes as observed in the palladium-cata-
lyzed aryl amination reaction.3a,22
Mech a n istic Con sid er a tion s. There is little mecha-
nistic information about couplings conducted with the
Ni(0)/SIPr‚HCl/NaO-t-Bu catalyst combination, but the
catalytic cycle for the amination reaction is presumably
similar to that postulated for the palladium-catalyzed
amination of aryl halides using Pd/carbene systems.17
The first step involves formation of Ni(0) by reduction of
Ni(acac)2 with NaO-t-Bu-activated sodium hydride fol-
lowed by coordination of the carbene generated from
SIPr‚HCl to the metal center. Transmission electron
microscopy coupled energy-dispersive X-ray spectra of the
Ni/carbene catalyst thus obtained revealed a homoge-
neous distribution of uniformly sized amorphous and
subnanometrical Ni(0) particles. The strong electron-
donating property of the carbene ligand facilitates the
oxidative addition of the aryl chloride to Ni(0). From
results obtained with anilines and primary alkylamines,
it seems apparent that aryl amido nickel species are
involved in the second step of the catalytic cycle. Finally,
the steric bulk of the carbene generated from SIPr‚HCl
may accelerate the carbon-nitrogen bond forming reduc-
tive elimination. On the basis of these observations, a
likely pathway for carbon-nitrogen couplings mediated
by the Ni(0)/SIPr‚HCl/NaO-t-Bu catalyst is depicted in
Scheme 3.
Sch em e 3. P r op osed Mech a n ism for th e
Am in a tion of Ar yl Ch lor id es
It should be noted that diphenylamine, a sterically
hindered aromatic amine, and R- or â-naphthylamine
(experiments not reported), did not provide any coupling
product when reacted with chlorobenzene. By contrast,
N-naphthyl-N-phenylamine could be obtained in 82%
yield by coupling p-anisidine and 1-chloronaphthalene
(entry 4, Table 3).
Additionally, the Ni-catalyzed arylation reaction has
been successfully employed for the polyamination of aryl
dichlorides. 4,4′-Dichlorobenzophenone reacted with 3
equiv of N-methylaniline in the presence of an excess of
NaO-t-Bu in dioxane at 100 °C to give bis[4-(methyl-
anilino)phenyl]methanone in 84% yield (entry 22, Table
3).
Ar yla tion of P r im a r y Alk yla m in es. Finally, in the
case of primary alkylamines, acceptable yields could only
be realized with activated aryl chlorides. 4-Chloroben-
zophenone was efficiently coupled with n-hexylamine or
cyclohexylamine to give the desired products in 65% and
85% yield, respectively. Using a neutral substrate such
as chlorobenzene, the reaction rate was slower and a
substantial amount of dehalogenated product was ob-
served (Scheme 2). The lower reactivity of primary
(22) Widenhoefer, R. A.; Buchwald, S. L. Organometallics 1996, 15,
3534.
(23) (a) Arduengo, A. J ., III. U.S. Patent 5 077 414, 1991. (b)
Arduengo, A. J ., III; Krafczyk, R.; Schmutzler, R. Tetrahedron 1999,
55, 14523-14534.

Coupling of Aryl Chlorides and Amines
J . Org. Chem., Vol. 67, No. 9, 2002 3035
1
isolated as a yellow oil (53%). H NMR (400 MHz, CDCl3): δ
Con clu sion
7.33 (d, J ) 8.0 Hz, 2H), 6.86 (d, J ) 8.0 Hz, 2H), 6.64 (dd, J
) 16.0, 12.0 Hz, 1H), 5.60 (d, J ) 16.0 Hz, 1H), 5.09 (d, J )
12.0 Hz, 1H), 3.87-3.84 (m, 4H), 3.18-3.14 (m, 4H). 13C NMR
(CDCl3, 100 MHz): δ 150.81, 136.22, 129.43, 127.08, 115.34,
In summary, we have developed a novel protocol for
the amination of aryl chlorides which is based on nickel/
N-heterocyclic carbene cross-coupling methodology. The
Ni(0)/SIPr‚HCl catalyst combined with NaO-t-Bu proved
to be efficient and high yielding for the arylation of
secondary cyclic or acyclic amines and anilines. The
reaction is widely applicable to a variety of electron-rich,
electron-poor, and neutral aryl chlorides as well as
heterocyclic halides. Good to excellent yields were ob-
tained regardless of the substitution pattern of the aryl
chloride. Studies are under way to further expand the
scope of this methodology to primary alkylamines as well
as to understand the mechanistic pathway of the nickel-
catalyzed process.
111.03, 66.80, 49.05. MS: m/ z 189. Anal. Calcd for C12H15
-
NO: C, 76.16, H, 7.99, N, 7.40. Found: C, 76.3, H, 8.1, N, 7.3.
N,N-Diben zyl-3-p yr id in a m in e (Ta ble 2, En tr y 22). The
general procedure was used to couple 3-chloropyridine and
N,N-dibenzylamine. The reaction was conducted at 65 °C in
THF with 10 mol % Ni(0), 10 mol % SIPr‚HCl, and 20 mmol
of N,N-dibenzylamine. The title compound was isolated as a
1
light yellow oil (54%). H NMR (400 MHz, CDCl3): δ 8.14 (d,
J ) 1.8 Hz, 1H), 7.90 (d, J ) 4.0 Hz, 1H), 7.33-7.15 (m, 12H),
4.62 (s, 4H). 13C NMR (CDCl3, 100 MHz): δ 144.59, 137.54,
137.21, 134.57, 128.51, 126.93, 126.25, 123.31, 118.77, 53.89.
MS: m/ z 274. Anal. Calcd for C19H18N2: C, 83.18, H, 6.61, N,
10.21. Found: C, 83.3, H, 6.3, N, 10.4.
Gen er a l P r oced u r e for th e Ar yla tion of An ilin es. A 50
mL Schlenk tube was loaded with degreased NaH (16 mmol),
Ni(acac)2 (0.5 mmol, 5 mol %), SIPr‚HCl (1 mmol, 10 mol %),
and 6 mL of dioxane, and the mixture was heated to 100 °C.
A solution of t-BuOH (15 mmol) in 3 mL of dioxane was then
added dropwise, and the mixture was further stirred at 100
°C for 1/2 h. A solution of the aryl chloride (10 mmol) and the
amine (15 mmol) in 3 mL of dioxane was then added dropwise,
and the reaction was monitored by GC. After complete
consumption of the aryl chloride, the mixture was cooled to
room temperature and adsorbed onto silica gel. The crude
reaction mixture was purified by silica gel column chroma-
tography.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All reactions were carried out
using standard Schlenk techniques under an atmosphere of
nitrogen. Gas chromatographic analyses were performed on a
capillary gas chromatograph fitted with an “Optima 5” column
(22 m × 0.25 mm i.d. × 0.25 µm). All quantifications of reaction
constituents were achieved by gas chromatography using a
known quantity of decane as reference standard. Melting
points were taken on a Tottoli apparatus and are uncorrected.
The 1H, 19F, and 13C NMR spectra were recorded at 400.13,
235.0, and 100.40 MHz using CDCl3 as solvent. IR spectra
were recorded using NaCl cells or a mixture of compound/KBr.
Compounds previously described were characterized by 1H and
13C NMR, and their purity was confirmed by GC analysis. The
characterization data of these compounds are given in the
Supporting Information. All new compounds were fully char-
N-(4-Meth oxyph en yl)-2,6-dim eth ylan ilin e (Table 3, En -
tr y 10). The general procedure was used to couple 2,6-
dichlorotoluene and p-anisidine. The reaction was conducted
at 100 °C in dioxane with 5 mol % Ni(0) and 10 mol % SIPr‚
HCl. The title compound was isolated as a light yellow solid
acterized by H and 13C NMR, IR, and elemental analysis.
1
1
(86%). Mp: 53 °C. IR (NaCl, cm-1): νNH 3406. H NMR (400
THF and dioxane were distilled under nitrogen from sodium
benzophenone ketyl. tert-Butyl alcohol was distilled from
sodium before use. Sodium hydride (65% in mineral oil) was
purchased from Fluka and used after two washings with THF
under nitrogen. Aryl halides were purchased from commercial
sources and used without further purification. Amines were
purchased from commercial sources and distilled or passed
through alumina before use. Nickel(II) acetylacetonate was
purchased from Acros and used as received. All imidazolium
salts were synthesized according to literature procedures.1,2
Gen er a l P r oced u r e for th e Ar yla tion of Secon d a r y
Cyclic Am in es. A 50 mL Schlenk tube was loaded with
degreased NaH (16 mmol), Ni(acac)2 (0.5 mmol, 5 mol %), SIPr‚
HCl (0.5 mmol, 5 mol %), and 6 mL of solvent (THF or
dioxane), and the mixture was heated to reflux. A solution of
t-BuOH (15 mmol) in 3 mL of THF or dioxane was then added
dropwise followed by the amine (15 mmol), and the mixture
was further stirred for 1/2 h. A solution of the aryl chloride
(10 mmol) in 3 mL of THF or dioxane was then added, and
the reaction was monitored by GC. After complete consumption
of the aryl chloride, the mixture was cooled to room temper-
ature and adsorbed onto silica gel. The crude reaction mixture
was purified by silica gel chromatography.
3-Mor p h olin oa n ilin e (Ta ble 2, En tr y 13). The general
procedure was used to couple 3-chloroaniline and morpholine.
The reaction was conducted at 65 °C in THF with 5 mol %
Ni(0) and 5 mol % SIPr‚HCl. The title compound was isolated
as a brown oil (68%). IR (NaCl, cm-1): νNH 3349. 1H NMR (400
MHz, CDCl3): δ 7.04-6.99 (m, 1H), 6.31-6.29 (m, 1H), 6.19-
6.17 (m, 2H), 3.79-3.77 (m, 4H), 3.55 (br s, NH2), 3.06-3.04
(m, 4H). 13C NMR (CDCl3, 100 MHz): δ 152.17, 147.23, 129.62,
107.00, 105.96, 102.20, 66.59, 48.99. MS: m/ z 178. Anal. Calcd
for C10H14N2O: C, 67.39, H, 7.92, N, 15.72. Found: C, 67.4,
H, 7.9, N, 15.9.
MHz, CDCl3): δ 7.11-7.01 (m, 3H), 6.75 (d, J ) 8.0 Hz, 2H),
6.50 (d, J ) 8.0 Hz, 2H), 3.74 (s, 3H), 2.20 (s, 6H). 13C NMR
(100 MHz, CDCl3): δ 140.08, 139.23, 134.85, 128.56, 128.44,
124.99, 124.87, 123.58, 115.26, 114.83, 114.68, 55.70, 18.36.
MS: m/ z 227. Anal. Calcd for C15H17NO: C, 79.26, H, 7.54,
N, 6.16. Found: C, 79.1, H, 7.4, N, 6.3.
N-(2-E t h ylp h en yl)a n ilin e (Ta b le 3, E n t r y 11). The
general procedure was used to couple chlorobenzene and 2-eth-
ylaniline. The reaction was conducted at 100 °C in dioxane
with 5 mol % Ni(0) and 10 mol % SIPr‚HCl. The title compound
was isolated as a light yellow oil (96%). IR (NaCl, cm-1): νNH
1
3399. H NMR (400 MHz, CDCl3): δ 7.15-7.23 (m, 4H), 7.09
(td, J ) 8.0, 2.0 Hz, 1H), 6.95 (td, J ) 8.0, 2.0 Hz, 1H), 6.88-
6.80 (m, 3H), 5.30 (s, NH), 2.55 (q, J ) 8.0 Hz, 2H), 1.19 (t, J
) 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 144.43, 140.36,
134.71, 129.15, 128.81, 126.53, 122.51, 120.05, 120.01, 116.87,
24.15, 13.77. MS: m/ z 197. Anal. Calcd for C14H15N: C, 85.24,
H, 7.66, N, 7.10. Found: C, 85.4, H, 7.3, N, 7.3.
N-Meth yl-N-p h en yla n ilin e (Ta ble 3, En tr y 18). The
general procedure was used to couple chlorobenzene and
N-methylaniline. The reaction was conducted at 100 °C in
dioxane with 5 mol % Ni(0) and 10 mol % SIPr‚HCl. The title
compound was isolated as a light yellow oil (84%). 1H NMR
(400 MHz, CDCl3): δ 7.24 (t, J ) 8.0 Hz, 4H), 7.01 (d, J ) 8.0
Hz, 4H), 6.92 (td, J ) 8.0, 2.0 Hz, 2H), 3.29 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 148.97, 129.13, 121.20, 120.39, 40.18.
MS: m/ z 183. Anal. Calcd for C13H13N: C, 85.21, H, 7.15, N,
7.64. Found: C, 85.3, H, 7.0, N, 7.7.
N-Eth yl-N-p h en yl-3-p yr id in a m in e (Ta ble 3, En tr y 21).
The general procedure was used to couple 3-chloropyridine and
N-ethylaniline. The reaction was conducted at 100 °C in
dioxane with 5 mol % Ni(0) and 10 mol % SIPr‚HCl. The title
compound was isolated as a light yellow oil (47%). 1H NMR
(400 MHz, CDCl3): δ 8.28 (br s, 1H), 8.11 (br s, 1H), 7.34 (t, J
) 8.0 Hz, 2H), 7.20-7.18 (m, 1H), 7.13-7.10 (m, 4H), 3.80 (q,
J ) 8.0 Hz, 2H), 1.25 (t, J ) 8.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 146.29, 144.02, 140.28, 140.04, 129.59, 124.68,
123.49, 123.39, 123.34, 46.23, 12.37. MS: m/ z 198. Anal. Calcd
4-(4-Vin ylp h en yl)m or p h olin e (Ta ble 2, En tr y 15). The
general procedure was used to couple 4-chlorostyrene and
morpholine. The reaction was conducted at 65 °C in THF with
5 mol % Ni(0) and 5 mol % SIPr‚HCl. The title compound was

3036 J . Org. Chem., Vol. 67, No. 9, 2002
Desmarets et al.
for C13H14N2: C, 78.75, H, 7.12, N, 14.13. Found: C, 78.7, H,
7.3, N, 14.0.
125.52, 125.03, 113.91, 40.20. MS: m/ z 392. Anal. Calcd for
C27H24N2O: C, 82.62, H, 6.16, N, 7.14. Found: C, 82.4, H, 6.0,
N, 7.1.
Bis[4-(m eth yla n ilin o)p h en yl]m eth a n on e (Ta ble 3, En -
tr y 22). The general procedure was used to couple 4,4′-
dichlorobenzophenone and N-methylaniline. The reaction was
conducted at 100 °C in dioxane with 10 mol % Ni(0), 20 mol %
SIPr‚HCl, 10 mmol of 4,4′-dichlorobenzophenone, 30 mmol of
N-methylaniline, and 36 mmol of NaO-t-Bu. The title com-
pound was isolated as a yellow solid (84%). Mp: 112 °C. IR
(NaCl, cm-1): νCO 1629. 1H NMR (400 MHz, CDCl3): δ 7.71
(d, J ) 8.8 Hz, 4H), 7.93 (t, J ) 8.0 Hz, 4H), 7.26-7.16 (m,
6H), 6.81 (d, J ) 8.8 Hz, 4H), 3.38 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ 193.86, 151.83, 147.56, 131.81, 129.71, 128.21,
Ack n ow led gm en t. We thank Dr. J . Ghanbaja for
transmission electron microscopy and energy dispersive
X-ray experiments.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization of all compounds prepared, and
references to known products. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O016352L