Amination reactions of aryl halides with nitrogen-containing reagents mediated by palladium/imidazolium salt systems

Article abstract of DOI:10.1021/jo010613+

Nucleophilic N-heterocyclic carbenes have been conveniently used as catalyst modifiers in amination reactions involving aryl chlorides, aryl bromides, and aryl iodides with various nitrogen-containing substrates. The scope of a coupling process using a Pd(0) or Pd(II) source and an imidazolium salt in the presence of a base, KO^tBu or NaOH, was tested using various substrates. The Pd₂(dba)₃/IPr·HCl (1, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) system presents the highest activity with respect to electron-neutral and electron-rich aryl chlorides. The ligand is also effective for the synthesis of benzophenone imines, which can be easily converted to the corresponding primary amines by acid hydrolysis. Less reactive indoles were converted to N-aryl-substituted indoles using as supporting ligand the more donating SIPr·HCl (5, SIPr = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene). The Pd(OAc)₂/SIPr·HCl/NaOH system is efficient for the N-arylation of diverse indoles with aryl bromides. The general protocol developed has been applied successfully to the synthesis of a key intermediate in the synthesis of an important new antibiotic. Mechanistically, palladium-to-ligand ratio studies strongly support an active species bearing one nucleophilic carbene ligand.

Full text of DOI:10.1021/jo010613+

J . Org. Chem. 2001, 66, 7729-7737
7729
Am in a tion Rea ction s of Ar yl Ha lid es w ith Nitr ogen -Con ta in in g
Rea gen ts Med ia ted by P a lla d iu m /Im id a zoliu m Sa lt System s
Gabriela A. Grasa, Mihai S. Viciu, J inkun Huang, and Steven P. Nolan*
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148
snolan@uno.edu
Received J une 15, 2001
Nucleophilic N-heterocyclic carbenes have been conveniently used as catalyst modifiers in amination
reactions involving aryl chlorides, aryl bromides, and aryl iodides with various nitrogen-containing
substrates. The scope of a coupling process using a Pd(0) or Pd(II) source and an imidazolium salt
in the presence of a base, KOtBu or NaOH, was tested using various substrates. The Pd2(dba)3/
IPr‚HCl (1, IPr ) 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) system presents the highest
activity with respect to electron-neutral and electron-rich aryl chlorides. The ligand is also effective
for the synthesis of benzophenone imines, which can be easily converted to the corresponding
primary amines by acid hydrolysis. Less reactive indoles were converted to N-aryl-substituted
indoles using as supporting ligand the more donating SIPr‚HCl (5, SIPr ) 1,3-bis(2,6-diisopropy-
lphenyl)-4,5-dihydroimidazol-2-ylidene). The Pd(OAc)2/SIPr‚HCl/NaOH system is efficient for the
N-arylation of diverse indoles with aryl bromides. The general protocol developed has been applied
successfully to the synthesis of a key intermediate in the synthesis of an important new antibiotic.
Mechanistically, palladium-to-ligand ratio studies strongly support an active species bearing one
nucleophilic carbene ligand.
In tr od u ction
ing ligation plays a crucial role in dictating the efficiency
of the catalytic system.8 To this end, bulky monodentate
phosphine or bidentate PX (X ) P, N, O) ligands are
usually employed.8,9 Ligand properties make possible the
activation of inexpensive aryl chlorides as partners in
amination reaction.9 However, despite their effectiveness
in controlling reactivity and selectivity in organometallic
chemistry and homogeneous catalysis,10 tertiary phos-
phines are often air-sensitive and are subject to P-C
bond degradation at elevated temperatures. As a conse-
quence, the use of higher phosphine concentration in such
catalytic processes is often required.11
Palladium-catalyzed synthesis of N-substituted anilines
using aryl halides or halide equivalents has proven to
be a very useful and versatile method in organic synthe-
sis.1 The N-aryl moiety represents an important motif
in natural products2a and pharmaceutical and medicinal
compounds,2b as well as in polymers and materials.3-6
Early development of N-aryl synthesis proved to be quite
difficult and limited in generality.7 Consequently, transi-
tion-metal-assisted amination of aryl halides has devel-
oped in the past few years as a most viable and direct
method leading to the synthesis of a large variety of
substituted amines.8 Studies by Hartwig and Buchwald
on catalytic amination have shown that metal-support-
(8) For representative examples of amination of aryl chlorides, see:
(a) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1999,
38, 2413-2416. (b) Bei, X.; Uno, T.; Norris, J .; Turner, H. W.;
Weinburg, W. H.; Guram, A. S.; Petersen, J . L. Organometallics 1999,
18, 1840-1853. (c) Bei, X.; Guram, A. S.; Turner, H. W.; Weinburg,
W. H. Tetrahedron. Lett. 1999, 40, 1237-1240. (d) Old, D. W.; Wolfe,
J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 9722-9723.
(e) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1988, 120,
7369-7370. (f) Brenner, E.; Fort, Y. Tetrahedron Lett. 1998, 39,
5359-5362. (g) Yamamoto, T.; Nishiyama, M.; Kole, Y. Tetrahedron
Lett. 1998, 39, 2367-2370. (h) Wolfe, J . P.; Buchwald, S. L. J . Am.
Chem. Soc. 1997, 119, 6054-6058. (i) Riermeir, T. H.; Zapf, A.;
Beller, M. Top. Catal. 1997, 4301-309. (j) Reddy, N. P.; Tanaka, M.
Tetrahedron Lett. 1997, 38, 4807-4810. (k) Stauffer, S. R.; Lee, S.;
Stambuli, J . P.; Hauck, S. I.; Hartwig, J . F. Org. Lett. 2000, 2, 1423-
1426.
(9) For more examples dealing with couplings involving aryl chlo-
rides, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999,
38, 2411-2413. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
1998, 37, 3387-3388. (c) Reetz, M. T.; Lohmer, G.; Schwickardi, R.
Angew. Chem., Int. Ed. 1998, 37, 481-483. (d) Littke, A. F.; Fu, G. C.
J . Org. Chem. 1999, 64, 10-11. (e) Bei, X.; Guram, A. S.; Turner, H.
W.; Weinburg, W. H. Tetrahedron Lett. 1999, 40, 3855-3858. (f)
Indolese, A. F. Tetrahedron Lett 1997, 38, 3513-3516. (g) Saito,
S.; Oh-tani, S.; Miyaura, N. J . Org. Chem. 1997, 62, 8024-8030. (h)
Saito, S.; Sakai, M.; Miyaura, N. Tetrahedron Lett. 1996, 37, 2993-
2996.
(1) For important recent reviews of palladium- and nickel-mediated
aryl amination, see: (a) Wolfe, J . P.; Wagaw, S.; Marcoux, J . F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818. (b) Hartwig, G.
F. Acc. Chem. Res. 1998, 31, 852-860. (c) Hartwig, J . F. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2046-2067. (d) Hartwig, J . F. Synlett 1997,
329-340. (e) Yang, B. H.; Buchwald, S. L. J . Organomet. Chem. 1999,
576, 125-146.
(2) (a) Peat, A. J .; Buchwald, S. L. J . Am. Chem. Soc. 1996, 118,
1028-1030. (b) Hong, Y. P.; Tanoury, G. J .; Wilkinson, H. S.; Bakale,
R. P.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 1997, 38, 5663-
5666. (c) Hong, Y.; Senanayake, C. H.; Xiang, T.; Vandenbossche, C.
P.; Tanoury, G. J .; Bakale, R. P.; Wald, S. A. Tetrahedron Lett. 1998,
39, 3121-3124.
(3) (a) Louie, J .; Hartwig, J . F. J . Am. Chem. Soc. 1997, 119, 11695-
11696. (b) Kanbara, T.; Honma, A.; Hasehawa, K. Chem Lett. 1996,
1135-1136.
(4) Singer, R. A.; Sadighi, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 213-214.
(5) Thayumanavan, S.; Barlow, S.; Marder, S. R. Chem. Mater. 1997,
9, 3231-3235.
(6) (a) Goodson, F. E.; Hartwig, J . F. Macromolecules 1998, 31,
1700-1703. (b) Zhang, X.-X.; Sadighi, J . P.; Mackewitz, T. W.;
Buchwald, S. P. J . Am. Chem. Soc. 2000, 122, 7606-7607.
(7) (a) March, J . Advanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992. (b) Mitchell, H.; Leblanc, Y. J . Org. Chem. 1994, 59, 682-
687. (c) Banfi, A.; Bartoletti, M.; Bellora, E.; Bignotti, M.; Turconi, M.
Synthesis 1994, 775-776. (d) Hattori, T.; Sakamoto, J .; Hayashizaka,
N.; Miyano, S. Synthesis 1994, 199-202.
(10) Applications of phosphine ligands in homogeneous catalysis:
(a) Parshall, G. W.; Ittel, S. Homogeneous Catalysis; J . Wiley and Sons:
New York, 1992. (b) Homogeneous Catalysis with Metal Phosphine
Complexes; Pignolet, L. H., Ed.; Plenum: New York, 1983.
10.1021/jo010613+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/25/2001

7730 J . Org. Chem., Vol. 66, No. 23, 2001
Grasa et al.
Sch em e 1. Im id a zoliu m Ch lor id e Liga n d s
With the isolation of free N-heterocyclic carbenes in
1991 by Arduengo et al.12 and the use of these com-
pounds as ancillary ligation in homogeneous catalysis,
this area of catalysis represents a rapidly developing
field. Early studies have shown that nucleophilic N-
heterocyclic carbenes13 represent a very versatile class
of ligands, mimicking tertiary phosphines, as they act
as two-electron donors and their steric and electronic
properties can be modulated by appropriate substitu-
tion on the heterocyclic nitrogen atoms.14 A solution
calorimetric study of nucleophilic carbenes aimed at
determining steric and electronic properties of a series
of these ligands allowed us to better understand/quantify
these effects.15 The nucleophilic carbene ligands appear
to have several advantages over commonly utilized
phosphines: (i) metal complex stabilizing effect, (ii)
improved thermal stability, (iii) metal complex resistance
to ligand dissociation. These factors reveal that the use
of stoichiometric amounts of ligand as excess is not
required in order to prevent aggregation of the catalyst,
which yields bulk metal.13c As a consequence of these
attractive features, the number of catalytic reactions
making use of nucleophilic carbenes as catalyst modifiers
is increasing. Specific examples are the use of metal-
carbene complexes in hydrosilylation,16 Ru-catalyzed
furan synthesis,17 and olefin metathesis.15a,18 A most
successful application of carbenes as supporting ligands
is their role in various C-C couplings involving aryl
halides. We have successfully employed these ligands in
Stille,19 Suzuki-Miyaura,20 Kumada,21 and Hiyama22
couplings. Reports by Fu, Hartwig, and Buchwald on the
use of metal centers modified by donating, sterically
demanding phosphine ligands directed us to test bulky
electron-donating carbenes as ligands and catalyst modi-
fiers in the amination reaction. An account of early
catalytic amination results has appeared.23 We now
present a broader study into the use and applications of
the nucleophilic carbene ligands as ancillary ligands in
the amination reaction.
Resu lts a n d Discu ssion
From solution calorimetry experiments we now have
a clearer picture of the reasons behind the stabilizing
effects of nucleophilic N-heterocyclic carbenes on orga-
nometallic systems. We have most recently focused our
efforts on palladium-mediated processes that appear to
benefit from the use of sterically demanding, electron-
donating ligands. These electron-rich systems permit the
use of aryl chlorides as partners in cross-coupling reac-
tions. The use of aryl chlorides in coupling chemistry has
proven difficult but would economically benefit a number
of industrial processes.24 We now present a study on
palladium-mediated aryl amination dealing with ligand
effects and functional group tolerance.
Effect of th e Liga n d on th e Am in a tion of 4-Ch lo-
r otolu en e w ith N-Meth yla n ilin e. Considering the
major effect of the use of bulky carbene ligands in the
related C-C bond formation processes discussed above,
we wondered if catalytic amination could be performed
with the help of a judiciously selected bulky imidazolium
salt. On the basis of our recent success with IMes‚HCl25
(2, IMes 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-yli-
dene) and IPr.‚HCl21 (1, IPr 1,3-bis(2,6-diisopropylphen-
yl)imidazol-2-ylidene) as ancillary ligand precursors in
cross couplings involving aryl chlorides, a similar proto-
col was used to perform the amination of aryl chlorides.
In an effort to select the most effective imidazolium
salt, a number of 1,3-aryl-substituted imidazolium chlo-
rides (Scheme 1, 1-4) were used in a model reaction
(Table 1).
(11) Collman, J . P.; Hegedus, L. S.; Norton, J . R.; Finke, R. G. in
Principles and Applications of Organotransition Metal Chemistry;
University Science: Mill Valley, CA, 1987.
(12) Arduengo, A. J ., III; Harlow R. L.; Kline, M. J . Am. Chem. Soc.
1991, 113, 361-363.
(13) (a) Regitz, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 725-
728. (b) Arduengo, A. J ., III; Krafczyc, R. Chem. Zeit. 1998, 32, 6-14.
(c) Herrmann, W. A.; Kocher, C. Angew. Chem., Int. Ed. Engl. 1997,
36, 2163-2187.
(14) (a) McGuiness, D. S.; Green, M. J .; Cavell, J . K.; Skelton, B.
W.; White, A. H. J . Organomet. Chem. 1998, 565, 165-178. (b)
Herrmann, W. A.; Elison, M.; Fischer, J .; Ko¨cher, C.; Artus, G. R. J .
Angew. Chem., Int. Ed. Engl. 1995, 34, 2371-2374.
(15) (a) Huang, J .; Stevens, E. D.; Nolan, S. P.; Petersen, J . L. J .
Am. Chem. Soc. 1999, 121, 2674-2678. (b) Huang, J .; Schanz, H.-J .;
Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18, 2370-2375.
(16) Herrmann, W. A.; Goosen, L. T.; Ko¨cher, C.; Artus, G. R. J .
Angew. Chem., Int. Ed. Engl. 1996, 35, 2805-2807.
(17) Ku¨cu¨bay, H.; Cetinkaya, B.; Salaheddine, G.; Dixneuf, P. H.
Organometallics 1996, 15, 2434-2439.
The bulky (vide infra) IPr‚HCl (1) was found to be the
most effective imidazolium salt examined, leading to
isolation of the coupled product in a 98% isolated yield
(Table 1, entry 5). All other imidazolium salts (2-4) that
were investigated required longer reaction times to
(18) (a)Weskamp, T.; Schattenmann, W. C.; Spiegler, M.; Herrmann,
W. A. Angew. Chem., Int. Ed. Engl. 1998, 37, 2490-2493. (b) Scholl,
M.; Trnka, T. M.; Morgan, J . P.; Grubbs, R. H. Tetrahedron Lett. 1999,
40, 2674-2678. (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001,
34, 18-29. (d) J afarpour, L.; Nolan, S. P. Adv. Organomet. Chem. 2001,
46, 181-222.
(19) Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3, 119-122.
(20) Zhang, C.; Huang, J .; Trudell, M. T.; Nolan, S. P. J . Org. Chem.
1999, 64, 3804-3805.
(24) (a) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047-1062.
(b) Applied Homogeneous Catalysis with Organometallic Compounds;
Cornils, B., Herrmann, W. A., Eds.; VCH: Weinheim, 1996.
(25) (a) Arduengo, A. J ., III; Dias, H. V. R.; Harlow, R. L.; Kline, M.
J . Am. Chem. Soc. 1992, 114, 5530-5534. (b) Arduengo, A. J ., III; Dias,
H. V. R.; Calabrese, J . C.; Davidson, F. J . J . Am. Chem. Soc. 1992,
114, 4391-4393.
(21) Huang, J .; Nolan, S. P. J . Am. Chem. Soc. 1999, 121, 9889-
9890.
(22) Lee, H. M.; Nolan, S. P. Org. Lett. 2000, 2, 2053-2055.
(23) Huang, J .; Grasa, G. A.; Nolan, S. P. Org. Lett. 1999, 1, 1307-
1309.

Amination Reactions of Aryl Halides
J . Org. Chem., Vol. 66, No. 23, 2001 7731
cycle1c for the cross-coupling reaction of nitrogen contain-
ing reagents with aryl halides is said to involve an
oxidative addition of the aryl halide, followed by tran-
samination and reductive elimination, as outlined in
Figure 1.28 The optimization experiments enable us to
gain mechanistic insights into this catalytic system. The
electron-rich carbene ligands, usually better donors than
tertiary phosphines,15a,29,30 favor the oxidative addition
step.31 Theoretical studies32,33a have suggested that a Pd/L
ratio of 1:2 (mutually cis ligands) favor the oxidative
addition step, and, as a consequence, the reductive
elimination step is thermodynamically disfavored. This
is in agreement with the slower reaction rate given by a
palladium/imidazolium salt ratio of 1:2 observed for IPr‚
HCl (1). It should be stated here that complexes with two
carbene ligands are quite stable as examplified by
platinum-based systems recently synthesized in our
laboratories.34 The steric effects provided by ortho sub-
stituents on the carbene aryl groups may also influence
the efficiency of the catalytic transformation in a dra-
matic fashion. Our thermochemistry studies15b,18d on
ruthenium systems involving these carbenes show that
ITol is the best electron donor (ITol > IMes ) IXy > IPr)
while IPr is the most bulky ligand (IPr > IMes > IXy >
ITol). As a consequence, three major factors appear to
influence the activity of the palladium/imidazolium salt
system: electronic properties of the carbene ligands affect
the oxidative addition capability of palladium, while their
bulk and number around palladium accelerate the reduc-
tive elimination step.30-35 On the basis of these observa-
tions, a reactive intermediate can be envisioned as a
reactive three-coordinate or most likely a solvent-
stabilized or halide-bridging four-coordinate species. The
formulation of similar reactive intermediates has been
proposed by Hartwig for aryl amination36 and by Buch-
wald37 for Suzuki-Miyaura coupling.
Ta ble 1. Am in a tion of 4-Ch lor otolu en e Usin g Differ en t
Im id a zoliu m Ch lor id es
entry
L
time (h)
yielda (%)
1
2
3
4
5
none
3
3
3
3
3
NR
<5
11
22
98
ITol (7)
IXy (6)
IMes (2)
IPr (3)
a
Isolated yields are the average of two runs.
achieve complete consumption of the aryl chloride and
afforded lower yields.26
Su sbstitu tion P a tter n s in Rea ction s of Ar yl Ch lo-
r id es w ith Va r iou s Am in es. A survey of catalytic cross-
coupling of aryl halides with primary and secondary
cyclic or acyclic amines using IPr‚HCl (1) as the support-
ing ligand is provided in Table 2. The role of the added
base KOtBu is 2-fold: it initially deprotonates the imi-
dazolium chloride to form the free carbene ligand in situ,
which can then coordinate to Pd(0). It also serves as a
strong base to neutralize the HX formed in the course of
the coupling reaction. This catalytic system proved to be
general and efficient as shown by results presented in
Table 2.
The less reactive unactivated aryl chlorides reacted
with various amines including primary (Table 2, entries
6, 7, and 9) and secondary cyclic (Table 2, entries 1-3
and 12) or acyclic (Table 2, entries 5 and 13) amines in
high yields. The reaction of 4-chlorotoluene with highly
hindered amines (Table 2, entries 8 and 9) led to lower
yields.
Room -Tem p er a tu r e Am in a tion of Ar yl Br om id es
a n d Ar yl Iod id es. Generally, aminations involving aryl
bromides and iodides proceed under conditions milder
than those involving aryl chlorides. To examine the
halide substituent effect, the efficiency and selectivity of
the present catalytic system for amination of aryl bro-
mides and iodides was investigated. Both aryl bromides
and iodides (Table 3) reacted with amines smoothly at
room temperature. Most interesting in these studies
involving an aryl bearing both chloro and iodo (or bromo)
substituents is the observation that bromo and iodo
functionalities can be converted at room temperature
(Table 3, entries 3 and 4) and the remaining chloro
functionality can subsequently be converted at more
elevated temperatures. This could prove to be a signifi-
cant advantage in process chemistry.
Exten d ed Scop e a n d Ap p lica tion s of Am in a tion
Rea ction . Am in a tion of Heter oa r om a tic Ha lid es.
The amination technology based on Pd(dba)2/IPr‚HCl
system is also applicable to heteroaryl halides, as il-
lustrated in Table 5. Using 2-chloropyridine and mor-
pholine as substrates leads to a 99% isolated yield (Table
(27) (a) See ref 9b. (b) Kawatsura, M.; Hartwig, J . F. J . Am. Chem.
Soc. 1999, 121, 1473-1478.
(28) The initial oxidative addition of imidazolium salts has recently
been observed in the course of a study on arylhalide dehalogenation
involving Pd(0) sources. This mode of activation in the present system
under basic conditions cannot be excluded. For further details on
imidazolium C-H oxidative addition, see: Viciu, M. S.; Grasa, G. A.;
Nolan, S. P. Organometallics 2001, 20, 3607-3612.
(29) (a) McGuiness, D. S.; Cavell, K. J .; Skelton, B. W.; White A. H.
Organometallics 1999, 18, 1596-1605. (b) Lappert, M. F. J . Organomet.
Chem. 1988, 358, 185-214.
Effect of th e P a lla d iu m (0)/Im id a zoliu m Sa lt Ra tio
on Am in a tion Rea ction s. During our optimization
efforts and in order to understand the reaction mecha-
nism, the influence of palladium/ligand ratio was inves-
tigated. We have found that a 1:1 palladium-ligand ratio
affords optimum reaction rates (Table 4).
(30) (a) Lappert, M. F. J . Organomet. Chem. 1975, 100, 139-159.
(b) Schwarz, J .; Bo¨hm, V. P. W.; Gardiner, M. G.; Grosche, M.;
Hermann, W. A.; Hieringer, W.; Raudaschl-Sieber, G. Chem. Eur. J .
2000, 6, 1773-1780.
(31) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585-
9595.
This optimum stoichiometry was suspected on the basis
of previous work on Suzuki-Miyaura couplings mediated
by an imidazolium salt/palladium system. Others have
also observed this optimum ligand/metal ratio in phos-
phine/palladium catalytic systems.27 A general catalytic
(32) Su, M.-D.; Chu, S.-Y. Inorg. Chem. 1988, 37, 3400-3406.
(33) (a)Sakaki, S.; Biswas, B.; Sugimoto, M. Organometallics 1998,
17, 1278-1289. (b) Wolfe, J . P.; Tomori, H.; Sadighi, J . P.; Yin, J .;
Buchwald, S. L. J . Org. Chem. 2000, 65, 1158-1174.
(34) Viciu, M. S.; Nolan, S. P. Manuscript in preparation.
(35) (a) J ones, W. D.; Kuykendall, V. L. Inorg. Chem. 1991, 30,
2615-2622. (b) Hartwig, J . F.; Richards, S.; Baranano, D.; Paul, F. J .
Am. Chem. Soc. 1996, 118, 3626-3633.
(26) The saturated imidazolium systems have been reported to also
be very active with aryl chlorides in this system. See: Stauffer, S.;
Hauck, S. I.; Lee, S.; Stambuli, J .; Hartwig, J . F. Org. Lett. 2000, 2,
1423-1426.
(36) Alcazar-Roman, L. M.; Hartwig, J . F.; Rheingold, A. L.; Liable-
Sands, L. M.; Guzei, I. A. J . Am. Chem. Soc. 2000, 122, 4918-4630.
(37) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J . Am.
Chem. Soc. 1999, 121, 9550-9561.

7732 J . Org. Chem., Vol. 66, No. 23, 2001
Ta ble 2. Am in a tion of Ar yl Ch lor id es w ith Va r iou s Am in esa
Grasa et al.
a
Reaction conditions: 1.0 mmol of aryl chloride, 1.2 mmol of amine, 1.5 mmol of KOtBu, 1.0 mol % Pd2(dba)3, 4.0% IPr‚HCl (2 L/Pd),
b
3 mL of dioxane, 100 °C. Reactions were complete in 3-24 h, and reaction times were not minimized. Isolated yields.
5, entry 1). In general, the coupling of chloropyridines
and 2-bromopyridine resulted in high to moderate
yields.
substitution, and are usually incompatible with many
functional groups and often involve protection and depro-
tection steps.40
It is well-known that nitrogen-cotaining molecules can
act as ligands and as a result displace weakly binding
ligands with consequences on the activity of catalytic
systems. One example is Pd(0)/P(o-tol)3 system, which is
not capable of the amination of heteroaryl halides.38
However, results from Table 5 suggest that the Pd(dba)2/
IPr‚HCl system is not negatively affected by nitrogen-
containing substrates.
Am in a t ion of Ar yl Ha lid es w it h a n Am m on ia
Equ iva len t. The extension of amination reaction to the
synthesis of benzophenone imine adducts using ben-
zophenone imine as an ammonia surrogate represents
an efficient alternative route to the synthesis of N-
unsubstituted anilines.39 Synthetic routes to N-unsub-
stituted anilines often involve nitration, reduction, or
Given the efficiency IPr‚HCl as ancillary ligand for the
amination reaction, the same protocol was used to
perform the amination of aryl halides with benzophenone
imine. This catalytic system proved efficient for catalytic
amination of various aryl chlorides with benzophenone
imine as shown in Table 6.
Benzophenone imine reacts with less reactive unacti-
vated aryl chlorides in high yields (Table 6, entries 1, 2,
and 5). Ortho-substituted aryl chlorides reacted with
benzophenone imine without difficulty (Table 6, entries
(39) (a) Wolfe, J . P.; Ahman, J .; Sadighi, J . P.; Singer, R. A.;
Buchwald, S. L. Tetrahedron. Lett. 1997, 38, 6367-6370. (b) Mann,
G.; Hatwig, J . F.; Driver, M. S.; Fernandez-Rivan, C. J . Am. Chem.
Soc. 1998, 120, 827-828. (c) Prashad, M.; Hu, B.; Lu, Y.; Draper, R.;
Har, D.; Repic, O.; Blacklock, T. J . J . Org. Chem. 2000, 65, 2612-
2614.
(40) (a)Marchini, P.; Liso, G.; Reho, A. J . Org. Chem. 1975, 40,
3453-3456. (b) Lane, C. F. Synth. 1975, 135-146.
(38) Paul, F.; Hartwig, J . F. Organometallics 1995, 14, 3030-3039.

Amination Reactions of Aryl Halides
J . Org. Chem., Vol. 66, No. 23, 2001 7733
Ta ble 3. Am in a tion In volvin g Ar yl Br om id es a n d Id od id es w ith Va r iou s Am in esa
a
Reaction conditions: 1.0 mmol of aryl halides, 1.2 mmol of amine, 1.5 mmol of KOtBu, 1.0 mol % Pd2(dba)3, 4.0% IPr‚HCl (2 L/Pd),
b
3 mL of dioxane, room temperature. Reactions were complete in 3-30 h, and reaction times were not minimized. Isolated yields.
Ta ble 4. In flu en ce of P a lla d iu m (0)/Im id a zoliu m Sa lt Ra tio on Am in a tion Rea ction sa
a
Reaction conditions: 1.0 mmol of aryl chloride, 1.2 mmol of amine, 1.5 mmol of KOtBu. 1.0 mol % Pd2(dba)3, 4.0% IPr‚HCl (2 L/Pd)
b
or 2.0% IPr‚HCl (1L/Pd), 3 mL of dioxane, 100 °C. Isolated yields.
3 and 4). 4-Chlorotoluene and 4-chloroanisole required
longer reaction times at 80° C, and the isolated products
were contaminated with benzophenone imine. The reac-
tions are significantly faster and the isolated products
are pure when reactions are conducted at 100 °C. The
amination reaction of aryl bromides proceed generally in
high yields (Table 7) at 100 °C. Performing the reaction
at 80 °C resulted in longer reaction times and lower
yields. A possible explanation is that, while the oxidative
addition of the aryl bromide substrate occurs rapidly, the
Pd-N bond formation is slower for the LPd(Ar)Br
complex.33b
moted cleavage of the substrate. Only 3,6-bis(trifluoro-
methyl)bromobenzene (Table 7, entry 3) and 4-chloro-
pyridine hydrochloride (Table 6, entry 6) afforded a
maximum 60% isolated yield. The use of weaker bases
such as Cs2CO3, K2CO3, or K3PO4 gave only poor conver-
sions.
The use of benzophenone imine as a coupling partner
with various aryl halides lead to excellent results due to
its relative low steric hindrance and sp2 hybridized
nitrogen. We believe the reductive-elimination step is
facilitated39a by these electronic and steric factors. The
acidic cleavage39a of some benzophenone imine adducts
leads to various primary anilines in good to high yields
(Table 8).
Our attempts to use activated aryl halides and KOtBu
as a base were not successful, due to the base-pro-

7734 J . Org. Chem., Vol. 66, No. 23, 2001
Grasa et al.
Ta ble 6. Am in a tion of Ar yl Ch lor id es w ith
Ben zop h en on e Im in ea
F igu r e 1. General catalytic cycle for amination reaction.
a
Reaction conditions: 1.0 mmol of aryl chloride, 1.05 mmol of
Ta ble 5. Am in a tion of Ch lop yr id in es a n d
Br om op yr id in es w ith Va r iou s Am in esa
benzophenone imine, 1.5 mmol of KOtBu, 2.0 mol % Pd(dba)2, 2.0
mol % IPr‚HCl, 3 mL of dioxane, 80° C. Isolated yields. c The
b
reaction was performed at 100 °C. 2.5 mmol of KOtBu were used.
d
e All reactions were monitored by GC.
Ta ble 7. Am in a tion of Ar yl Br om id es w ith
Ben zop h en on e Im in ea
a
Reaction conditions: 1.0 mmol of aryl bromide, 1.05 mmol of
benzophenone imine, 1.5 mmol of KOtBu, 2.0 mol % Pd(dba)2, 2.0
mol % IPr‚HCl, 3 mL of dioxane, 100 °C. Isolated yields. c The
b
d
reaction was performed at 80 °C. All reactions were monitored
by GC.
active41 or useful intermediates in the synthesis of bio-
logically active agents.42 However, catalytic N-arylation
of indoles is somehow limited to aryl iodides and bro-
mides due to the involvement in the reaction of aromatic
a
Reaction conditions: 1.0 mmol of chloro or bromopyridine, 1.1
mmol of amine, 1.5 mmol of KOtBu, 1.0 mol % Pd2(dba)3, 2.0 mol
b
% IPr‚HCl (L/Pd ) 1), 3 mL of dioxane, 100 °C. Isolated yields.
c All reactions were monitored by GC.
N-Ar yla tion of Ar yl In d oles. N-Aryl indoles have
(41) Perregaard, J .; Arut, J .; Bogrso, K. P.; Hyttel, J .; Sa´nchez, C.
attracted much attention since they can be biologically
J . Med. Chem. 1992, 35, 1090-1101.

Amination Reactions of Aryl Halides
J . Org. Chem., Vol. 66, No. 23, 2001 7735
Ta ble 8. Con ver tion of Ben zop h en on e Im in e Ad d u cts to
N-Un su bstitu ted An ilin es
Ta ble 10. Am in a tion of Ar yl Br om id es w ith Va r iou s
In d olesa
a
Isolated yields.
Ta ble 9. Effect of th e Im id a zoliu m Ch lor id es a n d Ba ses
on N-Ar yl Su bstitu tion of In d ole w ith Br om oben zen e
entry
L
base
time (h)
yielda (%)
1
2
3
4
5
6
IPr
ICy
SIMes
SIPr
SIPr
SIPr
NaOH
NaOH
NaOH
NaOH
KOtBu
K3PO4
24
3
3
3
3
NR
30
66
88
<5
<5
3
a
Isolated yields.
nitrogen.43 Hartwig and co-workers have reported one
example of an aryl chloride as partner in this coupling.44
Given the success of Pd(0)/IPr‚HCl/KOtBu system for
the amination reaction of aryl and heteroaryl halides as
well as for the synthesis of benzophenone imine adducts,
we were interested to extend the scope and generality of
this system to the synthesis of N-aryl indoles. Nonethe-
less, we have found that the standard amination condi-
tions did not affect the arylation of indoles. Hence, we
sought different carbene ligands and bases in order to
functionalize indoles. The Pd(OAc)2/SIPr‚HCl (5)/NaOH45
system led to an 88% conversion of 4-bromotoluene in 3
h in the presence of indole (Table 9, entry 3). Investiga-
tion of other saturated imidazolium salts and bases led
to lower yields. It appears that NaOH is needed to
generate the free carbene, the dihydroimidazolium car-
bene being more donating than IPr.46
a
Reaction conditions: 1.0 mmol of aryl bromide, 1.1 mmol of
indole, 2 mmol of KOtBu, 2.0 mol % Pd(OAc)2, 2.0 mol % SIPr‚HCl,
3 mL of dioxane, 100 °C. Isolated yields. c The reaction was
b
d
performed in toluene. All reactions were monitored by GC.
rich and ortho-substituted substrates lead to low or
moderate yields and slower reaction rates.47
Since the palladium/imidazolium salt systems display
high reactivity with aryl chlorides in the arylation of
diverse amines, we tested their use in the synthesis of a
pharmaceutical target. Linezolid is member of a new
class of antibiotics.48 One of the important features of the
oxazolidinones is an aryl N-substituted amine moiety
(Scheme 2) that could potentially be assembled via a
palladium-mediated C-N bond formation. The synthesis
of the strategic intermediate to the oxazolidinones, N-(2-
fluorophenyl)morpholine, was isolated in good yields
under unoptimized conditions (Scheme 2).
This catalytic system was found to be effective for a
variety of aryl bromides and indole derivatives (Table 10).
4-Bromotoluene and bromobenzene are highly reactive
with respect to various substituted indoles, while electron-
(45) Pd(dba)2 or PdCl2/SIPr‚HCl/NaOH systems did not affect the
arylation of indole.
(42) Sarges, R.; Howard H. R.; Koe, B. K.; Weissman, A. J . Med.
Chem. 1989, 32, 437-444.
(46) (a) Lee, H. M.; J iang, T.; Stevens, E. D.; Nolan, S. P. Organo-
metallics 2001, 20, 1255-1258. (b) Scholl, M.; Sheng, D.; Lee. C. W.;
Grubbs, R. H. Org. Lett. 1999, 1, 953-956.
(43) Mann, G.; Hartwig, J . F.; Driver, M. S.; Ferna´ndez-Rivas, C.
J . Am. Chem. Soc. 1998, 120, 827-829.
(47) This system has not been found effective for the reaction of aryl
chlorides with indoles.
(44) Hartwig, J . F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K.
H.; Alcazar-Roman, L. M. J . Org. Chem. 1999, 64, 5575-5580.
(48) Chem. Eng. News 2000, March 6, 43.

7736 J . Org. Chem., Vol. 66, No. 23, 2001
Grasa et al.
Sch em e 2. Syn th esis of Lin ezolid In ter m ed ia te
screw cap vials with magnetic stirring, unless otherwise
indicated. All reported yields are isolated yields, unless
otherwise stated, and are the average of two runs.
Con clu sion
In summary, palladium/imidazolium salt systems were
found to be very efficient in the amination reaction
involving aryl chlorides and aryl bromides. The Pd(0)/
IPr‚HCl/KOtBu system was found to be highly effective
for the amination of electron-neutral, electron-poor aryl
chlorides, as well as sterically hindered substrates with
a variety of primary and secondary cyclic and acyclic
amines. This catalytic system proved its effectiveness in
the amination of various heteroaryl halides. The use of
benzophenone imine as an ammonia equivalent for
catalytic amination of a variety of aryl chlorides as well
as aryl bromides proceeds in high yields. Acidic cleavage
of the imine adducts leads to the formation of primary
anilines. The scope of the palladium-nucleophilic carbene
aryl amination reaction was extended to the synthesis
of substituted aryl indoles. The more donating saturated
carbene SIPr in combination with an inexpensive strong
base (NaOH) mediates this process. Ongoing catalytic
investigations are aimed at expanding the role of nucleo-
philic carbenes as supporting ligation in homogeneous
catalysis.
Syn th esis of Dih yd r oim id a zoliu m Ch lor id es. Anilines
(mesitylamine 0.4 mol 5.4 g) (Aldrich) were reacted in metha-
nol (20 mL) with glyoxal (0.2 mol, 40% aqueous solution,
Aldrich) at room temperature in the presence of a few drops
of formic acid. After the mixture was stirred for 3 h, the yellow
precipitate, the diazabutadiene, was filtered, washed with
methanol, and dried in vacuum (yield 92%). Hydrogenation of
the diazabutadiene (0.01 mol 3.92 g) was performed in a
MeOH/THF (40/60) mixture in the presence of NaBH4 (0.1 mol,
3.78 g). After 1.5 h, the solution turned white, indicating
reaction completion. A saturated aqueous solution of NH4Cl
(20 mL) was used to quench the reaction. The diamine was
extracted three times with ether (20 mL) and washed with
deionized water (10 mL). Ether extracts were dried over
MgSO4 and evaporated under reduced pressure to afford the
substituted diamine (97%, 3.6 g). One equivalent of diamine,
1.1 equiv of NH4Cl ,and 2.5 equiv of triethyl orthoformate were
stirred together at 110 °C under an argon flow. After 1.5 h,
the reaction mixture turned to a solid. The solid was dissolved
in a minimum amount of CHCl3 and reprecipitated with ether.
1
The H NMR of the product was comparable with previously
reported spectroscopic data for the desired product.50 The
desired product was obtained in 85% yield in this manner. A
similar experimental procedure was used in the synthesis of
SIPr‚HCl.
Exp er im en ta l Section
Gen er a l P r otocol Used for Am in a tion Rea ction . Under
an atmosphere of argon 1,4,-dioxane (3 mL), KOtBu (168 mg,
1.5 mmol), aryl halide (1.0 mmol), and amine (1.2 mmol) were
added in turn to a Schlenk tube charged with Pd2(dba)3 (10
mg, 0.01 mmol), 1 (17 mg, 0.04 mmol or 8 mg, 0.02 mmol),
and a magnetic stirring bar. The Schlenk tube was placed in
a 100 °C oil bath and stirred for 3-30 h. The mixture was
then allowed to cool to room temperature. The mixture was
diluted with water then extracted with diethyl ether. The
extracts were combined, washed with saturated saline solu-
tion, and then dried over MgSO4. The solvent was removed
under vacuum and the residue was purified by flash chroma-
tography (hexane or hexane/ethyl acetate (10:1)).
Gen er al Con sider ation s. All aryl halides (Aldrich), amines
and indoles were purchased from Aldrich and purified prior
to use. 1,4-Dioxane and toluene (anhydrous, Aldrich) were
distilled under argon from sodium benzophenone ketyl. Potas-
sium tert-butoxide, potassium phosphate, and sodium hy-
droxyde (Aldrich) were stored under argon in a MBraun
glovebox or in desiccators over anhydrous calcium carbonate.
(Tris(dibenzylideneacetone)dipalladium(0), bis-(dibenzylide-
neacetone)palladium(0), and palladium acetate were pur-
chased from Strem Chemical Co. Flash chromatography was
performed on silica gel 60 (230-400 mesh) (Natland Interna-
tional Corp.) using hexanes or hexanes/ethyl acetate ) 15:1.
The imidazolium salts IPr‚HCl (1, 1,3-bis(2,6-diisopropylphe-
nyl)imidazolium chloride), IMes‚HCl (2, 1,3-bis(2,4,6-trimeth-
ylphenyl)imidazolium chloride), IXy‚HCl (3, 1,3-bis(2,6-di-
methylphenyl)imidazolium chloride), and ITol‚HCl (4, 1,3-bis-
(tolyl)imidazolium chloride) were prepared according to re-
ported procedures.49 1H and 13C nuclear magnetic resonance
spectra were recorded on a Varian-300 or Varian-400 MHz
spectrometer at ambient temperature in CDCl3 (Cambridge
Isotope Laboratories, Inc.). Elemental analyses were performed
by Desert Analysis, Tucson, AZ. All reactions were carried out
under an atmosphere of argon in oven-dried-glassware or in
Wor k u p Meth od B. The reaction mixture was allowed to
cool to room temperature and absorbed directly on chroma-
tography column.
Gen er a l P r otocol for Am in a tion of Ar yl Ha lid es w ith
Ben zop h en on e Im in e. Under an atmosphere of argon 1,4,-
dioxane (3 mL), KOtBu (168 mg, 1.5 mmol), aryl halide (1.0
mmol), and benzophenone imine (1.05 mmol) were added in
turn to a screw-capped vial equipped with a Teflon septum
and magnetic stirring bar charged with Pd(dba)2 (10.9 mg, 0.02
mmol) and (8 mg, 0.02 mmol). The vial was placed in an oil
bath at the indicated temperature and stirred for the indicated
(49) (a) Arduengo, A. J ., III. US patent
Arduengo, A. J ., III, Dias, H. V. R.; Harlow, R. L.; Kline, M. J . Am.
Chem. Soc. 1992, 114, 5530-5534.
5 077 414, 1991; (b)
(50) Arduengo, A. J .; Krafczyk, R.; Schmutzler, R.; Craig, A.; Hugh,
A.; Goerlich, J . R.; William, J . Tetrahedron 1999, 55, 14523-14534.

Amination Reactions of Aryl Halides
J . Org. Chem., Vol. 66, No. 23, 2001 7737
time. The reaction was monitored by GC. In some cases, the
yields were determined by GC using biphenyl as internal
standard. The mixture was then allowed to cool to room
temperature. The mixture was directly absorbed onto a chro-
matography column and eluted with hexane or hexane/ethyl
acetate (15:1). Benzophenone imine adducts were converted
to the corresponding N-unsubstituted anilines according to the
reported procedure.36a
Gen er a l P r otocol Used for N-Ar yla tion of In d oles w ith
Ar yl Br om id es. Under an atmosphere of argon, 1,4 dioxane
(3 mL), NaOH (80 mg, 2 mmol), arylhalide (1.0 mmol), and
indole (1.1 mmol) were added in turn to a screw-capped vial
equipped with a Teflon septum and magnetic stirring bar
charged with Pd(dba)2 (10.9 mg, 0.0 mmol), and 5 (8 mg, 0.02
mmol). The vial was placed in an oil bath at the indicated
temperature and stirred for the indicated time. The reaction
was monitored by GC. In some cases, the yields were deter-
mined by GC using biphenyl as internal standard. The mixture
was then allowed to cool to room temperature. The mixture
was directly absorbed onto chromatography column and eluted
with hexane or hexane/ethyl acetate (15:1).
Ack n ow led gm en t. The National Science Founda-
tion, Eli Lilly and Co., the Albermarle Corp., the
Louisiana Board of Regents, and the Petroleum Re-
search Fund administered by the ACS are gratefully
acknowledged for support of this research.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization of new compounds and references to
known compounds are provided. This material is free of charge
via the Internet at http://pubs.acs.org.
J O010613+