Simple, efficient catalyst system for the palladium-catalyzed amination of aryl chlorides, bromides, and triflates

Article abstract of DOI:10.1021/jo991699y

Palladium complexes supported by (o-biphenyl)P(t-Bu)₂ (3) or (o- biphenyl)PCy₂ (4) are efficient catalysts for the catalytic amination of a wide variety of aryl halides and triflates. Use of ligand 3 allows for the room-temperature catalytic amination of many aryl chloride, bromide, and triflate substrates, while ligand 4 is effective for the amination of functionalized substrates or reactions of acyclic secondary amines. The catalysts perform well for a large number of different substrate combinations at 80-110 °C, including chloropyridines and functionalized aryl halides and triflates using 0.5-1.0 mol % Pd; some reactions proceed efficiently at low catalyst levels (0.05 mol % Pd). These ligands are effective for almost all substrate combinations that have been previously reported with various other ligands, and they represent the most generally effective catalyst system reported to date. Ligands 3 and 4 are air-stable, crystalline solids that are commercially available. Their effectiveness is believed to be due to a combination of steric and electronic properties that promote oxidative addition, Pd-N bond formation, and reductive elimination.

Full text of DOI:10.1021/jo991699y

1158
J . Org. Chem. 2000, 65, 1158-1174
Sim p le, Efficien t Ca ta lyst System for th e P a lla d iu m -Ca ta lyzed
Am in a tion of Ar yl Ch lor id es, Br om id es, a n d Tr ifla tes
J ohn P. Wolfe,† Hiroshi Tomori, J oseph P. Sadighi,‡ J ingjun Yin, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received October 29, 1999
Palladium complexes supported by (o-biphenyl)P(t-Bu)2 (3) or (o-biphenyl)PCy2 (4) are efficient
catalysts for the catalytic amination of a wide variety of aryl halides and triflates. Use of ligand 3
allows for the room-temperature catalytic amination of many aryl chloride, bromide, and triflate
substrates, while ligand 4 is effective for the amination of functionalized substrates or reactions of
acyclic secondary amines. The catalysts perform well for a large number of different substrate
combinations at 80-110 °C, including chloropyridines and functionalized aryl halides and triflates
using 0.5-1.0 mol % Pd; some reactions proceed efficiently at low catalyst levels (0.05 mol % Pd).
These ligands are effective for almost all substrate combinations that have been previously reported
with various other ligands, and they represent the most generally effective catalyst system reported
to date. Ligands 3 and 4 are air-stable, crystalline solids that are commercially available. Their
effectiveness is believed to be due to a combination of steric and electronic properties that promote
oxidative addition, Pd-N bond formation, and reductive elimination.
Owing to the many important applications of aniline
derivatives, and the limitations of most methods for their
synthesis, a considerable amount of effort has been
recently devoted to the development of catalysts that are
capable of effecting the cross-coupling of amines with aryl
halides and sulfonates.1 However, the proper choice of
catalyst (Pd source, ligand choice) is crucial for the
success of these reactions. It would be desirable to have
one ligand (or a small class of ligands) that is capable of
handling all possible substrate combinations. Our group,
and others, have recently reported catalysts based on
bulky, electron-rich phosphines that are capable of
transforming inexpensive and readily available aryl
chlorides (as well as aryl bromides) into aniline deriva-
tives, thereby expanding the substrate scope of the
palladium-catalyzed amination methodology.2 Herein we
disclose results of a detailed study of the use of these
ligands in aryl amination processes.
F igu r e 1.
4 (Figure 1) are excellent ligands for C-N,3a C-C,3a,b and
C-O3c bond-forming reactions of aryl chloride substrates.
Catalysts that employ 3 are sufficiently active to promote
the room-temperature catalytic amination and Suzuki
coupling of aryl chloride substrates,3a,b,d,e and catalysts
derived from 4 are effective for the Suzuki coupling of
hindered substrates.3b These ligands also promote some
Suzuki coupling and catalytic amination reactions at very
low catalyst levels (0.000001-0.1 mol % Pd).3a Ligands
3 and 4 are air-stable, crystalline solids that are prepared
in a single step and are now commercially available.4
Although 3 is effective for the room-temperature ami-
nation of several aryl chloride substrates, the scope of
aryl chloride aminations is much broader when ligands
3 or 4 are employed at higher temperatures (80-110 °C).
This is particularly relevant for reactions of functional-
ized aryl halides, as the room-temperature reactions
require the use of the strong base NaOt-Bu. Ligand 3 is
effective for aminations of electron-rich or -neutral aryl
chlorides with a wide variety of amine coupling partners;
Our first catalysts for the amination of aryl chlorides
used ligands 1 and 2 (Figure 1).2e However, the prepara-
tion of these phosphines required a multistep synthesis.
We recently reported that the simple phosphines 3 and
† Present address: Department of Chemistry, University of Cali-
fornia, Irvine, CA 92697-2025.
‡ Present address: Department of Chemistry, California Institute
of Technology, Pasadena, CA, 91125.
(1) (a) Yang, B. H.; Buchwald, S. L. J . Organomet. Chem. 1999, 576,
125-146. (b) Hartwig, J . F. Angew. Chem., Int. Ed. Engl. 1998, 37,
2046-2067. (c) Wolfe, J . P.; Wagaw, S.; Marcoux, J .-F.; Buchwald, S.
L. Acc. Chem. Res. 1998, 31, 805-818.
(2) (a) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett.
1998, 39, 617-620. (b) Yamamoto, T.; Nishiyama, M.; Koie, Y.
Tetrahedron Lett. 1998, 39, 2367-2370. (c) Reddy, N. P.; Tanaka, M.
Tetrahedron Lett. 1997, 38, 4807-4810. (d) Hamann, B. C.; Hartwig,
J . F. J . Am. Chem. Soc. 1998, 120, 7369-7370. (e) Old, D. W.; Wolfe,
J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 9722-9723. (f)
Bei, X.; Guram, A. S.; Turner, H. W.; Weinberg, W. H. Tetrahedron
Lett. 1999, 40, 1237-1240. (g) Bei, X.; Uno, T.; Norris, J .; Turner, H.
W.; Weinberg, W. H.; Guram, A. S.; Peterson, J . L. Organometallics
1999, 18, 1840-1853. (h) A procedure employing the Herrmann-Beller
palladacycle has been used for some C-N bond-forming reactions of
aryl chlorides at 135 °C; mixtures of regioisomers are often observed.
Riermeier, T. H.; Zapf, A.; Beller, M. Top. Catal. 1997, 4, 301-309
and references therein.
(3) (a) A portion of this work has been previously communicated.
See: Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1999,
38, 2413-2416. (b) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald,
S. L. J . Am. Chem. Soc. 1999, 121, 9550-9561. (c) Aranyos, A.; Old,
D. W.; Kiyomori, A.; Wolfe, J . P.; Sadighi, J . P.; Buchwald, S. L. J .
Am. Chem. Soc. 1999, 121, 4369-4378. (d) Hartwig has recently
reported examples of room-temperature catalytic amination of aryl
bromides and chlorides using P(t-Bu)3. See: Hartwig, J . F.; Kawatsura,
M.; Hauck, S. I.; Shaughnessy, K.; Alcazar-Roman, L. M. J . Org. Chem.
1999, 64, 5575-5580. (e) Nolan has also recently reported aminations
of aryl chlorides using nucleophilic carbenes as ligand. See: Huang,
J .; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307-1309.
(4) Ligands 3 and 4 are commercially available from Strem Chemical
Co.
10.1021/jo991699y CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/02/2000

Palladium-Catalyzed Amination
J . Org. Chem., Vol. 65, No. 4, 2000 1159
Ta ble 1. Room -Tem p er a tu r e Ca ta lytic Am in a tion of Ar yl
Ch lor id esa
The reaction of benzylamine with 4-chlorotoluene was
slow with 1-2 mol % catalyst; the desired product was
obtained in good yield when 5 mol % of the palladium
catalyst was employed (Table 1, entry 4). Excess benzyl-
amine (1.5 equiv) was employed to minimize the forma-
tion of diaryl(alkyl) amine side products. Under these
conditions a ratio of 8-9/1 diaryl/monoaryl product was
observed. A larger amount of diarylated side product was
formed at room-temperature than at 80 °C (see below).
This procedure was also effective for the arylation of
s-butylamine with m-chloroanisole (entry 12). In this case
no diarylation was observed when 1.2 equiv of amine was
employed. Use of Pd(OAc)2 as the palladium source was
required for most of the room-temperature reactions,
although the reaction of n-hexylamine with the highly
activated 4-chlorobenzonitrile gave the best results when
Pd2(dba)3 was employed. In contrast to what has been
previously observed,5,6c the reaction of a primary amine
or primary aniline with an electron-deficient aryl halide
afforded small amounts of diarylated side products; a
ratio of ∼14-15/1 diarylamine/triarylamine was observed
in the reaction of 4-chlorobenzonitrile with n-hexylamine
or p-toluidine. The weak base K3PO4 was ineffective for
the room-temperature reactions, even for highly activated
substrates such as 4-chloronitrobenzene.
Unfortunately, the scope of the room-temperature
reactions was somewhat limited. For example, the reac-
tion of m-chloroanisole with n-hexylamine proceeded to
only 19% conversion in 18 h. The requirement for Pd-
(OAc)2 as a precatalyst precluded the use of primary
anilines as coupling partners (see below), except for the
reaction of p-toluidine with 4-chlorobenzonitrile, which
was effective when 2.5 mol % of Pd2(dba)3 was employed
as the palladium source. The functional group tolerance
of the process is currently limited owing to the need to
employ the strong base NaOt-Bu. However, nitrile func-
tionality was tolerated even for arylations of primary
anilines, which react with halobenzonitriles at higher
temperatures (80 °C) in the presence of NaOt-Bu to form
large amounts of amidine side products.
a
Reaction conditions: 1.0 equiv of aryl chloride, 1.2 equiv of
amine, 1.4 equiv of NaOt-Bu, 1-2 mol % Pd(OAc)2, 2-4 mol % 3,
toluene (1 mL/mmol halide), rt. Reaction times have not been
minimized. Yields represent isolated yields (average of two or more
experiments) of compounds estimated to be g95 % pure as judged
by 1H NMR and GC analysis (known compounds) and combustion
b
analysis (new compounds). The reaction was conducted with 1.5
equiv of benzylamine. c Pd2(dba)3 used in place of Pd(OAc)2.
reactions involving secondary acyclic amines or aryl
chlorides bearing base-sensitive functionality are typi-
cally more efficient using 4. Aryl bromides and triflates
are also effectively coupled with amines using catalysts
based on 3 or 4; the Pd/4 catalyst is the most efficient
system reported to date for the coupling of electron-rich
aryl bromides with primary anilines.
Ca ta lytic Am in a tion of Un a ctiva ted Ar yl Ch lo-
r id es a t 80-110 °C. As shown in Table 2, the scope of
the catalytic amination of aryl chlorides is considerably
broader at 80-110 °C than at room temperature. A
catalyst system derived from Pd(OAc)2 or Pd2(dba)3
functions well for a variety of substrates including those
that are electron-rich and/or ortho-substituted. Even the
very hindered 2,6-dimethylchlorobenzene was a suitable
substrate, although higher reaction temperatures and/
or larger amounts of catalyst were required for reactions
to proceed to completion in e24 h.
Resu lts
Room -Tem p er a tu r e Ca ta lytic Am in a tion of Ar yl
Ch lor id es. Initial attempts to effect the room-temper-
ature catalytic amination of aryl chlorides using 2 were
in general unsuccessful despite the utility of this ligand
for room-temperature Suzuki coupling reactions of aryl
chlorides.2e The one exception was when 4-chloroben-
zonitrile, an activated aryl chloride, was combined with
morpholine. However, use of ligand 3 provided catalysts
with higher activity than was previously observed with
2. Catalysts comprised of 3/Pd(OAc)2 were sufficiently
reactive to promote the room-temperature catalytic ami-
nation of a variety of aryl chloride substrates.3a As shown
in Table 1, the reaction is effective for both electron-rich
and electron-deficient substrates, and a variety of amines
are suitable coupling partners. For example, both p- and
o-chloroanisole could be converted to aniline derivatives
in g90% yield using 1-2 mol % catalyst (entries 7, 11).
A variety of amine coupling partners may be used
including primary and secondary anilines, primary amines,
cyclic secondary amines, and diarylamines. Benzophe-
none imine, which serves as an NH3 equivalent,7 and
(5) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc. 1996,
118, 7215-7216.
(6) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1348-1350. (b) Louie, J .; Hartwig, J . F.
Tetrahedron Lett. 1995, 36, 3609-3612. (c) Driver, M. S.; Hartwig, J .
F. J . Am. Chem. Soc. 1996, 118, 7217-7218. (d) Marcoux, J .-F.; Wagaw,
S.; Buchwald, S. L. J . Org. Chem. 1997, 62, 1568-1569. (e) Sadighi,
J . P.; Harris, M. C.; Buchwald, S. L. Tetrahedron Lett. 1998, 39, 5327-
5330.
(7) Wolfe, J . P.; A° hman, J .; Sadighi, J . P.; Singer, R. A.; Buchwald,
S. L. Tetrahedron Lett. 1997, 38, 6367-6370.

1160 J . Org. Chem., Vol. 65, No. 4, 2000
Ta ble 2. P a lla d iu m -Ca ta lyzed Am in a tion of Un a ctiva ted Ar yl Ch lor id esa
Wolfe et al.
a
Reaction conditions: 1.0 equiv of aryl halide, 1.2 equiv of amine, 1.4 equiv of NaOt-Bu, cat. Pd(OAc)2, cat. 3 (2L/Pd), toluene (2
mL/mmol halide), 80 °C. Reaction times have not been minimized. Pd2(dba)3 used in place of Pd(OAc)2. c The reaction was conducted at
b
100 °C. The reaction was conducted at 110 °C. e The reaction was conducted with 1.5 equiv of amine. f A ratio of 1.5 L/Pd was employed.
d
benzophenone hydrazone8 are also suitable substrates.
Use of 2, 5, or 6 as ligands for the coupling of di-n-
butylamine with 4-chlorotoluene gave higher yields than
were obtained with 3 or 4 (entry 6); use of 3 or 4 resulted
in the formation of aryl(tert-butyl)ether byproducts (∼10%).
reactions of primary amines with p-substituted aryl
chlorides, with n-hexylamine producing more diarylation
(12/1 monoaryl/diaryl) than benzylamine (21/1 monoaryl/
diaryl) in reactions with 4-chlorotoluene. Diarylated
products were not observed with o-substituted aryl
chlorides. Reactions of primary anilines were inefficient
if Pd(OAc)2 was employed as a precatalyst, but use of Pd2-
(dba)3 for these reactions provided excellent results.
Some substrate combinations that gave outstanding
results with the BINAP catalyst system5 (for the analo-
gous aryl bromides) were either inefficient or required
high temperatures or long reaction times. For example,
the reaction of 4-bromobenzonitrile with n-hexylamine
proceeds to completion rapidly and in essentially quan-
titative yield using the BINAP catalyst system (0.05 mol
% Pd).5 However, the reaction of 4-chlorobenzonitrile with
n-hexylamine required 40 h at 110 °C to proceed to
completion with 1 mol % Pd (see below in Table 5, entry
11).
Reactions of primary aliphatic amines with unhindered
aryl halides afforded good yields of the aryl(alkyl)amine
products with the 3/Pd catalyst at 80 °C; 1.5 equiv of
amine was employed to minimize the formation of dia-
rylated side products in these reactions. The ratios of
monoaryl/diaryl products were typically ∼10-20/1 for
For some substrates it was possible to conduct reac-
tions with low catalyst loadings (0.05 mol % Pd),3a
although to date these conditions are only effective for a
limited number of substrate combinations (Table 3). For
example, the reaction of N-methylaniline with 4-chloro-
toluene proceeds to completion in 22 h using 0.025 mol
% Pd2(dba)3 and 0.1 mol % 3 at 100 °C affording the
(8) The Pd-catalyzed arylation of benzophenone hydrazone and the
subsequent transformation of the aryl hydrazone products to indoles
have been previously reported by this group. See: (a) Wagaw, S.; Yang,
B. H.; Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 6621-6622. (b)
Wagaw, S.; Yang, B. H.; Buchwald, S. L. J . Am. Chem. Soc. 1999, 121,
10251-10263. (c) Hartwig has also reported the catalyzed arylation
step, but not the subsequent conversion into indoles: Hartwig, J . F.
Angew. Chem., Int. Ed. Engl. 1998, 37, 2090-2093.

Palladium-Catalyzed Amination
J . Org. Chem., Vol. 65, No. 4, 2000 1161
Ta ble 3. Am in a tion of Ar yl Ch lor id es a t Low Ca ta lyst
Loa d in ga
Ta ble 4. P a lla d iu m -Ca ta lyzed Am in a tion of
Ch lor op yr id in esa
a
Reaction conditions: 1.0 equiv of aryl chloride, 1.2 equiv
amine, 1.4 equiv of NaOt-Bu, 0.025 mol % Pd2(dba)3, 0.1 mol % 3,
toluene (1 mL/mmol halide), 110 °C. Reaction times have not been
minimized. Yields represent isolated yields (average of two or more
experiments) of compounds estimated to be g95 % pure as judged
by 1H NMR and GC analysis (known compounds) and combustion
b
analysis (new compounds). The reaction was conducted at 100
°C. c The reaction was conducted at 80 °C.
desired product in 95% yield. However, although the
reaction of 4-chlorotoluene with p-toluidine is efficient
with 0.5 mol % Pd (Table 2, entry 3), it only proceeds to
41% conversion in 48 h at 110 °C using 0.05 mol % Pd.
a
Reaction conditions: 1.0 equiv of chloropyridine, 1.2 equiv of
Ca ta lytic Am in a tion of Ch lor op yr id in es. Previous
studies in our laboratory demonstrated that bromopyri-
dine substrates were effective coupling partners in
catalytic amination reactions provided that the chelating
phosphine ligands BINAP or DPPP were employed;9
nonchelating triarylphosphines were displaced from the
metal by the pyridine substrate leading to catalyst
deactivation.9,10 Aminations of 2-chloropyridines were
possible, although fairly high catalyst loadings (4 mol %
Pd) were required.9
amine, 1.4 equiv of NaOt-Bu, cat. Pd(OAc)2, cat. 3, toluene (2 mL/
mmol halide), 110 °C. b The reaction was conducted at 100 °C.c The
d
reaction was conducted using 1.5 equiv of amine. The reaction
was conducted using 3.0 equiv amine. e 2.8 equiv of K3PO4 used
in place of NaOt-Bu. f 1,4-Dioxane (1 mL/mmol halide) was used
g
as the solvent. 1,4-Dioxane (2 mL/mmol halide) was used as the
h
solvent. 2.8 equiv of NaOt-Bu was employed.
11
2e
weaker bases such as Cs2CO3 or K3PO4 greatly im-
proves the functional group compatibility of these reac-
tions.
Catalytic amination of aryl chloride substrates bearing
a variety of base-sensitive functional groups was achieved
using catalysts derived from 2, 3, and 4 when K3PO4 was
employed as the stoichiometric base (Table 5). The
reaction conditions tolerated the presence of enolizable
ketones, methyl esters, nitriles, and nitro groups; a
variety of amines were efficient coupling partners, but
reactions of primary aliphatic amines usually required
longer reaction times, higher temperatures, and/or larger
catalyst loadings. Although the Pd/3 catalyst was useful
for some substrate combinations, the best results were
generally obtained with either 2 or 4; catalysts based on
2 were slightly more reactive than those derived from 4.
Reactions that proved to be inefficient when Pd(OAc)2
was employed as a precatalyst usually gave better results
when Pd2(dba)3 was used. Substrates that contained
functional groups ortho to the aryl chloride were much
less reactive. Acceptable yields were obtained for the
reaction of 2-chloronitrobenzene or methyl-2-chloroben-
zoate with primary anilines (entries 15, 16); however,
reactions with aliphatic amines resulted in the formation
of large amounts of side products arising from reduction
and/or homocoupling of the aryl chloride, and typically
proceeded to <80% conversion even with 10 mol % of the
palladium catalyst. Despite the relatively low reactivity
When the mixtures of Pd(OAc)2 and 2, 3, or 4 were
employed, 2-, 3-, and 4-chloropyridine proved to be viable
substrates in catalytic amination reactions. While the
chloropyridine derivatives reacted more slowly than other
aryl halides, use of 1 mol % Pd(OAc)2 at 100-110 °C
provided acceptable results (Table 4). Despite the dimin-
ished reactivity of these substrates relative to other aryl
chlorides, a variety of amines proved to be suitable
coupling partners. Reactions catalyzed by Pd/3, that
provided unacceptable results were usually more efficient
if Pd/4 or Pd/2 were employed. Use of the Pd/4 catalyst
system necessitated the addition of excess amine (1.5-
3.0 equiv) for reactions with primary amines in order to
minimize the formation of doubly arylated products. As
expected, aminations of the more reactive 2-chloropyri-
dine were considerably faster than those of 3-chloropy-
ridine. Use of the mild base K3PO4 was effective for the
amination of 4-chloropyridine HCl with morpholine. The
use of this base gave cleaner but slower reactions.
Ca ta lytic Am in a tion of F u n ction a lized Ar yl Ch lo-
r id es. The use of the strong base NaOt-Bu in catalytic
amination reactions leads to a relatively low level of
functional group tolerance.1 However, employment of
(9) Wagaw, S.; Buchwald, S. L. J . Org. Chem. 1996, 61, 7240-7241.
(10) Hartwig has also demonstrated the displacement of triarylphos-
phines by pyridine in LPd(Ar)X complexes. See: Paul, F.; Patt, J .;
Hartwig, J . F. Organometallics 1995, 14, 3030-3039.
(11) Wolfe, J . P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359-
6362.

1162 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe et al.
Ta ble 5. P a lla d iu m -Ca ta lyzed Am in a tion of
F u n ction a lized Ar yl Ch lor id esa
is of interest. The chemistry that we report uses either
Pd(OAc)2 or Pd2(dba)3, both of which are commercially
available, as the palladium source for the amination
chemistry. The reactions that are described in the previ-
ous paper were “assembled in the drybox in sealed
reaction vessels”; none of the reactions that we report
involved the use of a glovebox. The exception to this is
that bulk quantities of NaOt-Bu were stored in a glove-
box. Smaller quantities were removed and used for 1-2
weeks while being stored in a desiccator between uses.
Probably the largest difference between the two ligand
types is the degree of their air sensitivity. To probe this,
we prepared a solution of 3 in toluene and let it stir for
15 days in the air at room temperature. During this time
an average of 3% of the ligand was oxidized to the
phosphine oxide. We also compared the stability of P(t-
Bu)3 and 3 in side-by-side experiments by stirring toluene
solutions of the two ligands (individually) for 2 h at room
temperature in the air. Analysis by GC showed that all
of 3 remained, while 97% of the P(t-Bu)3 had been
destroyed. Ligand 3 is a nicely crystalline material that
is stable for at least six months in the solid state in the
air (in a desiccator).
Ca ta lytic Am in a tion of Ar yl Br om id es. A number
of catalyst systems have previously been developed for
the palladium-catalyzed amination of aryl bromides.1,2d,e,g,5,6
However, there remain several substrate combinations
that are not efficiently handled by the available catalysts.
For example, the coupling of primary anilines with
electron-rich aryl bromides, such as 4-bromoanisole, is
often problematic with catalysts based on triarylphos-
phine ligands (either chelating or monodentate). Ad-
ditionally, for experimental simplicity, it is desirable to
have a small family of ligands that are capable of
transforming many different substrate combinations such
that large libraries of ligands are not required to optimize
reactions.
The reaction conditions that were effective for the
room-temperature catalytic amination of aryl chlorides
proved to be inefficient for aryl bromide substrates.
However, use of a catalyst comprised of Pd2(dba)3/3
allowed for the arylation of primary and secondary
anilines at room temperature (Table 6). Room-tempera-
ture aminations of aryl bromides with aliphatic amines
were slow under these conditions; however, use of 1.5-
2.5 mol % Pd2(dba)3 with KOt-Bu as base in THF solvent
allowed for the arylation of morpholine and benzylamine.
It is worth noting that a significantly larger amount of
double arylation of benzylamine was observed at room
temperature (6/1 monoaryl/diaryl) than at 80 °C (29/1
monoaryl/diaryl) with 0.5 mol % Pd. The use of KOt-Bu/
THF was unsatisfactory for the arylation of di-n-butyl-
amine; however, this substrate was efficiently coupled
with 4-tert-butylbromobenzene using Pd2(dba)3/5 in DME
solvent (NaOt-Bu as base). The functional group toler-
ance of the room-temperature reactions is currently
limited owing to the requirement to employ a strong base.
As was observed for the catalytic amination of aryl
chlorides, the scope of the amination reaction of aryl
bromides was significantly broader at 80-100 °C (Table
7). Excellent results for the arylations of anilines with
electron-rich or -neutral aryl bromides are obtained with
catalysts comprised of Pd2(dba)3/3; this system appears
to be the most effective catalyst developed to date for
these types of substrates. While the 3/Pd catalyst was
usually less effective for reactions of aryl bromides with
a
Reaction conditions: 1.0 equiv of aryl chloride, 1.2 equiv of
amine, 1.4 equiv of K3PO4, cat. Pd2(dba)3, cat. 4, DME (2 mL/mmol
b
halide), 100 °C. The reaction proceeded to 99% conversion.
c Pd(OAc)2 used in place of Pd2(dba)3. The reaction was conducted
d
at 80 °C. e The reaction was conducted at 110 °C. f The reaction
g
was conducted with 3.0 equiv of amine. NaOt-Bu, toluene used
in place of K3PO4, DME.
of aryl chlorides containing ortho functional groups, a
primary aniline with an ethyl ester in the ortho position
was efficiently coupled with 4-chlorobenzonitrile using
only 1 mol % Pd (entry 12). Other electron-deficient
anilines such as 4-nitroaniline were also effectively
arylated.
During the preparation of this article, a report was
given by Hartwig and co-workers describing the applica-
tion of tri-tert-butylphosphine,3d a ligand first used for
aromatic amination by Nishiyama et al. at Tosoh,2a,b for
the aminations of aryl chlorides and bromides under mild
conditions. As such, a brief comparison of the “user
friendliness” of the P(t-Bu)3 system with the one reported
in this paper, both of which are commercially available,

Palladium-Catalyzed Amination
J . Org. Chem., Vol. 65, No. 4, 2000 1163
Ta ble 6. Room -Tem p er a tu r e Ca ta lytic Am in a tion of Ar yl
Br om id esa
Ta ble 7. P a lla d iu m -Ca ta lyzed Am in a tion of Ar yl
Br om id esa
a
Reaction conditions: 1.0 equiv of aryl bromide, 1.2 equiv of
amine, 1.4 equiv of NaOt-Bu, 0.5-2.5 mol % Pd2(dba)3, (1-5 mol
% Pd), 2-10 mol % 3, toluene (1 mL/mmol halide), rt. Reaction
b
times have not been minimized. KOt-Bu and THF were used in
place of NaOt-Bu and toluene. c DME used as solvent.
aliphatic amines, excellent results were obtained using
a combination of 4 and Pd2(dba)3. This catalyst functioned
well for reactions of both cyclic and acyclic secondary
amines, although marginally better results were obtained
in the reaction of di-n-butylamine with 4-tert-butylbro-
mobenzene when 5 was employed. Substrates such as
piperidine and di-n-butylamine, which often give poor
results with the BINAP catalyst, were effectively coupled
using the 4/Pd2(dba)3 catalyst system. In contrast to what
was observed for the reaction of 4-chlorotoluene with di-
n-butylamine, only trace amounts (1-2%) of aryl(tert-
butyl)ether side products were observed in the reaction
of 4-tert-butylbromobenzene with di-n-butylamine. Use
of 3 provided the best results for the amination of
5-bromo-m-xylene with benzylamine. The scope of reac-
tions catalyzed by ligand 4 appears to be similar to the
scope of catalytic amination processes that employ either
BINAP or PPF-OMe as the ligand for palladium, al-
though reactions of primary aliphatic amines require the
use of 3. Use of Pd2(dba)3 is essential for the success of
most amination reactions of aryl bromide substrates
using ligands 3-5. For example, the reaction of 5-bromo-
m-xylene with benzylamine proceeded to only 31% con-
version after 22 h at 80 °C using Pd(OAc)2/3 as the
catalyst (0.5 mol % Pd). Use of Pd2(dba)3 in place of Pd-
(OAc)2 afforded the desired product in 90% yield after
17 h. Although high yields are obtained in reactions of
aryl bromides with primary amines with the Pd/3 cata-
lyst, much faster reactions are observed when the BINAP
ligand is used for these processes;5 the reaction of
5-bromo-m-xylene with benzylamine is complete in ∼3 h
using the Pd2(dba)3/BINAP catalyst system under similar
a
Reaction conditions: 1.0 equiv of aryl bromide, 1.2 equiv of
amine, 1.4 equiv of NaOt-Bu, cat. Pd2(dba)3, cat. ligand 3, toluene
b
(2 mL/mmol halide), 80 °C. Pd(OAc)2 used in place of Pd2(dba)3.
c The reaction was conducted at 100 °C. K3PO4 used in place of
d
NaOt-Bu. e DME (1 mL/mmol halide) was used as solvent. f Tolu-
ene (1 mL/mmol halide) was used as the solvent. g Contains ∼2.5%
of 4,4′-dicyanobiphenyl.
reaction conditions (0.5 mol % Pd). The amination of
functionalized aryl bromides proceeds in high yield using
ligands 2 or 4 with K3PO4 as the stoichiometric base
(entries 11-15).
The reactions of many aryl bromides with aliphatic
amines using the 3/Pd catalyst system are slower than
the corresponding reactions of aryl chloride substrates.
For example, the reaction of 4-chlorotoluene with mor-
pholine is complete in <65 min at 80 °C with 0.5 mol %
Pd, while the reaction of 4-bromotoluene with the same
amine proceeds only to 29% conversion in the same
amount of time. A competition experiment was conducted
in which equimolar amounts of 4-bromotoluene and
4-chlorotoluene were reacted with 1.2 equiv of morpholine
(Scheme 1). Not suprisingly, the bromide reacted con-
siderably more rapidly than the chloride.
Higher yields were occasionally obtained for reactions
of aryl chloride substrates. For example, the reaction of

1164 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe et al.
Sch em e 1
Ta ble 8. Room -Tem p er a tu r e Ca ta lytic Am in a tion of Ar yl
Tr ifla tesa
Ta ble 9. P a lla d iu m -Ca ta lyzed Am in a tion of Ar yl
Tr ifla tesa
a
Reaction conditions: 1.0 equiv of aryl triflate, 1.2 equiv of
amine, 1.4 equiv of NaOt-Bu, cat. Pd(OAc)2, cat ligand 3, toluene
b
(1 mL/mmol halide), rt. Pd2(dba)3 used in place of Pd(OAc)2.
d
c Toluene (3 mL/mmol triflate) was used as solvent. A L/Pd ratio
of 1/0.8 was used.
2-bromo-p-xylene with N-methyl aniline afforded the
desired product in good yield (75%) using ligand 4; a 90%
yield was obtained for the corresponding aryl chloride
substrate with a catalyst comprised of Pd/3 (see above).12
However, for most comparable systems, both bromides
and chlorides gave similar yields under optimized condi-
tions.
a
Reaction conditions: 1.0 equiv of aryl chloride, 1.2 equiv of
amine, 1.4 equiv of K3PO4, cat. Pd2(dba)3, cat. ligand 3, DME (2
b
mL/mmol halide), 80 °C. Pd(OAc)2 used in place of Pd2(dba)3.
c NaOt-Bu used in place of K3PO4. THF used as solvent. e Toluene
d
Ca ta lytic Am in a tion of Ar yl Tr ifla tes. Aryl triflates
are desirable substrates owing to their ease of prepara-
tion from readily available phenols.13 Catalytic amina-
tions of aryl triflates have been previously effected using
Pd/BINAP14a,b or Pd/dppf14c catalyst systems; these cata-
lysts are usually inefficient for the arylation of secondary
acyclic amines.14 Reactions of electron-deficient aryl
triflates often give low yields owing to NaOt-Bu-promoted
cleavage of the triflate substrate; use of cesium carbonate
with the Pd/BINAP catalyst gives improved results for
these systems, although 3-5 mol % Pd was often required
in these reactions.14b
The first room-temperature catalytic aminations of aryl
triflates were accomplished using catalysts derived from
3 with NaOt-Bu as the base (Table 8). While this protocol
was effective for the amination of electron-rich or -neutral
aryl triflates, poor results were obtained for electron-
deficient aryl triflates owing to base-promoted cleavage
used as solvent.
of the triflate substrate. Use of weaker bases such as K3-
PO4 or Cs2CO3 gave only small amounts of desired
products; most of the starting aryl triflate remained
unreacted.
As expected, the scope of aryl triflate aminations was
considerably broader at 80 °C (Table 9). Reactions of both
electron-rich and electron-deficient aryl triflates pro-
ceeded in high yield using a catalyst comprised of Pd and
3 or 4 using K3PO4 as the stoichiometric base. As was
observed for aryl bromide reactions, arylations of anilines
were typically faster than those of aliphatic amines.
Diaryl ether side products were occasionally observed
(presumably arising from hydrolysis of the triflate fol-
lowed by arylation of the resulting phenol). The reactions
of 4-tert-butylphenyl triflate with benzylamine or di-n-
butylamine were extremely slow when K3PO4 was used
as base, even with up to 5 mol % of the palladium catalyst
at 110 °C. However, use of NaOt-Bu in place of K3PO4
for these reactions provided acceptable yields of the
desired products and required only 1 mol % Pd at 80 °C,
although the yield for the reaction of benzylamine with
4-tert-butylphenyl triflate was higher at room tempera-
ture (77%) than at 80 °C (68%).
(12) Use of ligand 3 for the reaction of 2-bromo-p-xylene with
N-methylaniline gave only 60% conversion.
(13) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1987, 109,
5478-5486.
(14) (a) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997, 62, 1264-
1267. (b) A° hman, J .; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363-
6366. (c) Louie, J .; Driver, M. S.; Hamann, B. C.; Hartwig, J . F. J .
Org. Chem. 1997, 62, 1268-1273.

Palladium-Catalyzed Amination
J . Org. Chem., Vol. 65, No. 4, 2000 1165
Sch em e 2a
The steric bulk of the ligands may accelerate the C-N
bond-forming reductive elimination,18a as well as promote
the rate of N-Pd bond formation via the formation of
(monophosphine)palladium complexes.1b,18b-g Although
attempts to isolate palladium complexes of these ligands
have thus far been unsuccessful owing to the high
solubility of these complexes as well as a competing
cyclometalation reaction, circumstantial evidence sug-
gests that monophosphine complexes are involved in
these reactions. The room-temperature amination of
4-chlorotoluene with N-methylaniline proceeds at roughly
the same rate regardless of the ratio of 3/Pd that is
employed; the reaction proceeds to 75 ( 9% conversion
after 2 h when a L/Pd ratio of 1.2/1 is employed, and to
69 ( 1% conversion after 2 h with a L/Pd ratio of 2/1.
We believe that other factors may also be of impor-
tance; for example, the π-system of the ortho aromatic
group on these ligands may participate in an interaction
with the unoccupied metal d-orbital.19 Examination of
molecular models suggest that this interaction is steri-
cally favorable (Figure 2), and further circumstantial
evidence for this interaction is provided by the fact that
room-temperature reactions conducted with ligand 7 are
a
Key: (a) Pd2(dba)3 (0.25 mol %), 3 (1.0 mol %), NaO-t-Bu (1.4
equiv), toluene, 80 °C; (a′) Pd2(dba)3 (0.5 mol %), 3 (2.0 mol %),
NaO-t-Bu (1.4 equiv), toluene, 80 °C; (b) (BOC)2O (1.2-1.3 equiv),
4-DMAP (0.2-0.5 equiv), THF, 60 °C.
Ap p lica t ion s Tow a r d t h e Syn t h esis of Oligo-
a n ilin es. The high reactivity of the Pd2(dba)3/3 catalyst
system toward electron-rich aryl chlorides and aryl
bromides has proven useful in the synthesis of p-
oligoaniline derivatives. We have previously demon-
strated the synthesis of these compounds by palladium
catalysis, using BINAP as the supporting ligand.15 The
less expensive chelating ligand DPEphos6e,16 may also be
used. Most of the aryl halide substrates were 4-bromo-
N-(tert-butoxycarbonyl)diarylamines, which react rela-
tively slowly with the triarylphosphine-ligated palladium
catalysts; catalyst loadings in the range of 2-6 mol %
palladium are typically necessary to achieve complete
conversions. The combination of Pd2(dba)3 and ligand 3
is a far more active catalyst toward this class of aryl
bromides; catalyst loadings of 1 mol % palladium are
sufficient to achieve efficient coupling reactions. In
addition, a dimer-derived aryl chloride, more readily
obtained than the corresponding aryl bromide, may now
be employed as a substrate. The synthesis of pentaaniline
and nonaaniline derivatives is shown in Scheme 2.
generally much less efficient than those that employ 3.
For example, the reaction of 4-chlorotoluene with mor-
pholine proceeds to completion in 20 h and affords the
desired product in 94% isolated yield when 3 is employed.
Use of 7 for this coupling afforded only 33% conversion
(33% GC yield) in 22 h. This trend was observed for
several substrate combinations. The metal-arene inter-
action presumably serves to stabilize the catalyst. Of
importance is that it forces the arene derived from the
aryl halide substrate into an orientation in which it is
pependicular to the N-Pd bond. Such an orientation
should stereoelectronically favor reductive elimination
(Figure 2).20
The lower reactivity of chloropyridine derivatives rela-
tive to other aryl chlorides may be due to the ability of
the pyridine nitrogen to coordinate strongly to palladium,
(as observed for (o-tol)3PPd(Ar)X complexes),9,10 thereby
(18) (a) Hartwig, J . F.; Richards, S.; Baranano, D.; Paul, F. J . Am.
Chem. Soc. 1996, 118, 3626-3633. (b) Hartwig, J . F.; Paul, F. J . Am.
Chem. Soc. 1995, 117, 5373-5374. (c) Paul, F.; Patt, J .; Hartwig, J . F.
J . Am. Chem. Soc. 1994, 116, 5969-5970. (d) Louie, J .; Hartwig, J . F.
J . Am. Chem. Soc. 1995, 117, 11598-11599. (e) Driver, M. S.; Hartwig,
J . F. J . Am. Chem. Soc. 1995, 117, 4708-4709. (f) Louie, J .; Paul, F.;
Hartwig, J . F. Organometallics 1996, 15, 2794-2805. (g) Hartwig, J .
F. Synlett 1997, 329-340. (h) J ones has demonstrated that steric bulk
facilitates C-C bond-forming reductive elimination in ruthenium
complexes, see: J ones, W. D.; Kuykendall, V. L. Inorg. Chem. 1991,
30, 2615-2622.
(19) Metal-π interactions have been observed in other palladium
complexes. (a) Ossor, H.; Pfeffer, M.; J astrzebski, J . T. B. H.; Stam, C.
H. Inorg. Chem. 1987, 26, 1169-1171. (b) Falvello, L. R.; Fornies, J .;
Navarro, R.; Sicilia, V.; Tomas, M. Angew. Chem., Int. Ed. Engl. 1990,
29, 891-893. (c) Sommovigo, M.; Pasquali, M.; Leoni, P.; Braga, D.;
Sabatino, P. Chem. Ber. 1991, 124, 97-99. (d) Li, C.-S.; Cheng, C.-H.;
Liao, F.-L.; Wang, S.-L. J . Chem. Soc., Chem. Commun. 1991, 710-
712. (e) Kannan, S.; J ames, A. J .; Sharp, P. R. J . Am. Chem. Soc. 1998,
120, 215-216. (f) Kocˇovsky´, P.; Vyskocˇil, S.; C´ısarˇova´, I.; Sejbal, J .;
Tisˇlerova´, I.; Smrcˇina, M.; Lloyd-J ones, G. C.; Stephen, S. C.; Butts,
C. P.; Murray, M.; Langer, V. J . Am. Chem. Soc. 1999, 121, 7714-
7715.
Discu ssion
The catalytic cycle for the amination reactions is
presumably similar to that postulated for the palladium-
catalyzed amination of aryl bromides using the Pd/P(o-
tol)3 catalyst system. Although the reasons for the high
reactivity of catalysts based on 2-6 are not completely
understood, several structural features of these ligands
appear to contribute to their effectiveness. The electron-
rich phosphine group serves to accelerate the oxidative
addition process and allows for the transformation of aryl
chloride substrates that react sluggishly when palladium
complexes bearing triarylphosphine ligands are used.17
(15) Sadighi, J . P.; Singer, R. A.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 4960-4976.
(16) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J .; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J . Organometallics 1995,
14, 3081-3089.
(20) Biaryl-forming reductive elimination from Pt(II) has been
postulated to occur via a transition state in which both arenes are
perpendicular to the coordination plane. See: Braterman, P. S.; Cross,
R. J .; Young, G. B. J . Chem. Soc., Dalton Trans. 1977, 1892-1897.
(17) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047-1062.

1166 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe et al.
triflates, although the rates of reactions of aliphatic
amines with aryl bromides are slower with catalysts
supported by these ligands than with the Pd/BINAP
catalyst system. In general, reactions of aryl bromides
and triflates with primary aliphatic amines and primary
anilines are more efficient with 3; ligand 4 provides the
best results for reactions of these substrates with second-
ary aliphatic amines.
The effectiveness of these ligands is believed to be due
to a unique combination of steric and electronic proper-
ties. Their electron-rich nature promotes oxidative ad-
dition; their steric bulk facilitates reductive elimination
and promotes reactivity via monophosphine intermedi-
ates, which presumably promotes all steps of the catalytic
cycle.
F igu r e 2. Chem 3-D representation of hypothetical LPdX2.
The family of ligands 3 and 4 exhibit excellent general-
ity in catalytic amination reactions, and their scope
encompasses nearly all of the transformations that can
be effected with P(o-tol)3, BINAP, PPF-OMe, DPPF, and
P(t-Bu)3. Furthermore, their ease of preparation, com-
mercial availability, and exceptional air stability are
substantial benefits over other catalyst systems for
reactions of aryl chloride, bromide, and triflate sub-
strates.
F igu r e 3. Chem 3-D representation of hypothetical LPd(Ar-
)(morpholine).
decreasing the rate of one or more steps in the catalytic
cycle. However, the fact that aminations of chloropy-
ridines proceed effectively at 110 °C suggests that the
pyridine nucleophile is not capable of irreversibly dis-
placing the basic phosphine ligand from the metal.9,10
The selectivity for the reaction of an aryl bromide in
the presence of an aryl chloride (in the competition
experiment described above) demonstrates that while the
overall process is faster for aryl chloride substrates, as
expected, the oxidative addition of the aryl bromide
substrate is faster than that of the aryl chloride. The
reductive elimination processes should proceed at the
same rate for both aryl chlorides and aryl bromides; thus,
the Pd-N bond-forming step must be slower for the LPd-
(Ar)Br complex than for the LPd(Ar)Cl complex and is
presumably rate-limiting for the reactions of aryl bro-
mides with aliphatic amines. In contrast, NMR experi-
ments have shown that oxidative addition is most likely
the rate-limiting step in catalytic amination reactions
that employ Pd/BINAP or Pd/DPPF catalysts.2d,21 Aryl-
ations of aniline substrates were faster for aryl bromides
than for the analogous aryl chlorides. It is possible that
the increased acidity of anilines relative to aliphatic
amines increases the rate of Pd-N bond formation to the
point that oxidative addition becomes rate-limiting.
In conclusion, use of 2-6 allows for the efficient
palladium-catalyzed amination of aryl chloride sub-
strates. Catalysts based on 3 effect this transformation
at room temperature for some substrate combinations
and work well for reactions of primary amines with
unhindered aryl chlorides and arylations of aniline
substrates at 80 °C. Reactions of functionalized sub-
strates with potassium phosphate as the base at 80-100
°C are most effective with 2 and 4; these ligands
frequently work for reactions of secondary amines that
are inefficient with 3. Reactions of di-n-butylamine are
improved with the use of 5 or 6. Certain substrate
combinations react efficiently at low catalyst loadings
(0.05 mol % Pd), although most reactions require moder-
ate levels of palladium (0.5-1.0 mol %). Ligands 3 and 4
are also effective for the amination of aryl bromides and
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All reactions were carried out
under an argon atmosphere in oven-dried glassware. Elemen-
tal analyses were performed by Atlantic Microlabs Inc, Nor-
cross, GA, or E&R Microanalytical Laboratory, Parsippany,
NJ . Toluene was distilled under nitrogen from molten sodium.
Anhydrous DME was purchased from Aldrich Chemical Co.
and was used without further purification. THF was distilled
under argon from sodium benzophenone ketyl. Aryl halides
were purchased from commercial sources and were used
without further purification with the exception of 2-chloro-p-
xylene and 5-bromo-m-xylene, which were passed through
alumina to remove colored impurities. Aryl triflates were
prepared according to previously published procedures.13,14
Amines were purchased from commercial sources and were
passed through alumina before use. Ligands 2-6 were pre-
pared as previously described.2e,3a-c Palladium acetate and tris-
(dibenzylideneacetone)dipalladium(0) were purchased from
Strem Chemical company. Sodium tert-butoxide was purchased
from Aldrich Chemical Co.; the bulk of this material was stored
under nitrogen in a Vacuum Atmospheres glovebox. Small
portions (1-2 g) were removed from the glovebox in glass vials,
stored in the air in desiccators filled with anhydrous calcium
sulfate, and weighed in the air. Tribasic potassium phosphate
was purchased from Fluka Chemical Company. Tetramer
bromide (12) (see Scheme 2) was prepared according to
previously published procedures.15 IR spectra reported in this
paper were obtained by placing neat samples directly on the
DiComp probe of an ASI REACTIR in situ IR instrument.
Yields in Tables 1-9 refer to isolated yields (average of two
runs) of compounds estimated to be g95% pure as determined
by 1H NMR and GC analysis or combustion analysis. Com-
pounds previously reported by this group were characterized
by 1H NMR; their purity was confirmed by GC analysis.
Compounds that are described in more than one table (or more
than once in the same table) were completely characterized
once. Other samples of these compounds were characterized
by comparing their 1H NMR spectra to those of the fully
characterized product; their purity was confirmed by GC
analysis. The characterization data of known compounds are
given in the Supporting Information. The procedures described
in this section are representative, thus the yields may differ
from those given in Tables 1-9.
o-(Di-ter t-bu tylp h osp h in o)cycloh exylben zen e (7). An
(21) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 2000, 65, 1144.
oven-dried Schlenk flask was allowed to cool to room temper-

Palladium-Catalyzed Amination
J . Org. Chem., Vol. 65, No. 4, 2000 1167
ature under an argon purge and was charged with 1,2-
dibromobenzene (1.2 mL, 10.0 mmol), ether (20 mL), and THF
(20 mL). The mixture was cooled to -119 °C with stirring using
an ethanol/N2 cold bath. A solution of n-butyllithium in
hexanes (1.6 M, 5.8 mL, 9.3 mmol) was added slowly dropwise.
The mixture was stirred at -119 °C for 45 min, and then
cyclohexanone (0.98 mL, 9.5 mmol) was added to the mixture.
The mixture was stirred at -119 °C for 30 min, then warmed
to room temperature, and stirred for 17 h. The mixture was
quenched with saturated aqueous ammonium chloride (20
mL), diluted with ether (50 mL), and poured into a separatory
funnel. The layers were separated, and the aqueous phase was
extracted with ether (20 mL). The organic layers were com-
bined and washed with brine (20 mL), dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. The
crude material was purified by flash chromatography on silica
gel to afford 1.91 g of 1-(o-bromophenyl)cyclohexanol, which
was judged to be ∼86% pure by GC analysis. This material
was used without further purification.
3.90 (m, 1H), 1.85-1.60 (m, 5H), 1.51-1.25 (m, 5H), 1.14 (d,
18H, J ) 11.6 Hz); 31P NMR (121 MHz, CDCl3) δ 13.0; 13C
NMR (75 MHz, CDCl3) δ 155.7, 155.4, 135.0, 134.7, 128.8,
126.34, 126.27, 123.85, 40.8, 40.3, 34.4, 32.3, 31.9, 30.7, 30.5,
26.7, 26.3; IR (neat, cm-1) 2927, 1461, 1175, 768. Anal. Calcd
for C20H33P: C, 78.90; H, 10.93. Found: C, 78.96; H, 11.31.
Gen er a l P r oced u r e for Room -Tem p er a tu r e Ca ta lytic
Am in a tion of Ar yl Ch lor id es a n d Tr ifla tes. An oven-dried
resealable Schlenk flask was evacuated and backfilled with
argon. The flask was charged with Pd(OAc)2 (2.2 mg, 0.01
mmol, 1 mol %), 3 (6.0 mg, 0.02 mmol, 2 mol %), and NaOt-
Bu (135 mg, 1.4 mmol). The flask was evacuated and backfilled
with argon and then capped with a rubber septum. Toluene
(0.5 mL), the aryl chloride or triflate (1.0 mmol), the amine
(1.2 mmol), and additional toluene (0.5 mL) were added
through the septum (aryl halides or amines that were solids
at room temperature were added as solids following the
addition of NaOt-Bu). The septum was replaced with a Teflon
screwcap, the flask was sealed, and the mixture was stirred
at room temperature until the starting aryl chloride or triflate
had been completely consumed as judged by GC analysis.
During the course of the reaction, the mixture was observed
to form a gel (at around 50% conversion) and then liquefy again
as the reaction proceeded to completion. Following the com-
plete consumption of the aryl chloride or triflate starting
material, the mixture was diluted with ether (20 mL), filtered
through Celite, and concentrated in vacuo. The crude material
was purified by flash chromatography on silica gel.
A round-bottomed flask was purged with argon and charged
with 1-(o-bromophenyl)cyclohexanol (1.78 g, 7.0 mmol), dichlo-
romethane (28 mL), triethylsilane (1.5 mL, 9.1 mmol), and
trifluoroacetic acid (1.1 mL, 14.7 mmol). The mixture was
stirred at room temperature for 1.5 h, and then was quenched
with solid potassium carbonate (ca. 2 g). The mixture was
diluted with ether (50 mL) and transferred to a separatory
funnel. The mixture was washed with saturated aqueous
NaHCO3 (50 mL), and the organic phase was dried over
anhydrous magnesium sulfate, filtered, and concentrated in
vacuo to afford a mixture of 1-bromo-2-cyclohexylbenzene and
1-(2-bromophenyl)cyclohexene. The crude material was placed
into a round-bottomed flask, and the flask was purged with
argon. THF (2 mL) was added, and the mixture was cooled to
0 °C with stirring. A solution of BH3 in THF (1 M, 7.0 mL, 7.0
mmol) was added dropwise to the mixture. The mixture was
stirred at 0 °C for 1.5 h, then warmed to room temperature,
and stirred for 19 h. Acetic acid (4 mL) was added, and the
mixture was stirred at room temperature for 6 h. The mixture
was then diluted with ether (50 mL) and poured into a
separatory funnel. The mixture was washed with aqueous
NaOH (1 M, 50 mL), the layers were separated, and the
aqueous phase was extracted with ether (50 mL). The com-
bined organic phases were washed with brine (50 mL), dried
over anhydrous magnesium sulfate, filtered, and concentrated
in vacuo. The crude material was purified by flash chroma-
tography on silica gel to afford 555 mg of 1-bromo-2-cyclo-
hexylbenzene, which was judged to be 93% pure by GC
analysis. This material was used without further purification.
An oven-dried Schlenk flask was cooled to room temperature
under an argon purge and was charged with magnesium
turnings (27 mg, 1.1 mmol), THF (1 mL), and 1,2-dibromo-
ethane (8 µL). The mixture was stirred at room temperature
for 10 min, and then 1-bromo-2-cyclohexylbenzene (239 mg,
1.0 mmol) was added in one portion. The mixture was stirred
at room temperature for 20 min and then immersed in a 60
°C oil bath for 15 min. The mixture was cooled to room
temperature, the septum was removed from the flask, and
copper(I) chloride (104 mg, 1.05 mmol) was added. The flask
was capped with the septum and purged with argon for 1 min.
The flask was charged with di-tert-butylchlorophosphine (0.23
mL, 1.2 mmol) and additional THF (1 mL). The mixture was
immersed in a 60 °C oil bath with stirring for 26 h, then cooled
to room temperature, and filtered, and the solids were washed
with 1:1 ether:hexanes (50 mL). The organic solution was
poured into a separatory funnel and washed with 30% aqueous
ammonium hydroxide solution (3 × 50 mL) and brine (50 mL).
The organic phase was dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The crude material was
purified by flash chromatography on silica gel to afford the
title compound as a white solid (141 mg), which was judged
to be 92% pure by GC analysis. This material was recrystal-
lized from methanol to afford 101 mg (∼3% overall from 1,2-
dibromobenzene) of the title compound as a white, crystalline
solid, mp 101-102 °C: 1H NMR (300 MHz, CDCl3) δ 7.75-
7.65 (m, 1H), 7.40-7.20 (m, 2H), 7.15-7.05 (m, 1H), 4.05-
Wor k u p Meth od B. Following complete consumption of the
aryl chloride or triflate starting material, the mixture was
diluted with ether (50 mL) and transferred to a separatory
funnel. The mixture was washed with aqueous HCl (1 M, 2 ×
20 mL), washed with brine (20 mL), dried over anhydrous
magnesium sulfate, filtered and, concentrated in vacuo. The
crude product was purified by flash chromatography on silica
gel.
Ar yl Ch lor id es.
N-Meth yl-N-p h en yl-p-tolu id in e22 (Table 1, entry 1). The
general procedure using workup method B gave 197 mg (100%)
of the title compound as a colorless oil.
N-(4-Meth ylp h en yl)m or p h olin e22,23 (Table 1, entry 2).
The general procedure gave 166 mg (94%) of the title com-
pound as a white solid.
N,N-Dibu tyl-p-tolu id in e22,24 (Table 1, entry 3). The gen-
eral procedure was modified such that 2 mol % Pd(OAc)2 and
3 mol % 3 were employed. When the 4-chlorotoluene had been
completely consumed, 30% H2O2 (1 mL) was added to the
reaction mixture in order to oxidize the phosphine ligand. The
mixture was stirred at room temperature for 5 min, then
diluted with ether (20 mL), and transferred to a separatory
funnel. The layers were separated, and the organic layer was
washed with water (20 mL) and saturated aqueous Fe(SO)4
(20 mL). The combined aqueous layers were extracted with
ether; the organic extracts were combined, and the aqueous
layer was discarded. The combined organic extracts were
extracted with aqueous HCl (1 M, 4 × 50 mL), the organic
layer was discarded, and the aqueous extracts were combined
and basified to pH 14. The aqueous layer was extracted with
ether (4 × 50 mL), and the combined organic extracts were
washed with brine, dried over anhydrous magnesium sulfate,
filtered through a plug of silica gel, and concentrated in vacuo
to afford 172 mg (79%) of the title compound as a colorless oil.
N-Ben zyl-p-tolu id in e (Table 1, entry 4).2e The general
procedure was followed using 5 mol % Pd(OAc)2 and 1.5 equiv
of benzylamine. When the 4-chlorotoluene had been completely
consumed as judged by GC analysis, the reaction mixture was
diluted with THF (5 mL), and 30% aqueous hydrogen peroxide
(5 mL) was added to oxidize the phosphine. The mixture was
stirred at room temperature for 5 min, then diluted with ether
(50 mL), and transferred to a separatory funnel. The layers
were separated, and the organic layer was washed with water
(22) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1996, 61, 1133-
1135.

1168 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe et al.
(20 mL) and saturated aqueous FeSO4 (20 mL). The aqueous
washes were discarded, the organic phase was extracted with
aqueous 1M HCl (4 × 50 mL), and the organic layer was
discarded. The combined aqueous layers were basified to pH
14 with aqueous 6 M NaOH and then extracted with ether (3
× 50 mL). The combined organic layers were washed with
brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated to afford 158 mg (80%) of a colorless oil.
1586, 1150, 1065, 700. Anal. Calcd for C15H17NO2: C, 74.05;
H, 7.04. Found: C, 73.90; H, 7.01.
Ar yl Tr ifla tes.
N-(4-ter t-Bu tylp h en yl)m or p h olin e (Table 8, entry 1).29
The general procedure gave 170 mg (78%) of the title com-
pound as a white solid.
N-(4-ter t-Bu tylp h en yl)-p-a n isid in e (Table 8, entry 2).
The general procedure using Pd2(dba)3 and 3 mL toluene/mmol
aryl triflate gave 195 mg (76%) of the title compound as a pale
yellow solid.
N-(2,5-Xylyl)p yr r olid in e25,26 (Table 1, entry 5). The gen-
eral procedure gave 169 mg (97%) of the title compound as a
colorless oil, which was determined to contain e1% of 3 as
N-(4-ter t-Bu tylp h en yl)ben zyla m in e (Table 8, entry 3).
The general procedure gave 184 mg (77%) of the title com-
pound as a colorless oil.
1
judged by H NMR and GC analysis.
N-(2,5-Xylyl)ben zyla m in e (Table 1, entry 6). The general
procedure was modified such that 2 mol % Pd(OAc)2 and 4 mol
% 3 were employed. When the aryl halide had been completely
consumed, 30% H2O2 (2 mL) and THF (1 mL) were added to
the reaction mixture. The mixture was stirred at room tem-
perature for 5 min, then diluted with ether (20 mL), and
transferred to a separatory funnel. The layers were separated,
and the organic layer was washed with water (20 mL) and
saturated aqueous Fe(SO)4 (20 mL). The combined aqueous
layers were extracted with ether; the organic extracts were
combined, dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo. The crude material was then
purified by flash chromatography on silica gel to afford 196
mg (99%) of the title compound as a colorless oil: 1H NMR
(250 MHz, CDCl3) δ 7.41-7.26 (m, 5H), 6.96 (d, 1H, J ) 7.3
Hz), 6.51-6.46 (m, 2H), 4.36 (s, 2H), 3.790 (s, br, 1H), 2.26 (s,
3H), 2.12 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 145.9, 139.5,
129.9, 128.6, 127.6, 127.2, 118.9, 117.8, 110.8, 48.3, 21.5, 17.1;
IR (neat, cm-1) 3438, 1582, 1453, 795. Anal. Calcd for
N-(4-Meth oxyp h en yl)m or p h olin e (Table 8, entry 4).22,23
The general proceudre gave 170 mg (88%) of the title com-
pound as a white solid.
N-(p-Tolyl)-p-a n isid in e (Table 8, entry 5).30 The general
procedure using Pd2(dba)3 gave 151 mg (71%) of the title
compound as a pale yellow solid.
N-(3,4-Dim eth ylp h en yl)p yr r olid in e (Table 8, entry 6).
The general procedure gave 132 mg (75%) of the title com-
pound as a colorless oil.
Gen er a l P r oced u r e for Room -Tem p er a tu r e Ca ta lytic
Am in a tion of Ar yl Br om id es. An oven-dried resealable
Schlenk flask was evacuated and backfilled with argon. The
flask was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol, 1 mol
% Pd), 3 (6.0 mg, 0.02 mmol, 2 mol %), and NaOt-Bu (135 mg,
1.4 mmol). The flask was evacuated and backfilled with argon
and then capped with a rubber septum. Toluene (0.5 mL), the
aryl bromide (1.0 mmol), the amine (1.2 mmol), and additional
toluene (0.5 mL) were added through the septum (aryl
bromides or amines that were solids at room temperature were
added as solids following the addition of NaOt-Bu). The septum
was replaced with a Teflon screwcap, the flask was sealed,
and the mixture was stirred at room temperature until the
starting aryl bromide had been completely consumed as judged
by GC analysis. During the course of the reaction, the mixture
was observed to form a gel (at around 50% conversion) and
then liquefy again as the reaction proceeded to completion.
Following the complete consumption of the aryl bromide
starting material, the mixture was diluted with ether (20 mL),
filtered through Celite, and concentrated in vacuo. The crude
material was purified by flash chromatography on silica gel.
Wor k u p Meth od B. Following complete consumption of the
aryl bromide starting material, the mixture was diluted with
ether (50 mL) and transferred to a separatory funnel. The
mixture was washed with aqueous HCl (1 M, 2 × 20 mL),
washed with brine (20 mL), dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel.
N-Meth yl-N-(4-ter t-bu tylp h en yl)a n ilin e (Table 6, entry
1).29 The general procedure using workup method B gave 221
mg (92%) of the title compound as a colorless oil.
C
15H17N: C, 85.26; H, 8.11. Found: C, 85.14; H, 8.12.
N-(4-Meth oxyp h en yl)m or p h olin e22,23 (Table 1, entry 7).
The general procedure was modified such that 2 mol % Pd-
(OAc)2 and 4 mol % 3 were employed. The procedure afforded
173 mg (90%) of the title compound as a white solid.
N-(4-Cya n op h en yl)m or p h olin e25,27 (Table 1, entry 8). The
general procedure gave 158 mg (84%) of the title compound
as a white solid.
N-(4-Cya n op h en yl)-n -h exyla m in e (Table 1, entry 9).5 The
general procedure using 2.5 mol % Pd2(dba)3 gave 144 mg
(71%) of the title compound as a white solid.
N-(4-Cya n op h en yl)-p-tolu id in e (Table 1, entry 10).11 The
general procedure using 2.5 mol % Pd2(dba)3 gave 169 mg
(81%) of the title compound as a tan solid.
N-(2-Meth oxyp h en yl)ben zyla m in e28 (Table 1, entry 11).
The general procedure gave 211 mg (99%) of the title com-
pound as a colorless oil.
N-(3-Meth oxyp h en yl)-s-bu tyla m in e (Table 1, entry 12).
The general procedure using 5 mol % Pd(OAc)2 gave 159 mg
(89%) of the title compound as a colorless oil: 1H NMR (300
MHz, CDCl3) δ 7.06 (t, 1H, J ) 8.0 Hz), 6.25-6.12 (m, 3H),
3.77 (s, 3H), 3.55 (s, br, 1H), 3.41-3.31 (m, 1H), 1.63-1.43
(m, 2H), 1.16 (d, 3H, J ) 6.3 Hz), 0.94 (t, 3H, J ) 7.3 Hz); 13
C
N-(4-ter t-Bu tylp h en yl)-p-a n isid in e (Table 6, entry 2).
The general procedure using workup method B gave 224 mg
(88%) of the title compound as a pale yellow solid.
N,N-Dibu tyl-4-ter t-bu tyla n ilin e (Table 6, entry 3).6d The
general procedure using 1.5 mol % Pd2(dba)3, ligand 5, and
DME solvent gave 214 mg (82%) of the title compound as a
colorless oil.
NMR (75 MHz, CDCl3) δ 160.7, 148.9, 129.8, 106.2, 101.6, 98.9,
55.0, 49.8, 29.7, 20.3, 10.5; IR (neat, cm-1) 3397, 1613, 1208,
1158, 1050 Anal. Calcd for C11H17NO: C, 73.70; H, 9.56.
Found: C, 73.77; H, 9.65.
N-Meth yl-N-(3,5-d im eth oxyp h en yl)a n ilin e (Table 1, en-
try 13). The general procedure gave 238 mg (98%) of the title
compound as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
7.32-7.26 (m, 2H), 7.10-7.01 (m, 3H), 6.12-6.06 (m, 3H), 3.73
(s, 6H), 3.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.3, 150.9,
148.6, 129.2, 122.3, 97.5, 92.4, 55.2, 40.3; IR (neat, cm-1) 2939,
N-(2,5-Xylyl)-p-a n isid in e (Table 6, entry 4).25 The general
procedure using workup method B gave 206 mg (91%) of the
title compound as a colorless oil.
N-Ben zyl-3,5-xylid en e (Table 6, entry 5).5 The general
procedure was followed using 2.5 mol % Pd2(dba)3, KOt-Bu,
1.5 equiv of benzylamine, and THF as solvent. When the aryl
bromide had been completely consumed as judged by GC
analysis, the reaction mixture was diluted with THF (5 mL),
and 30% aqueous hydrogen peroxide (5 mL) was added to
oxidize the phosphine. The mixture was stirred at room
(23) Tsuji, Y.; Huh, K. T.; Ohsugi, Y.; Watanabe, Y. J . Org. Chem.
1985, 50, 1365-1370.
(24) Watanabe, Y.; Tsjui, Y.; Ige, H.; Ohsuji, Y.; Ohta, T. J . Org.
Chem. 1984, 49, 3359-3363.
(25) Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119,
6054-6058.
(26) Walkup, R. E.; Searles, S., J r. Tetrahedron 1985, 41, 101-106.
(27) Kotsuki, H.; Kobayashi, S.; Suenaga, H.; Nishizawa, H. Syn-
thesis 1990, 1145-1147.
(29) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997, 62, 6066-
6068.
(30) Barton, D. H. R.; Donnelly, D. M. X.; Finet, J .-P.; Guiry, P. T.
J . Chem. Soc., Perkin Trans. 1 1991, 2095-2102.
(28) Pratt, E. F.; McGovern, T. P. J . Org. Chem. 1964, 29, 1540-
1543.

Palladium-Catalyzed Amination
J . Org. Chem., Vol. 65, No. 4, 2000 1169
temperature for 5 min, then diluted with ether (50 mL), and
transferred to a separatory funnel. The layers were separated,
and the organic layer was washed with water (20 mL) and
saturated aqueous FeSO4 (20 mL). The aqueous washes were
discarded, the organic phase was extracted with aqueous 1 M
HCl (4 × 50 mL), and the organic layer was discarded. The
combined aqueous layers were basified to pH 14 with aqueous
6 M NaOH and then extracted with ether (3 × 50 mL). The
combined organic layers were washed with brine, dried over
anhydrous magnesium sulfate, filtered, and concentrated to
afford 110 mg (52%) of the title compound as a colorless oil.
N-(3,5-Xylyl)m or p h olin e (Table 6, entry 6).31 The general
procedure using 1.5 mol % Pd2(dba)3, KOt-Bu, and THF solvent
gave 151 mg (79%) of the title compound as a colorless oil.
This material contained <3% 3,5-dimethylphenol as judged
by GC analysis.
N-(p-Tolyl)d ip h en yla m in e (Table 2, entry 4).34 The gen-
eral procedure gave 242 mg (93%) of the title compound as a
pale yellow solid.
N-Ben zyl-p-tolu id in e (Table 2, entry 5).2e The general
procedure was conducted on a 2 mmol scale using 1.5 equiv of
amine. The reaction was subjected to the same workup
described above for N-(4-methylphenyl)hexylamine to afford
344 mg (87%) of the title compound as a pale yellow oil. This
material contained 1% 3 as judged by GC and 1H NMR
analysis.
N,N-Dibu tyl-p-tolu id in e (Table 2, entry 6).22,24 The gen-
eral procedure using Pd2(dba)3 and 5 gave 193 mg (88%) of
the title compound as a pale yellow oil.
N,N-Dibu tyl-p-tolu id in e (Table 2, entry 6).22,24 The gen-
eral procedure using Pd2(dba)3 and 6 gave 199 mg (91%) of
the title compound as a pale yellow oil.
3,5-Dim eth yltr ip h en yla m in e (Table 6, entry 7).32 The
general procedure was followed; the product was isolated by
recrystallization from ethanol instead of chromatography to
give 238 mg (88%) of the title compound as a white solid.
N-(4-Meth oxyp h en yl)m or p h olin e (Table 6, entry 8).22,23
The general procedure using 1.5 mol % Pd2(dba)3, KOt-Bu, and
THF solvent afforded 159 mg (82%) of the title compound as
a white solid.
N-Eth yl-N-p h en yl-p-tolu id in e (Table 2, entry 7).32 The
general procedure gave 196 mg (93%) of the title compound
as a pale yellow oil.
N-(4-Meth ylp h en yl)p ip er id in e (Table 2, entry 8).22 The
general procedure gave 149 mg (85%) of the title compound
as a colorless oil.
N-Meth yl-N-p h en yl-2,5-xylid en e (Table 2, entry 9).5 The
general procedure conducted on a 2 mmol scale gave 374 mg
(89%) of the title compound as a colorless oil.
2-Meth oxy-2′-m eth yld ip h en yla m in e (Table 6, entry 9).30
The general procedure using 2 mol % Pd(OAc)2 and workup
method B gave 197 mg (92%) of the title compound as a pale
yellow oil.
N-(2,5-Xylyl)cycloh exyla m in e (Table 2, entry 10). The
general procedure using 1 mol % Pd(OAc)2 gave 197 mg (97%)
of the title compound as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 6.92 (d, 1H, J ) 7.4 Hz), 6.45-6.40 (m, 2H), 3.35-
3.25 (m, 2H), 2.28 (s, 3H), 2.08 (s, br, 5H), 1.80-1.55 (m, 3H),
1.45-1.10 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 145.1, 136.6,
130.0, 118.6, 116.8, 110.9, 51.4, 33.6, 26.0, 25.0, 21.6, 17.1; IR
(neat, cm-1) 3427, 2927, 1520, 789. Anal. Calcd for C14H21N:
C, 82.70; H, 10.41. Found: C, 82.51; H, 10.78.
Gen er a l P r oced u r e for th e Ca ta lytic Am in a tion of
Ar yl Ch lor id es a t 80-110 °C. An oven-dried resealable
Schlenk flask was evacuated and backfilled with argon. The
flask was charged with palladium acetate (0.5 mol %), 3 (1.0
mol %), and NaOt-Bu (1.4 equiv) and evacuated and backfilled
with argon. The flask was capped with a rubber septum, and
toluene (2 mL/mmol halide), the aryl chloride (1.0 equiv), and
the amine (1.2 equiv) were added through the septum (aryl
chlorides or amines that were solids at room temperature were
added as solids following the addition of NaOt-Bu). The septum
was replaced with a Teflon screwcap, the flask was sealed,
and the mixture was heated to 80 °C with stirring until the
starting aryl halide had been completely consumed as judged
by GC analysis. The mixture was cooled to room temperature,
diluted with ether (30 mL), filtered through Celite, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel.
Wor k u p Meth od B. Following complete consumption of the
aryl halide starting material, the mixture was diluted with
ether (50 mL) and transferred to a separatory funnel. The
mixture was washed with aqueous HCl (1 M, 2 × 20 mL),
washed with brine (20 mL), dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel.
N-(2,5-Xylyl)p yr r olid in e (Table 2, entry 11).25,26 The
general procedure conducted on a 2 mmol scale gave 346 mg
(99%) of the title compound as a colorless oil.
N-(2,5-Xylyl)m or p h olin e (Table 2, entry 12).2e The general
procedure conducted on a 2 mmol scale gave 340 mg (89%) of
the title compound as a colorless oil.
2-Meth oxy-2′,4′-d im eth yld ip h en yla m in e (Table 2, entry
13). The general procedure using Pd2(dba)3 gave 228 mg (94%)
of the title compound as a white solid, mp 90-91.5 °C: 1H
NMR (300 MHz, CDCl3) δ 7.16 (s, 1H), 7.12 (d, J ) 7.5 Hz,
1H), 7.05 (dd, J ) 7.66, 2.2 Hz, 1H), 6.93-6.84 (m, 3H), 6.79
(d, J ) 7.6 Hz, 1H), 5.86 (s, 1H), 3.93 (s, 3H), 2.31 (s, 3H),
2.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 148.2, 140.8, 136.5,
134.2, 130.9, 126.4, 123.1, 121.0, 120.4, 119.3, 114.6, 110.5,
55.8, 21.4, 17.7; IR (neat, cm-1) 3411, 3062, 3045, 3006, 2964,
2933, 2919, 2856, 2836, 1598, 1576, 1521, 1501, 1449, 1412,
1341, 1293, 1243, 1220, 1179, 1115, 1048, 1030, 1000, 886, 809,
772, 741, 708. Anal. Calcd for C15H17NO: C, 79.26; H, 7.54.
Found: C, 79.18; H, 7.56.
N-(4-Meth ylp h en yl)h exyla m in e (Table 2, entry 1).22 The
general procedure was conducted on a 2 mmol scale using 1.5
equiv of amine. Following completion of the reaction, the
mixture was cooled to room temperature, diluted with ether
(40 mL), and extracted with 1 M aqueous HCl (3 × 50 mL).
The organic phase was discarded, and the aqueous layer was
basified to pH 14 with 6 M aqueous NaOH. The aqueous phase
was extracted with ether (3 × 50 mL), and the ether layers
were combined, dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo to afford 318 mg (83%) of
the title compound as a white solid. This material contained
1% 3 as judged by GC and 1H NMR analysis.
N-Ben zyl-2,5-xylid en e (Table 2, entry 14). The general
procedure conducted on a 2 mmol scale gave 387 mg (92%) of
the title compound as a colorless oil.
N-(2,5-Dim eth ylp h en yl)a m in oa cetoa ld eh yd e Dieth yl
Aceta l (Table 2, entry 15). The general procedure conducted
on a 2 mmol scale using a reaction temperature of 100 °C gave
474 mg (100%) of the title compound as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 6.93 (d, 1 H, J ) 7.4 Hz), 6.48 (d, 1
H, J ) 7.4 Hz), 6.45 (s, 1 H), 4.74 (t, 1H, J ) 5.8 Hz), 3.80-
3.52 (m, 5 H), 3.28 (d, 2 H, J ) 5.7 Hz), 2.28 (s, 3 H), 2.10 (s,3
H), 1.25 (t, 6 H J ) 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 145.8,
136.8, 130.1, 119.4, 118.0, 111.1, 101.0, 62.4, 46.4, 21.8, 17.2,
15.6. IR (neat, cm-1) 3421, 1522, 1125, 1059, 793; Anal. Calcd
for C14H23NO2: C, 70.85; H, 9.77. Found: C,70.70; H, 9.84.
N-p-An isid ylp yr r olid in e (Table 2, entry 16).14a The gen-
eral procedure using 1 mol % Pd(OAc)2 gave 159 mg (90%) of
the title compound as a white solid.
N-(4-Meth ylp h en yl)m or p h olin e22,23 (Table 2, entry 2).
The general procedure conducted on a 2 mmol scale gave 316
mg (95%) of the title compound as a white solid.
Di-p-tolyla m in e (Table 2, entry 3).25,33 The general proce-
dure using Pd2(dba)3 gave 185 mg (93%) of the title compound
as a white solid.
(31) Vernaudon, P.; Rajoharison, H. G.; Roussel, C. Bull. Chem. Soc.
Fr. 1987, 205-211.
(32) Haga, K.; Oohashi, M.; Kaneko, R. B. Chem. Soc. J pn. 1984,
57, 1586-1590.
(33) Dictionary of Organic Compounds, 6th ed.; Cadogan, J . I. G.,
Ley, S. V., Pattenden, G., Raphael, R. A., Rees, C. W., Eds.; Chapman
& Hill: London, 1996; p 2611.
(34) Marsden, R. J . B. J . Chem. Soc. 1937, 627.

1170 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe et al.
4-[2-(p -An isid yl)et h yl]m or p h olin e (Table 2, entry 17).
The general procedure conducted on a 2 mmol scale gave 420
mg (89%) of the title compound as a pale yellow oil: 1H NMR
(300 MHz, CDCl3) δ 6.79 (d, 2 H, J ) 9.0 Hz), 6.61 (m, 2 H, J
) 9.0 Hz), 4.04 (br, s, 1 H), 3.75 (s, 3 H), 3.72 (m, 4 H, J ) 4.5
Hz), 3.12 (t, 2 H, J ) 6.0 Hz), 2.62 (t, 2 H, J ) 6.0 Hz), 2.47
(m, 4 H, J ) 4.5 Hz); 13C NMR (75 MHz, CDCl3) δ 152.3, 142.9,
115.1, 114.4, 67.1, 56.0, 57.5, 53.6, 41.1; IR (neat, cm-1) 3367,
2950, 1235, 1115, 1036. Anal. Calcd for C13H20N2O2: C, 66.07;
H, 8.53. Found: C, 65.87; H, 8.62.
1-(4-Meth oxyp h en yl)-4-m eth ylp ip er a zin e (Table 2, en-
try 18).35 The general procedure conducted on a 2 mmol scale
using ligand 4 gave 341 mg (83%) of the title compound as a
yellow solid.
4,4′-Dim eth oxyd ip h en yla m in e (Table 2, entry 19).30 The
general procedure using Pd2(dba)3 gave 217 mg (95%) of the
title compound as a pale yellow solid.
Ben zop h en on e N-(2-Meth oxyp h en yl)h yd r a zon e (Table
2, entry 20).36 The general procedure using Pd2(dba)3 gave 278
mg (92%) of the title compound as a pale yellow solid.
N-(2-Meth oxyp h en yl)ben zyla m in e (Table 2, entry 21).28
The general procedure conducted on a 2 mmol scale gave 423
mg (99%) of the title compound as a colorless oil.
N-(2-Meth oxyp h en yl)p yr r olid in e (Table 2, entry 22).37
The general procedure conducted on a 2 mmol scale gave 314
mg (89%) of the title compound as a colorless oil.
N-(p-Tolyl)-3,5-d im eth oxya n ilin e (Table 2, entry 23). The
general procedure using Pd2(dba)3 gave 228 mg (94%) of the
title compound as a white solid, mp 66.5-67.5 °C: 1H NMR
(300 MHz, CDCl3) δ 7.11 (d, J ) 8.6 Hz, 2H), 7.04 (d, J ) 8.5
Hz, 2H), 6.20 (d, J ) 2.1 Hz, 2H), 6.05 (t, J ) 2.2 Hz, 1H),
5.64 (s, 1H), 3.77 (s, 6H), 2.33 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 161.8, 146.3, 139.9, 131.6, 130.0, 120.0, 95.1, 92.5,
55.4, 20.9; IR (neat, cm-1) 3367, 3012, 966, 2937, 2840, 1594,
1513, 1478, 1459, 1254, 1200, 1189, 1165, 1144, 1057, 924, 822,
810, 770, 720, 683. Anal. Calcd for C15H17NO2: C, 74.05; H,
7.04. Found: C, 74.06; H, 7.23.
N-Ben zh yd r ilid en e-3,5-d im eth oxya n ilin e (Table 2, en-
try 24). The general procedure using Pd2(dba)3 (1 mol % Pd)
and ligand 4 gave 316 mg (100%) of the title compound as a
pale yellow solid, mp 101-102 °C: 1H NMR (300 MHz, CDCl3)
δ 7.76-7.71 (m, 2 H), 7.49-7.12 (m, 8 H), 6.06 (t, 1 H, J )
2.1), 5.91 (d, 2 H, J ) 2.1 Hz), 3.62 (s, 6 H); 13C NMR (75 MHz,
CDCl3) δ 168.5, 160.8, 153.14, 139.6, 136.3, 130.9, 129.5, 129.4,
128.8, 128.3, 128.1, 99.4, 96.1, 55.4; IR (neat, cm-1) 1594, 1208,
1154, 1123, 704. Anal. Calcd for C21H19NO2: C, 79.47; H, 6.03.
Found: C, 79.61; H, 6.19.
benzylamine and a reaction temperature of 100 °C gave 358
mg (97%) of a white solid, which was determined to be a 19/1
mixture (by 1H NMR) of the title compound and bis(2-pyridyl)-
benzylamine.
N-(2-P yr id yl)m or p h olin e (Table 4, entry 2).9 The general
procedure conducted on a 2 mmol scale using a reaction
temperature of 100 °C and ligand 4 gave 319 mg (97%) of the
title compound as a pale yellow oil.
N-Meth yl-N-(3-p yr id yl)a n ilin e (Table 4, entry 3).9 The
general procedure using 1 mol % Pd(OAc)2, ligand 4, and a
reaction temperature of 110 °C gave 178 mg (97%) of the title
compound as a pale yellow oil.
N-Meth yl-N-(3-p yr id yl)a n ilin e (Table 4, entry 3).9 The
general procedure using 1 mol % Pd(OAc)2, ligand 2, and a
reaction temperature of 110 °C gave 176 mg (96%) of the title
compound as a pale yellow oil.
N-Ben zyl-3-a m in op yr id in e (Table 4, entry 4).40 The gen-
eral procedure using 1 mol % Pd(OAc)2, 1.5 equiv of benzyl-
amine, and a reaction temperature of 110 °C gave 161 mg
(88%) of the title compound as a pale green solid.
N-Hexyl-3-a m in op yr id in e (Table 4, entry 5).9 The general
procedure using 3 equiv of hexylamine, 1 mol % Pd(OAc)2,
ligand 2, and a reaction temperature of 100 °C gave 134 mg
(75%) of the title compound as a white solid.
N-(3-P yr id yl)m or p h olin e (Table 4, entry 6).9 The general
procedure using 1 mol % Pd(OAc)2 and a reaction temperature
of 110 °C gave 116 mg (71%) of the title compound as a pale
yellow oil.
N,N-Dibu tyl-3-a m in op yr id in e (Table 4, entry 7).6d The
general procedure using 1 mol % Pd(OAc)2, ligand 2, and a
reaction temperature of 110 °C gave 171 mg (83%) of the title
compound as a pale yellow oil.
N-(4-P yr id yl)m or p h olin e (Table 4, entry 8).9 The general
procedure using 1 mol % Pd(OAc)2, 2 mol % 3, 2.8 equiv of
K3PO4, dioxane solvent, and a reaction temperature of 100 °C
gave 124 mg (76%) of the title compound as a white solid.
N-Ben zyl-4-a m in op yr id in e (Table 4, entry 9).41 The gen-
eral procedure using 1 mol % Pd(OAc)2, 2 mol % 4, 2.8 equiv
of NaOt-Bu, dioxane solvent, and a reaction temperature of
100 °C gave 132 mg (72%) of a white solid, mp 108-110 °C
(CH2Cl2/hexanes) (lit. mp 110.5-111 °C),41 which was deter-
mined to contain 3.6% of bis(4-pyridyl)benzylamine by 1H NMR
analysis.
N-Meth yl-N-(4-p yr id yl)a n ilin e (Table 4, entry 10).25 The
general procedure using 1 mol % Pd(OAc)2, 2 mol % 4, 2.8 equiv
of NaOt-Bu, dioxane solvent, and a reaction temperature of
100 °C gave 171 mg (93%) of a yellow oil.
N-(2,6-Dim eth ylp h en yl)m or p h olin e (Table 2, entry 25).
The general procedure using 1 mol % Pd(OAc)2, ligand 2, and
a reaction temperature of 110 °C gave 162 mg (86%) of the
title compound as a white solid, mp 86-87 °C: 1H NMR (300
MHz, CDCl3) δ 7.01-6.92 (m, 3 H), 3.79 (m, 4 H, J ) 4.5 Hz),
3.08 (m, 4 H, J ) 4.5 Hz), 2.34 (s, 6 H); 13C NMR (75 MHz,
CDCl3) δ 148.1, 137.1, 129.2, 125.5, 68.3, 50.2, 19.8; IR (neat,
cm-1) 1260, 1109, 939, 843, 782. Anal. Calcd for C12H17NO:
C, 75.36; H, 8.96. Found: C, 75.35; H, 9.26.
N-(2,6-Dim eth ylph en yl)ben zylam in e (Table 2, entry 26).38
The general procedure using 1 mol % Pd(OAc)2 and 1.5 equiv
of benzylamine gave 183 mg (87%) of the title compound as a
colorless oil.
2,6-Diisop r op yl-2′,6′-d im eth yld ip h en yla m in e (Table 2,
entry 27).6e The general procedure using Pd2(dba)3 (4 mol %
Pd) gave 212 mg (75%) of the title compound as a white solid.
Ch lor op yr id in e Der iva tives.
N-Ben zyl-2-a m in op yr id in e (Table 4, entry 1).39 The gen-
eral procedure conducted on a 2 mmol scale using 1.5 equiv of
Gen er a l P r oced u r e for th e Ca ta lytic Am in a tion of
Ar yl Br om id es a t 80-110 °C. An oven-dried resealable
Schlenk flask was evacuated and backfilled with argon. The
flask was charged with Pd2(dba)3 (2.3 mg, 0.0025 mmol, 0.5
mol % Pd), 3 (3.0 mg, 0.01 mmol, 1.0 mol %), and NaOt-Bu
(135 mg, 1.4 mmol) and evacuated and backfilled with argon.
The flask was capped with a rubber septum, and toluene (2
mL/mmol halide), the aryl bromide (1.0 mmol), and the amine
(1.2 mmol) were added through the septum (aryl bromides or
amines that were solids at room temperature were added as
solids following the addition of NaOt-Bu). The septum was
replaced with a Teflon screwcap, the flask was sealed, and the
mixture was heated to 80 °C with stirring until the starting
aryl bromide had been completely consumed as judged by GC
analysis. The mixture was cooled to room temperature, diluted
with ether (30 mL), filtered through Celite, and concentrated
in vacuo. The crude product was purified by flash chromatog-
raphy on silica gel.
Wor k u p Meth od B. Following complete consumption of the
aryl halide starting material, the mixture was diluted with
ether (50 mL) and transferred to a separatory funnel. The
mixture was washed with aqueous HCl (1 M, 2 × 20 mL) and
then with brine (20 mL), dried over anhydrous magnesium
(35) Davis, W.; Ross, W. C. J . J . Chem. Soc. 1949, 2831-2834.
(36) Busch, M.; Kunder, H. Ber. Dtsch. Chem. Ges. 1916, 49, 317-
334.
(37) Shim, S. C.; Huh, K. T.; Park, W. H. Tetrahedron 1986, 42,
259-263.
(38) Maccarone, E.; Mamo, A.; Torre, M. J . Org. Chem. 1979, 44,
1143-1145.
(40) Trifonov, L. S.; Orahovats, A. S. Helv. Chim. Acta 1987, 90,
1732-1736.
(41) Okuda, S.; Robison, M. M. J . Org. Chem. 1959, 24, 1008-1011.
(39) Sprinzak, Y. Org. Synth. Coll. Vol. IV 1963, 91-92.

Palladium-Catalyzed Amination
J . Org. Chem., Vol. 65, No. 4, 2000 1171
sulfate, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel.
N-(4-Meth ylp h en yl)m or p h olin e (Table 7, entry 1).22,23
The general procedure conducted on a 2 mmol scale using Pd-
(OAc)2 gave 329 mg (93%) of the title compound as a white
solid.
1509, 1235, 1031, 818. Anal. Calcd for C17H21NO: C, 79.96;
H, 8.29. Found: C, 79.85; H, 8.29.
N-(4-ter t-Bu tylp h en yl)ben zyla m in e (Table 9, entry 3).
The general procedure using Pd(OAc)2,1.5 equiv of benzyl-
amine, NaOt-Bu, and toluene as solvent gave 163 mg (68%)
of the title compound as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.40-7.26 (m, 5H), 7.20 (d, 2H, J ) 6.7 Hz), 6.60 (d,
4-Meth oxy-4′-(d im eth yla m in o)d ip h en yla m in e (Table 7,
entry 2).42 The general procedure gave 229 mg (95%) of the
title compound as a pale yellow solid.
2H, J ) 6.5 Hz), 4.31 (s, 2H), 3.95 (s, br, 1H), 1.27 (s, 9H); 13
C
NMR (75 MHz, CDCl3) δ 145.8, 140.3, 139.6, 128.6, 127.5,
127.1, 126.0, 112.5, 48.6, 33.8, 31.5; IR (neat, cm-1) 3416, 2961,
1613, 1521, 818. Anal. Calcd for C17H21N: C, 85.30; H, 5.85.
Found: C, 85.37; H, 8.91.
N-(p-Tolyl)-p-a n isid in e (Table 7, entry 3).30 The general
procedure gave 194 mg (91%) of the title compound as a pale
yellow solid.
N,N-Dibu tyl-p-ter t-bu tyla n ilin e (Table 9, entry 4).6d The
general procedure using Pd(OAc)2, 2 mol % 4, NaOt-Bu, and
toluene as solvent gave 185 mg (71%) of the title compound
as a colorless oil.
N-Eth yl-N-(3,5-d im eth ylp h en yl)a n ilin e (Table 7, entry
4).6d The general procedure using Pd(OAc)2 gave 188 mg (84%)
of the title compound as a pale yellow oil.
N-Ben zyl-3,5-xylid en e (Table 7, entry 5).5 The general
procedure using 1.5 equiv benzylamine gave 174 mg (82%) of
the title compound as a colorless oil.
4-Meth oxy-4′-n itr od ip h en yla m in e (Table 9, entry 5).44
The general procedure using K3PO4 as the base, 0.5 mol %
Pd2(dba)3, and DME as solvent (the material was purified by
crystallization from ethanol instead of by flash chromatogra-
phy) gave 183 mg (75%) of the title compound as a yellow solid.
N-(2-Meth oxyp h en yl)ben zyla m in e (Table 9, entry 6).28
The general procedure using 1.0 mol % Pd(OAc)2 gave 172 mg
(81%) of the title compound as a colorless oil.
N-Mesityl-3,4-(m eth ylen ed ioxy)a n ilin e (Table 7, entry
6).30 The general procedure gave 245 mg (96%) of the title
compound as a pale yellow solid.
N-(4-ter t-Bu tylp h en yl)p ip er id in e (Table 7, entry 7).14a
The general procedure using ligand 4 gave 185 mg (85%) of
the title compound as a white solid.
N,N-Dibu tyl-4-ter t-bu tyla n ilin e (Table 7, entry 8).6d The
general procedure using ligand 4 gave 222 mg (85%) of the
title compound as a colorless oil.
N-(3,4-Dim eth ylp h en yl)p yr r olid in e (Table 9, entry 7).
The general procedure using ligand 4 gave 155 mg (89%) of
the title compound as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 6.97 (d, 1H, J ) 8.1 Hz), 6.40-6.33 (m, 2H), 3.26-
N,N-Dibu tyl-4-ter t-bu tyla n ilin e (Table 7, entry 8).6d The
general procedure using ligand 5 gave 237 mg (91%) of the
title compound as a colorless oil.
3.21 (m, 4H), 2.23 (s, 3H), 2.16 (s, 3H), 2.00-1.94 (m, 4H); 13
C
NMR (75 MHz, CDCl3) δ 146.6, 137.0, 130.1, 113.3, 109.2, 47.8,
25.4, 20.2, 18.6; IR (neat, cm-1) 2922, 1613, 1363, 796. Anal.
Calcd for C12H17N: C, 82.23; H, 9.78. Found: C, 82.37; H, 9.81.
2-Meth oxy-4′-cya n od ip h en yla m in e (Table 9, entry 8).
The general procedure using THF solvent (the product was
purified by recrystallization from ethanol/hexanes instead of
by chromatography) gave 194 mg (87%) of the title compound
as a pale yellow solid, mp 108-109 °C: 1H NMR (300 MHz,
CDCl3) δ 7.50 (d, J ) 8.7 Hz, 2H), 7.37 (d, J ) 7.5 Hz, 1H),
7.08-6.94 (m, 5H), 6.38 (s, 1H), 3.89 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 150.2, 147.6, 133.8, 129.7, 123.4, 120.9, 120.1,
118.9, 115.6, 111.2, 101.8, 55.8; IR (neat, cm-1) 3321, 3045,
3002, 2968, 2929, 2831, 2217, 1611, 1598, 1586, 1522, 1507,
1488, 1459, 1341, 1328, 1295, 1248, 1175, 1111, 1028, 830, 820,
741. Anal. Calcd for C14H12N2O: C, 74.98; H, 5.39. Found: C,
74.95; H, 5.32.
N-Meth yl-N-p h en yl-2,5-xylid en e (Table 7, entry 9).5 The
general procedure using ligand 4 gave 159 mg (75%) of the
title compound as a colorless oil.
N-Allyl-2,5-xylid en e (Table 7, entry 10).43 The general
procedure gave 149 mg (93%) of the title compound as a
colorless oil.
Gen er a l P r oced u r e for th e Ca ta lytic Am in a tion of
Ar yl Tr ifla tes a t 65-80 °C. An oven-dried resealable Schlenk
flask was evacuated and backfilled with argon. The flask was
charged with Pd2(dba)3 (4.6 mg, 0.005 mmol, 1.0 mol % Pd), 3
(6.0 mg, 0.02 mmol, 2.0 mol %), and K3PO4 (297 mg, 1.4 mmol)
and evacuated and backfilled with argon. The flask was capped
with a rubber septum, and DME (2 mL/mmol halide), the aryl
triflate (1.0 mmol), and the amine (1.2 mmol) were added
through the septum (aryl triflates or amines that were solids
at room temperature were added as solids following the
addition of K3PO4). The septum was replaced with a Teflon
screwcap, the flask was sealed, and the mixture was heated
to 80 °C with stirring until the starting aryl triflate had been
completely consumed as judged by GC analysis. The mixture
was cooled to room temperature, diluted with ether (30 mL),
filtered through Celite, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel.
Wor k u p Meth od B. Following complete consumption of the
aryl halide starting material, the mixture was diluted with
ether (50 mL) and transferred to a separatory funnel. The
mixture was washed with aqueous HCl (1 M, 2 × 20 mL) and
then with brine (20 mL), dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel.
N-(4-ter t-Bu tylp h en yl)m or p h olin e (Table 9, entry 1).29
The general procedure using Pd(OAc)2, THF as solvent, and a
reaction temperature of 65 °C gave 201 mg (92%) of the title
compound as a white solid.
N-(4-Acetylp h en yl)-m -tolu id in e (Table 9, entry 9). The
general procedure using workup method B gave 211 mg (94%)
of the title compound as a yellow solid, mp 89-91 °C: 1H NMR
(300 MHz, CDCl3) δ 7.86 (d, 2H, J ) 6.9 Hz), 7.23 (t, 1H, J )
6.6 Hz), 6.97-6.87 (m, 4H), 6.11 (s, 1H), 2.53 (s, 3H), 2.35 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 196.4, 148.5, 140.5, 139.4,
130.6, 129.2, 128.7, 124.1, 121.3, 117.7, 114.3, 26.1, 21.4; IR
(neat, cm-1) 3312, 3053, 1656, 1583, 1278, 1166, 764. Anal.
Calcd for C15H15NO: C, 79.97; H, 6.71. Found: C, 79.77; H,
6.64.
N-(4-Nitr op h en yl)p ip er id in e (Table 9, entry 10).11,45 The
general procedure gave 168 mg (82%) of the title compound
as a yellow solid.
P r oced u r es for th e Ca ta lytic Am in a tion of Ar yl Ch lo-
r id es a t Low Ca ta lyst Loa d in gs. N-Meth yl-N-p h en yl-p-
tolu id in e22 (Table 3, entry 1). An oven-dried Schlenk flask
was evacuated and backfilled with argon. The flask was
charged with NaOt-Bu (270 mg, 2.8 mmol) and then evacuated
and backfilled with argon, and toluene (1 mL), 4-chlorotoluene
(0.24 mL, 2.0 mmol), and N-methylaniline (0.26 mL, 2.4 mmol)
were added through a rubber septum. A separate flask was
charged with Pd2(dba)3 (9.2 mg, 0.01 mmol) and ligand 3 (12.0
mg, 0.04 mmol) and was purged with argon. Toluene (4 mL)
was added, the mixture was stirred for 1 min at room
temperature, and then 200 µL of this solution (0.05 mol % Pd,
N-(4-ter t-Bu tylp h en yl)-p-a n isid in e (Table 9, entry 2).
The general procedure using workup method B gave 221 mg
(87%) of the title compound as a pale yellow solid, mp 80-82
°C: 1H NMR (300 MHz, CDCl3) δ 7.30-7.20 (m, 2H), 7.10-
6.75 (m, 6H), 5.50 (s, br, 1H), 3.20 (s, 3H), 1.29 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 154.8, 142.6, 142.4, 136.6, 126.0,
121.3, 115.7, 114.6, 55.5, 34.0, 31.5; IR (neat, cm-1) 3381, 2961,
(44) Ullmann, F.; J u¨ngel, K. Ber. Dtsch. Chem. Ges. 1909, 42, 1077-
1083.
(45) Verardo, G.; Giumanini, A. G.; Favret, G.; Strazzolini, P.
Synthesis 1991, 447-450.
(42) Wieland, H. Ber. Dtsch. Chem. Ges. 1920, 53, 1313-1328.
(43) Hussein, F. A.; Kazandji, S. Y. J . Indian Chem. Soc. 1966, 43,
663-668.

1172 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe et al.
0.1 mol % ligand 3) was added to the Schlenk flask followed
by additional toluene (1 mL). The septum was removed; the
flask was sealed with a Teflon screwcap and the mixture was
stirred at room temperature for 2 min and then heated to 100
°C with stirring until the starting aryl chloride had been
completely consumed as judged by GC analysis. The mixture
was cooled to room temperature, diluted with ether, and
filtered through Celite. The crude product was purified by flash
chromatography on silica gel to give 378 mg (96%) of the title
compound as a colorless oil.
F u n ction a lized Ar yl Ha lid es. An oven-dried resealable
Schlenk flask was evacuated and backfilled with argon. The
flask was charged with Pd2(dba)3 (4.6 mg, 0.005 mmol, 1 mol
% Pd), 4 (7.0 mg, 0.02 mmol, 2 mol %), and K3PO4 (297 mg,
1.4 mmol). The flask was evacuated and backfilled with argon
and capped with a rubber septum. DME (2 mL), the aryl halide
(1.0 mmol), and the amine (1.2 mmol) were added through the
septum (aryl halides or amines that were solids at room
temperature were added as solids following the addition of K3-
PO4). The septum was removed, and the flask was sealed with
a Teflon screwcap. The mixture was heated to 100 °C with
stirring until the starting aryl halide had been completely
consumed as judged by GC analysis. The mixture was cooled
to room temperature, diluted with ether or 1/1 ether/ethyl
acetate (40 mL), filtered through Celite, and concentrated in
vacuo. The crude material was purified by flash chromatog-
raphy on silica gel.
N-(4-Meth ylp h en yl)m or p h olin e22,23 (Table 3, entry 2). An
oven-dried Schlenk flask was evacuated and backfilled with
argon. The flask was charged with NaOt-Bu (270 mg, 2.8
mmol) and then evacuated and backfilled with argon, and
toluene (1 mL), 4-chlorotoluene (0.24 mL, 2.0 mmol), and
morpholine (0.20 mL, 2.4 mmol) were added through a rubber
septum. A separate flask was charged with Pd2(dba)3 (4.6 mg,
0.005 mmol) and ligand 4 (7.0 mg, 0.02 mmol) and was purged
with argon. THF (1 mL) was added, the mixture was stirred
for 1 min at room temperature, and then 100 µL of this solution
(0.05 mol % Pd, 0.1 mol % ligand 4) was added to the Schlenk
flask followed by additional toluene (1 mL). The septum was
removed; the flask was sealed with a Teflon screwcap, and the
mixture was stirred at room temperature for 2 min and then
heated to 100 °C with stirring until the starting aryl chloride
had been completely consumed as judged by GC analysis. The
mixture was cooled to room temperature, diluted with ether,
and filtered through Celite. The crude product was purified
by flash chromatography on silica gel to give 311 mg (88%) of
the title compound as a white solid.
Ar yl Ch lor id es.
N-(3-Cya n op h en yl)ben zyla m in e (Table 5, entry 1). The
general procedure using 2 mol % Pd(OAc)2 and 4 mol % 4 gave
163 mg (78%) of the title compound as a white solid, mp 69-
70 °C: 1H NMR (300 MHz, CDCl3) δ 7.40-7.14 (m, 6 H), 6.97
(ddd, 1 H, 7.5, 1.4, 1.0 Hz), 6.83-6.78 (m, 2 H), 4.37 (br s, 1
H), 4.33 (s, 2 H); 13C NMR (75 MHz, CDCl3) δ 148.4, 138.3,
129.9, 128.9, 127.6, 127.4, 120.8, 119.6, 117.3, 115.1, 112.9,
47.8; IR (neat, cm-1) 3386, 2229, 1600, 776, 691. Anal. Calcd
for C14H12N2: C, 80.74; H, 5.81. Found: C, 80.89; H, 5.66.
N-(3-Cya n op h en yl)p yr r olid in e (Table 5, entry 2).46 The
general procedure using Pd(OAc)2 gave 144 mg (84%) of the
title compound as a pale yellow solid, mp 85-86 °C.
N-(Dip h en ylm eth ylen e)-4-n itr oa n ilin e (Table 5, entry
3).47 The general procedure using ligand 2 was followed; the
product was purified by recrystallization from toluene/ethanol
rather than chromatography to give 249 mg (82%) of the title
compound as a pale yellow solid.
N-Meth yl-N-p h en yl-2,5-xylid en e5 (Table 3, entry 3). An
oven-dried Schlenk flask was evacuated and backfilled with
argon. The flask was charged with NaOt-Bu (270 mg, 2.8
mmol) and then evacuated and backfilled with argon, and
toluene (1 mL), 2-chloro-p-xylene (0.24 mL, 2.0 mmol), and
N-methylaniline (0.26 mL, 2.4 mmol) were added through a
rubber septum. A separate flask was charged with Pd2(dba)3
(9.2 mg, 0.01 mmol) and ligand 3 (12.0 mg, 0.04 mmol) and
was purged with argon. Toluene (4 mL) was added, the
mixture was stirred for 1 min at room temperature, and then
200 µL of this solution (0.05 mol % Pd, 0.1 mol % ligand 3)
was added to the Schlenk flask followed by additional toluene
(1 mL). The septum was removed; the flask was sealed with a
Teflon screwcap, and the mixture was stirred at room tem-
perature for 2 min and then heated to 100 °C with stirring
until the starting aryl chloride had been completely consumed
as judged by GC analysis. The mixture was cooled to room
temperature, diluted with ether, and filtered through Celite.
The crude product was purified by flash chromatography on
silica gel to give 391 mg (93%) of the title compound as a
colorless oil.
2-Meth oxy-2′,4′-d im eth yld ip h en yla m in e (Table 3, entry
4). An oven-dried, resealable Schlenk tube equipped with a
Teflon screwcap was evacuated and backfilled with argon. The
cap was removed, and the tube was charged with sodium tert-
butoxide (1.35 g, 14.0 mmol), tris(dibenzylideneacetone) di-
palladium (2.3 mg, 0.0025 mmol, 0.05 mol % Pd), and 3 (3.0
mg, 0.010 mmol, 0.10 mol %). The tube was capped with the
Teflon screwcap, evacuated, and backfilled with argon. The
screwcap was replaced with a rubber septum, and o-anisidine
(1.35 mL, 12.0 mmol) was added via syringe, followed by
2-chloro-p-xylene (1.34 mL, 10.0 mmol) and toluene (5 mL).
The tube was purged with argon for 3 min, and then the
septum was replaced with a Teflon screwcap; the tube was
sealed, and the contents were heated to 80 °C with stirring.
Analysis by gas chromatography after 14 h indicated complete
consumption of the aryl chloride. The reaction mixture was
cooled to room temperature, diluted with diethyl ether (50 mL),
and washed with a 1 M aqueous solution of phosphoric acid
(50 mL), followed by water (50 mL). The resulting solution was
dried over anhydrous potassium carbonate, filtered, and
concentrated in vacuo. The residue was purified by recrystal-
lization from methanol to give 2.20 g (97%) of the title
compound as white crystals.
4-Meth oxy-4′-n itr od ip h en yla m in e (Table 5, entry 4).44
The general procedure using ligand 3 was followed; the product
was purified by recrystallization from toluene/ethanol rather
than chromatography to give 222 mg (91%) of the title
compound as an orange solid.
1-(3-Acetylp h en yl)-4-m eth ylp ip er a zin e (Table 5, entry
5). The general procedure using ligand 2 gave 163 mg (75%)
of the title compound as a pale orange oil: 1H NMR (300 MHz,
CDCl3) δ 7.52 (dd, 1 H, J ) 2.2, 1.5 Hz), 7.41 (ddd, 1 H, J )
8.0, 1.5, 1.1 Hz), 7.33 (dd, 1 H, J ) 8.0, 8.0 Hz), 7.12 (ddd, 1
H, J ) 8.0, 2.2, 1.1 Hz), 3.27 (m, 4 H, J ) 4.8 Hz), 2.58 (m, 4
H, J ) 4.8 Hz), 2.58 (s, 3 H), 2.36 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 198.6, 151.5, 138.0, 129.3, 120.6, 120.0, 27.0, 114.8,
55.2, 49.0, 46.3; IR (neat, cm-1) 1681, 1441, 1296, 1260, 687;
HRMS calcd for C13H18N2O: 218.1419. Found: 218.1415.
N-(3-Acetylp h en yl)a n ilin e (Table 5, entry 6).48 The gen-
eral procedure gave 174 mg (82%) of the title compound as a
yellow solid.
N-(3-Acetylp h en yl)a n ilin e (Table 5, entry 6).48 The gen-
eral procedure using ligand 2 gave 179 mg (85%) of the title
compound as a yellow solid.
N-(4-Acetylp h en yl)m or p h olin e (Table 5, entry 7).2e,49 The
general procedure using Pd(OAc)2, ligand 3, and a reaction
temperature of 80 °C gave 187 mg (91%) of the title compound
as a pale yellow solid.
N-(4-Acetylp h en yl)-p-tolu id in e (Table 5, entry 8).11,50 The
general procedure gave 211 mg (94%) of the title compound
as a pink solid.
N-(4-Ca r bom eth oxyp h en yl)m or p h olin e (Table 5, entry
9).2e The general procedure using Pd(OAc)2 and a reaction
temperature of 80 °C gave 198 mg (90%) of the title compound
as a pale yellow solid.
(46) Sznaidman, M. L.; Meade, E. A.; Beauchamp, L. M.; Russell,
S.; Tisdale, M. Bioorg. Med. Chem. Lett. 1996, 6, 565-568.
(47) Reddelien, G. Ber. Dtsch. Chem. Ges. 1914, 47, 1355-1364.
(48) Elson, L. A.; Gibson, C. S. J . Chem. Soc. 1931, 2381-2388.
(49) Kotsuki, H.; Kobayashi, S.; Matsumoto, K.; Suenaga, H.;
Nishizawa, H. Synthesis 1990, 1147-1148.
Gen er a l P r oced u r e for th e Ca ta lytic Am in a tion of
(50) Iter, J .; Casadevall, A. Bull. Chem. Soc. Fr. 1969, 2342-2355.

Palladium-Catalyzed Amination
J . Org. Chem., Vol. 65, No. 4, 2000 1173
4-Ca r bom eth oxyp h en yl-4′-n itr od ip h en yla m in e (Table
5, entry 10). The general procedure was followed; the product
was isolated by recrystallization from methanol rather than
by chromatography to give 224 mg (82%) of the title compound
as a pale yellow solid, mp 160 °C: 1H NMR (300 MHz, CDCl3)
δ 8.19 (d, 2H, J ) 9.1 Hz), 8.04 (d, 2H, J ) 8.8 Hz), 7.21 (d,
2H, J ) 8.8 Hz), 7.12 (d, 2H, J ) 9.1 Hz), 6.54 (s, br, 1H), 3.92
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4, 148.0, 144.3, 140.8,
131.4, 126.0, 124.4, 118.4, 115.6, 52.1; IR (neat, cm-1) 3347,
2957, 1687, 1586, 1486, 1108, 830. Anal. Calcd for
2H), 1.46 (s, 9H), 1.44 (s, 9H), 0.249 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 154.4, 154.0, 144.8, 143.5, 141.1, 139.8, 137.6, 134.0,
133.9, 128.7, 127.3, 126.4, 126.1, 115.4, 81.4, 81.1, 28.5, 28.4,
-0.9; IR (neat, cm-1) 3456, 3367, 2979, 1704, 1688, 1521, 1511,
1370, 1335, 1285, 1248, 1164, 1057, 857, 839, 820, 766, 754.
Anal. Calcd for C31H41N3O4Si: C, 67.97; H, 7.54. Found: C,
68.10; H, 7.54.
N-(4-Ch lor oph en yl)-N-(ter t-bu toxycar bon yl)-N′-(diph e-
n ylm eth ylen e)-1,4-p h en ylen ed ia m in e (Dim er Ch lor id e
9). Palladium-catalyzed cross-coupling of 4-chloroaniline with
N-(diphenylmethylene)-4-bromoaniline was carried out using
DPEphos as the supporting ligand, under previously reported
conditions.6e The resulting diarylamine was converted to its
BOC-derivative under previously reported conditions.15 The
title compound was obtained as yellow crystals in 81% yield
(two steps): mp 166-168 °C; 1H NMR (300 MHz, CDCl3) δ
7.76 (d, J ) 8.2 Hz, 2H), 7.49-7.42 (m, 3H), 7.29-7.22 (m,
5H), 7.15-7.08 (m, 4H), 6.96 (d, J ) 8.8 Hz, 2H), 6.69 (d, J )
8.8 Hz, 2H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 169.0,
153.7, 149.6, 141.9, 139.6, 138.0, 136.2, 131.1, 130.5, 129.7,
129.5, 128.9, 128.7, 128.4, 128.1, 127.7, 127.3, 121.6, 81.4, 28.3;
IR (neat, cm-1) 3056, 3033, 3024, 3002, 2973, 1698, 1613, 1594,
1573, 1494, 1337, 1293, 1223, 1158, 1142, 1088, 1056, 1015,
C
14H12N2O4: C, 61.76; H, 4.44. Found: C, 61.75; H, 4.52.
N-(4-Cya n op h en yl)h exyla m in e (Table 5, entry 11).5 The
general procedure using NaOt-Bu, toluene solvent, and a
reaction temperature of 110 °C gave 153 mg (76%) of the title
compound as a pale yellow solid.
4-Cya n o-2′-ca r boeth oxyd ip h en yla m in e (Table 5, entry
12).11,14b The general procedure was followed; the product
purified by recrystallization from ethanol instead of by chro-
matography gave 195 mg (73%) of the title compound as a
yellow solid.
N-(3-Ca r bom eth oxyp h en yl)m or p h olin e (Table 5, entry
13).11,14b The general procedure gave 201 mg (91%) of the title
compound as a pale yellow oil.
959, 853, 836, 787, 768, 697, 677, 666. Anal. Calcd for C30H27
ClN2O2: C, 74.60; H, 5.63. Found: C, 74.70; H, 5.62.
-
N-(3-Ca r bom eth oxyp h en yl)-N-m eth yla n ilin e (Table 5,
entry 14). The general procedure gave 215 mg (89%) of the
title compound as a pale orange oil: 1H NMR (300 MHz,
CDCl3) δ 7.64 (dd, 1 H, J ) 2.7, 1.2 Hz), 7.56 (ddd, 1 H, J )
7.8, 2.7, 1.2 Hz), 7.35-7.25 (m, 3 H), 7.13 (ddd, 1 H, J ) 7.2,
2.7, 1.2 Hz), 7.10-7.01 (m, 3 H), 3.88 (s, 3 H), 3.34 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 167.4, 149.3, 148.7, 131.3, 129.6,
129.1, 123.4, 122.9, 122.3, 121.5, 119.4, 52.2, 40.4; IR (neat,
P en ta m er 10. Trimer amine 8 (0.845 g, 1.54 mmol), dimer
chloride 9 (0.676 g, 1.40 mmol), sodium tert-butoxide (0.188 g,
1.96 mmol), tris(dibenzylideneacetone) dipalladium (3.2 mg,
0.0035 mmol, 0.5 mol % Pd), and 3 (4.2 mg, 0.014 mmol, 1.0
mol %) were placed in an oven-dried, resealable Schlenk tube.
The tube was fitted with a Teflon screwcap, evacuated, and
backfilled with argon. The screwcap was replaced with a
rubber septum, and toluene (4 mL) was added via syringe. The
septum was replaced with the Teflon screwcap; the tube was
sealed, and the reaction mixture was heated to 80 °C with
stirring. Analysis by TLC after 12 h indicated the complete
consumption of the aryl chloride starting material. The reac-
tion mixture was cooled to room temperature, taken up in
dichloromethane (50 mL), washed with water (50 mL), dried
over anhydrous potassium carbonate, and filtered. The result-
ing solution was transferred to an oven-dried Schlenk flask
and converted to its BOC-derivative under previously reported
conditions.15 The resulting orange solid was crystallized from
ethanol, and the product was recrystallized from a mixture of
toluene and ethanol, affording the title compound as pale
yellow microcrystals, 1.32 g (86%): mp 191-193 °C; 1H NMR
(300 MHz, CDCl3) δ 7.75 (d, J ) 8.3 Hz, 2H), 7.46-7.41 (m,
5H), 7.29-7.26 (m, 3H), 7.19-7.09 (m, 16H), 6.97 (d, J ) 8.5
Hz, 2H), 6.69 (d, J ) 8.5 Hz, 2H), 1.46 (s, 9H), 1.45 (s, 18H),
1.40 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 168.8, 153.9, 153.8,
153.8, 149.2, 143.3, 140.6, 140.4, 140.3, 140.2, 140.2, 139.6,
138.1, 137.6, 136.1, 133.9, 131.0, 129.6, 129.4, 128.8, 128.3,
128.0, 127.6, 127.4, 127.1, 127.0, 126.2, 126.0, 121.5, 81.5, 81.5,
81.2, 28.4, -0.9; IR (neat, cm-1) 3002, 2975, 2935, 1706, 1511,
1368, 1328, 1293, 1252, 1160, 1059, 861, 839, 824, 766, 699.
Anal. Calcd for C66H75N5O8Si: C, 72.43; H, 6.91. Found: C,
72.25; H, 6.94.
cm-1) 1723, 1592, 1289, 1262, 1111. Anal. Calcd for C15H15
NO2: C, 74.67; H, 6.27. Found: C, 74.65; H, 6.13.
-
N-(3-Ca r bom eth oxyp h en yl)-N-m eth yla n ilin e (Table 5,
entry 14). The general procedure using ligand 2 gave 189 mg
(78%) of the title compound as a pale orange oil.
2-Nitr o-4′-m eth oxyd ip h en yla m in e (Table 5, entry 15).51
The general procedure was followed using 2.5 mol % Pd2(dba)3;
the product was isolated by recyrstallization from methanol
instead of by chromatogrophy to give 165 mg (68%) of the title
compound as a yellow solid.
2-Ca r bom eth oxy-3′-m eth yld ip h en yla m in e (Table 5, en-
try 16).52 The general procedure using 2.5 mol % Pd2(dba)3 gave
195 mg (81%) of the title compound as a colorless oil.
Ar yl Br om id es.
N-(3-Ca r bom eth oxyp h en yl)m or p h olin e (Table 7, entry
11). The general procedure using ligand 2 gave 193 mg (87%)
of the title compound as a pale yellow oil.
N-(3-Ca r bom eth oxyp h en yl)-N-m eth yla n ilin e (Table 7,
entry 12). The general procedure using 1.5 mol % Pd2(dba)3,
ligand 4, and 1 mL of DME/mmol bromide gave 140 mg (58%)
of the title compound as a pale yellow oil.
N-(4-Cya n op h en yl)ben zyla m in e (Table 7, entry 13).53
The general procedure using 3 mol % Pd(OAc)2 and 1 mL of
toluene/mmol bromide gave 165 mg (79%) of the title com-
pound as a white solid.
4-Acetyl-4′-m eth yld ip h en yla m in e (Table 7, entry 14).
The general procedure using 1 mL of toluene/mmol bromide
gave 210 mg (93%) of the title compound as a pale yellow solid.
2-Ca r bom eth oxy-3′-m eth yld ip h en yla m in e (Table 7, en-
try 15). The general procedure using 2.5 mol % Pd2(dba)3,
ligand 4, and 1 mL of DME/mmol halide gave 236 mg (98%)
of the title compound as a pale yellow oil.
P en ta m er Am in e 11. Prepared by analogy to previously
reported procedures.15 Obtained as a white solid: mp 145-
147 °C; 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J ) 8.3 Hz, 2H),
7.19-7.07 (m, 14H), 6.97 (d, J ) 8.4 Hz, 2H), 6.63 (d, J ) 8.4
Hz), 3.67 (broad s, 2H), 1.46 (s, 9H), 1.44 (s, 27H), 0.254 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 154.2, 153.8, 144.7, 143.3,
141.1, 140.3, 140.2, 140.1, 139.4, 137.6, 133.8, 133.7, 128.5,
127.4, 127.1, 127.0, 126.3, 126.0, 115.3, 81.5, 81.4, 81.0, 28.4,
-0.9; IR (neat, cm-1) 3444, 3371, 2977, 1710, 1513, 1368, 1322,
1287, 1252, 1162, 1059, 841, 830, 764. Anal. Calcd for
Oligoa n ilin es.
N-(4-Am in op h en yl)-N′-[4-(tr im eth ylsilyl)p h en yl]-N,N′-
bis(ter t-bu toxyca r bon yl)-1,4-p h en ylen ed ia m in e (Tr im er
Am in e 8). Prepared by analogy to previously reported proce-
dures.15 Obtained as a white solid: mp 161.5-163 °C; 1H NMR
(300 MHz, CDCl3) δ 7.43 (d, J ) 8.4 Hz, 2H), 7.18-7.11 (m,
6H), 6.98 (d, J ) 8.7 Hz 2H), 6.62 (d, J ) 8.7 Hz, 2H), 3.66 (s,
C
53H67N5O8Si: C, 68.43; H, 7.26. Found: C, 68.38; H, 7.26.
Non a m er 13. Pentamer amine 11 (0.424 g, 0.456 mmol),
tetramer bromide 1215 (0.395 g, 0.434 mmol), sodium tert-
butoxide (0.0584 g, 0.608 mmol), tris(dibenzylideneacetone)
dipalladium (2.0 mg, 0.0022 mmol, 1.0 mol % Pd), and 3 (2.6
mg, 0.0088 mg, 2.0 mol %) were placed in an oven-dried,
resealable Schlenk tube. The tube was fitted with a Teflon
screwcap, evacuated, and backfilled with argon. The screwcap
(51) Gale, D. J .; Wilshire, J . F. Aust. J . Chem. 1972, 25, 2145-2154.
(52) Legrand, L.; Lozac’h, N. Bull. Chem. Soc. Fr. 1969, 1173-1182.
(53) Grigg, R.; Mitchell, T. R. B.; Tongpenyai, N. Synthesis 1981,
442-444.

1174 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe et al.
was replaced with a rubber septum, and toluene (1.6 mL) was
added via syringe. The septum was replaced with the Teflon
screwcap; the tube was sealed, and the reaction mixture was
heated to 60 °C with stirring. Analysis by TLC after 8 h
indicated the complete consumption of the aryl bromide
starting material. The reaction mixture was cooled to room
temperature, taken up in dichloromethane (50 mL), and
washed with water (50 mL). The aqueous phase was extracted
with dichloromethane (15 mL). The combined organic portions
were dried over anhydrous potassium carbonate and filtered;
the resulting solution was transferred to an oven-dried Schlenk
flask and converted to its BOC-derivative under previously
reported conditions.15 The resulting orange solid was crystal-
lized from a mixture of toluene and ethanol, affording the title
compound as pale yellow microcrystals, 0.687 g (85%): mp
183-186 °C; 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J ) 7.3
Hz, 2H), 7.46-7.40 (m, 5H), 7.28-7.27 (m, 3H), 7.19-7.10 (m,
32H), 6.97 (d, J ) 8.3 Hz, 2H), 6.68 (d, J ) 8.3 Hz, 2H), 1.45
(s, 63H), 1.40 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 168.7,
153.8, 153.7, 153.7, 149.2, 143.2, 140.6, 140.4, 140.3, 140.2,
140.2, 140.1, 139.5, 138.0, 137.6, 136.1, 133.8, 130.9, 129.6,
129.4, 128.8, 128.3, 128.0, 127.5, 127.3, 127.1, 127.0, 126.2,
2975, 2933, 1708, 1509, 1368, 1328, 1310, 1289, 1252, 1156,
1054, 1017, 837, 766, 697. Anal. Calcd for C110H127N9O16Si: C,
71.06; H, 6.88. Found: C, 70.95; H, 6.81.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 58160), the National Cancer
Institute (training grant NCI CI T32CA09112), and the
Office of Naval Research for financial support of this
work. We also acknowledge Pfizer, Merck, and Novartis
for additional unrestricted support. J .P.W. is grateful
for a fellowship from the Organic Division of the
American Chemical Society sponsored by Schering-
Plough. H.T. thanks Sankyo Co. Ltd. for support. We
thank Mr. J ohn Kowalski for conducting initial experi-
ments on the room-temperature catalytic amination of
aryl bromides using ligand 3.
Su p p or tin g In for m a tion Ava ila ble: The characteriza-
tion data of known compounds. This material is available free
of charge via the Internet: http://pubs.acs.org.
125.9, 121.5, 81.5, 81.4, 81.4, 81.1, 28.4, -0.9; IR (neat, cm-1
)
J O991699Y