Scope and Limitations of the Pd/BINAP-Catalyzed Amination of Aryl Bromides

Article abstract of DOI:10.1021/jo9916986

Mixtures of Pd₂(dba)₃ or Pd(OAc)₂ and BINAP catalyze the cross-coupling of amines with a variety of aryl bromides. Primary amines are arylated in high yield, and certain classes of secondary amines are also effectively transformed. The process tolerates the presence of several functional groups including methyl and ethyl esters, enolizable ketones, and nitro groups provided that cesium carbonate is employed as the base. Most reactions proceed to completion with 0.5-1.0 mol % of the palladium catalyst; in some cases, catalyst levels as low as 0.05 mol % Pd may be employed. Reactions are considerably faster if Pd(OAc)₂ is employed as the precatalyst, and the order in which reagents are added to the reaction has a substantial effect on reaction rate. It is likely that the catalytic process proceeds via bis(phosphine)palladium complexes as intermediates. These complexes are less prone to undergo undesirable side reactions which lead to diminished yields or catalyst deactivation than complexes of the corresponding monodentate triarylphosphines.

Full text of DOI:10.1021/jo9916986

1144
J . Org. Chem. 2000, 65, 1144-1157
Scop e a n d Lim ita tion s of th e P d /BINAP -Ca ta lyzed Am in a tion of
Ar yl Br om id es
J ohn P. Wolfe† and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received October 29, 1999
Mixtures of Pd2(dba)3 or Pd(OAc)2 and BINAP catalyze the cross-coupling of amines with a variety
of aryl bromides. Primary amines are arylated in high yield, and certain classes of secondary amines
are also effectively transformed. The process tolerates the presence of several functional groups
including methyl and ethyl esters, enolizable ketones, and nitro groups provided that cesium
carbonate is employed as the base. Most reactions proceed to completion with 0.5-1.0 mol % of the
palladium catalyst; in some cases, catalyst levels as low as 0.05 mol % Pd may be employed.
Reactions are considerably faster if Pd(OAc)2 is employed as the precatalyst, and the order in which
reagents are added to the reaction has a substantial effect on reaction rate. It is likely that the
catalytic process proceeds via bis(phosphine)palladium complexes as intermediates. These complexes
are less prone to undergo undesirable side reactions which lead to diminished yields or catalyst
deactivation than complexes of the corresponding monodentate triarylphosphines.
The catalytic amination of aryl halides represents a
Pd/BINAP-catalyzed amination of aryl bromides, as well
as studies on the mechanism of this process.
mild alternative to classical methods of aryl C-N bond
formation and has many potential applications for the
synthesis of aniline derivatives which are inaccessible
through other routes.1 The most commonly used catalysts
for this transformation are based on chelating phosphines
such as BINAP and DPPF,1b and aryl bromides are the
most frequently employed substrates.1 Recent reports
have described the use of other catalyst systems based
on bulky, electron-rich, phosphine ligands.2 However, the
BINAP catalyst system remains the most active and
general catalyst for the coupling of aryl bromides with
primary amines.3a Additionally, the BINAP catalyst
system functions well in the presence of the weak base
cesium carbonate, allowing for a high level of functional
group tolerance.3b Although new catalyst systems tolerate
the presence of functional groups when potassium phos-
phate is employed as the base,2e,j the BINAP system
appears to give better results for reactions of primary
amines with functionalized substrates. In this paper, we
describe our studies on the scope and limitations of the
In addition to its utility in catalytic amination reactions
of aryl bromide substrates, the Pd/BINAP catalyst has
previously been shown to be highly effective for a wide
variety of carbon-heteroatom and carbon-carbon bond-
forming processes.1a,4-7 This catalyst allows for the
catalytic amination of aryl triflates4a,b and halopyridines,4c
catalyzes the room-temperature amination of aryl
iodides,4d and is useful for the N-arylation of benzophe-
none imine,4e which can be cleaved to afford primary
anilines.5 BINAP has been shown to inhibit substrate
racemization in the arylation of R-chiral amines4f and has
been utilized for the N-arylation of benzophenone hydra-
zone in an improved version of the Fisher indole
synthesis.4g,h Additionally, the Pd/BINAP catalyst pro-
motes both inter- and intramolecular C-O bond-forming
processes6 and is useful for the Pd-catalyzed R-arylation
of ketone enolates.7 Racemic BINAP8 is commercially
available and is an air-stable, crystalline solid.
Resu lts
Ca ta lytic Am in a tion of Ar yl Br om id es Usin g
Na O-t-Bu a s th e Ba se. The Pd/BINAP catalyst system
† Present address: Department of Chemistry, University of Cali-
fornia, Irvine, CA 92697-2025.
(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.
(4) (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) Wagaw, S.; Buchwald, S. L. J . Org. Chem. 1996, 61, 7240-
7241. (d) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997, 62, 6066-
6068. (e) Wolfe, J . P.; A° hman, J .; Sadighi, J . P.; Singer, R. A.; and
Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367-6370. (f) Wagaw,
S.; Rennels, R. A.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 8451-
8458. (g) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 6621-6622. (h) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J .
Am. Chem. Soc. 1999, 121, 10251-10263.
(5) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley and Sons: New York, 1991; Chapter 7.
(6) (a) Palucki, M.; Wolfe, J . P.; Buchwald, S. L J . Am. Chem. Soc.
1996, 118, 10333-10334. (b) Palucki, M.; Wolfe, J . P.; Buchwald, S. L
J . Am. Chem. Soc. 1997, 119, 3395-3396.
(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) Hartwig, J . F.; Kawatsura, M.; Hauck, S. I.;
Shaughnessy, K.; Alcazar-Roman, L. M. J . Org. Chem. 1999, 64, 5575-
5580 (i) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413-2416. (j) Wolfe, J . P.; Tomori, H.; Sadighi, J . P.; Yin, J .;
Buchwald, S. L. J . Org. Chem. 2000, 65, 1158.
(7) (a) Palucki, M.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119,
11108-11109. (b) A° hman, J .; Wolfe, J . P.; Troutman, M. V.; Palucki,
M.; Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 1918-1919.
(8) (a) Miyashita, A.; Takaya, H.; Souchi, T.; Noyori, R. Tetrahedron
1984, 40, 1245-1253. (b) Racemic BINAP is commercially available
from Strem Chemical Co.
(3) A portion of this work has prevously been communicated. See:
(a) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc. 1996,
118, 7215-7217. (b) Wolfe, J . P.; Buchwald, S. L. Tetrahedron Lett.
1997, 38, 6359-6362.
10.1021/jo9916986 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/02/2000

Pd/BINAP-Catalyzed Amination of Aryl Bromides
J . Org. Chem., Vol. 65, No. 4, 2000 1145
Ta ble 1. BINAP /P d -Ca ta lyzed Ar yla tion of P r im a r y Am in es
a
Reaction conditions: 1.0 equiv of ArBr, 1.1-1.2 equiv of amine, 1.4 equiv of NaO-t-Bu, cat. Pd2(dba)3, cat. BINAP, toluene (2 mL/
mmol halide), 80 °C. Yields in parentheses refer to yields obtained when P(o-tol)3 was used as the phosphine ligand. c Control experiments
b
showed no formation of the desired product after 17 h at 100 °C in the absence of palladium. Reaction conducted at 100 °C. e Pd(OAc)2
d
used in place of Pd2(dba)3; base added last to reaction mixture.
is effective for the cross-coupling of a variety of primary
amines with aryl bromides (Table 1). Significantly better
results were obtained using this catalyst than with
catalysts with P(o-tol)3 as ligands.9 For example, the
reaction of n-hexylamine with 5-bromo-m-xylene using
0.5 mol % Pd/BINAP afforded the desired product in 88%
yield; the P(o-tol)3 catalyst system (2 mol % Pd) gave only
35% yield.
Most reactions proceeded to completion in <24 h using
0.5 mol % of the Pd/BINAP catalyst, although substrates
that contained more than one ortho substituent required
higher reaction temperatures (100 °C) and primary
amines that were branched at the R position usually
required longer reaction times, higher temperatures, and/
or greater quantities of catalyst. Electronically neutral
or electron-deficient aryl bromides are efficiently trans-
formed; however, reactions of electron-rich aryl bromides
gave poor results unless the aryl bromide also contained
an ortho substituent. For example, the reaction of 4-bro-
moanisole with n-hexylamine using 0.5 mol % of the
palladium catalyst proceeded to 26% conversion affording
a ∼1/1 mixture of the desired product and anisole. In
contrast, the reaction of 4-bromo-3-methylanisole with
n-hexylamine proceeded to completion in 6 h with the
same catalyst loading; the desired product was obtained
in 95% yield. Functional groups, which were not sensitive
to the strong base NaO-t-Bu tolerated by the reaction
(9) (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.

1146 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe and Buchwald
Ta ble 2. Liga n d Effects on Ar yla tion of n -Hexyla m in ea
conditions included aryl halides containing acetals, ni-
triles, and tert-butyl esters in reactions with primary
amines.10 Amine substrates containing acetal, olefin, or
tertiary amine functionality were efficiently arylated.
Ortho substitution of the aryl halide substrate was also
well tolerated and in some instances (see above) was
beneficial. In some cases, it was possible to conduct the
reactions using only 0.05 mol % of the palladium catalyst
(Table 1, entries 2 and 6), although the generality of this
protocol has not yet been established.
For most reactions, Pd2(dba)3 was employed as the
precatalyst, although Pd(OAc)2 usually provided similar
results. Faster reactions were observed with Pd(OAc)2 if
the Pd and ligand were mixed in toluene prior to the
addition of the other reagents; this protocol is especially
important for the arylation of primary anilines (see
below). Typically, a 1.5/1 ratio of BINAP to Pd was
employed, although ratios of 1.0-2.0 L/Pd gave similar
results. Both racemic and nonracemic BINAP give similar
results for these transformations, although use of (()-
BINAP with Pd(OAc)2 necessitates the use of a modified
procedure (see below).
a
Reaction conditions: 1.0 equiv of ArBr, 1.1 equiv of amine,
1.4 equiv of NaO-t-Bu, 1 mol % Pd2(dba)3, 3 mol % ligand, toluene
(9 mL/mmol halide), 80 °C. Uncorrected GC ratio. c Ratio of L/Pd
b
) 2/1.
We felt that it was important to determine the effects,
if any, of large excesses of the amine component of the
reaction. Previously, we have shown that large excesses
of amines inhibit reactions that employ catalysts that
contain P(o-tol)3 ligands.11c Neither the reaction of 5-bromo-
m-xylene with n-hexylamine (see below) nor the reaction
of 5-bromo-m-xylene with benzylamine using the Pd2-
(dba)3/BINAP catalyst (0.5 mol % Pd) were inhibited by
excess amine (4.0 equiv).
Pd2(dba)3 was a more effective precatalyst for reactions
that used low levels of the palladium catalyst (0.05 mol
%Pd); thus, the effect of adding additional dba (dba )
trans,trans-dibenzylideneacetone) to the reaction of 5-
bromo-m-xylene with benzylamine using 0.5 mol % Pd2-
(dba)3 was examined. Addition of 5 mol % of dba (relative
to substrate) dramatically decreased the reaction rate.
The reaction proceeded to completion in <4 h with no
dba added, but with 5 mol % added dba the reaction
required ∼22 h to proceed to completion.
reaction of n-hexylamine with 5-bromo-m-xylene using
2 mol % Pd under relatively dilute conditions (0.11 M, 9
mL toluene/mmol halide), a ratio of ∼11.5/1 was obtained
for the same reaction using 0.5 mol % Pd under more
concentrated conditions (0.5 M, 2 mL toluene/mmol
halide). However, by employing an excess of amine (4.0
equiv) under the conditions of higher concentration (0.5
M), an ∼80/1 ratio of monoaryl/diaryl product was
produced. Use of 1.5 equiv of allylamine was employed
to minimize overarylation with 4-bromobiphenyl (a ratio
of ∼30/1 was observed by 1H NMR analysis in this
instance). Diarylated side products were not observed in
reactions of ortho-substituted or electron-deficient aryl
bromides. Primary amines with branching at the R-posi-
tion also gave little or no overarylation. A small amount
of phenylated amine side product (3%) was observed in
the reaction of 5-bromo-m-xylene with tert-butylamine,
presumably resulting from aryl exchange from the phos-
phine ligand.13 This problem is most likely a result of the
relatively high catalyst loading required for this reaction;
phenylation was not observed in reactions which em-
ployed only 0.5 mol % of the Pd catalyst.
Certain types of secondary amines were also efficiently
arylated using the Pd/BINAP catalyst system (Table 3).
These reactions provided the best results when conducted
without solvent. Considerably improved results were
obtained for several substrate combinations that gave low
yields with catalysts supported by P(o-tol)3 ligands. For
example, the reaction of N-methylaniline with 2-bro-
moanisole afforded the desired product in 75% isolated
yield using 0.5 mol % of the Pd/BINAP catalyst. In
comparison, the Pd/P(o-tol)3 catalyst did not produce the
desired product even with 2 mol % Pd. It was also
possible to couple N-methylpiperazine with 2-bromo-p-
xylene in 94% yield using only 0.05 mol % of the
Pd/BINAP catalyst. Acyclic secondary amines are, how-
ever, usually problematic substrates. For example, the
reaction of 4-tert-butylbromobenzene with di-n-butyl-
amine affords a 1/5.2 ratio of the desired product/arene
The main side products in the arylations of primary
amines were diaryl(alkyl)amines resulting from overary-
lation of the primary amine substrate. A variety of
different chelating ligands were examined for the aryla-
tion of n-hexylamine with 5-bromo-m-xylene (Table 2).
All ligands examined were inferior to BINAP for this
reaction, although Hartwig has demonstrated that, under
some conditions, DPPF is effective for certain classes of
substrates.12 The other ligands examined all provided
larger amounts of diarylated side products than were
observed with BINAP. With 0.5 mol % of the palladium
catalyst, ratios of monoaryl/diaryl products were typically
∼10-30/1 in procedures that employ only a slight excess
of the amine (1.1-1.2 equiv) in arylations with para- or
meta-substituted aryl bromides. Although a ratio of
monoarylation/diarylation of 39/1 was obtained for the
(10) Cyano groups are not tolerated in reactions of primary anilines
when NaO-t-Bu is employed as the base. Amidine side products
resulting from the addition of the primary aniline to the nitrile are
formed under these conditions.
(11) (a) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. Organo-
metallics 1996, 15, 2745-2754. (b) Widenhoefer, R. A.; Buchwald, S.
L. Organometallics 1996, 15, 3534-3542. (c) Widenhoefer, R. A.;
Buchwald, S. L. Unpublished results.
(13) Aryl exchange from phosphine ligands to palladium oxidative
addition complexes has been previously observed. See: Goodson, F.
E.; Wallow, T. I.; Novak, B. M. J . Am. Chem. Soc. 1997, 119, 12441-
12453.
(12) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1996, 118,
7217-7218.

Pd/BINAP-Catalyzed Amination of Aryl Bromides
J . Org. Chem., Vol. 65, No. 4, 2000 1147
Ta ble 3. BINAP /P d -Ca ta lyzed Ar yla tion of Secon d a r y Am in es
a
b
Yields in parentheses refer to yields obtained when P(o-tol)3 was used as the phosphine ligand. Control experiments showed no
formation of the desired product after 17 h at 100 °C in the absence of palladium. c Reaction run neat.
side product,14 and attempts to use N-methylaniline as
the substrate were, in general, only effective with ortho-
substituted aryl bromides (activated substrates exhibit
somewhat different reactivity; see below). Additionally,
while pyrrolidine and morpholine were coupled with
4-tert-butylbromobenzene in high yield, the analogous
reaction with piperidine gave a large amount of reduced
side products. Other catalyst systems have subsequently
been developed that are effective for reactions of acyclic
secondary amines, as well as piperidine.2d-j,14
nitrobenzene is sufficiently active to react slowly in
toluene,16 and rapidly in polar solvents in the absence of
a palladium catalyst, selective substitution of bromide
in the presence of chloride is obtained under catalytic
conditions. Interestingly, while piperidine, N-methyl-
aniline, and N-methylbenzyamine do not react well with
unactivated aryl bromides, their reaction with electron-
deficient aryl bromides gives functionalized aniline de-
rivatives in high yields (entries 1, 3, 6, 7, and 13).
Acetophenone derivatives are efficiently coupled with
anilines under these conditions, although reactions with
aliphatic amines do not work well.17 Reactions of aryl
bromides containing ortho functional groups are often
problematic when aliphatic amines are employed. With
anilines, however, they are more favorable; the reaction
of methyl-2-bromobenzoate with p-anisidine provided the
diarylamine product in 92% yield. Anilines containing
base-sensitive functional groups were also arylated in
good yields. In our studies, we also screened a variety of
other weak bases such as alkali metal carbonates and
phosphates,2e,j as well as organic bases such as tertiary
amines and DBU. These generally gave poorer results
in the amination reactions. The activated substrate
4-bromobenzonitrile was efficiently coupled with p-tolui-
dine in the presence of K2CO3; however, this protocol was
not generally effective even for other activated substrates.
Ca ta lytic Am in a tion of F u n ction a lized Ar yl Br o-
m id es Usin g Cs2CO3. Although use of NaO-t-Bu as the
stoichiometric base in catalytic amination reactions
provides for the fastest reactions and allows for use of
low catalyst loadings (0.05 mol % Pd) in some cases, its
basicity greatly limits the functional group tolerance of
the process. For example, methyl and ethyl esters react
to form amides or tert-butyl esters (depending on the
amine coupling partner), enolizable ketones are depro-
tonated, and nitroarenes decompose under these reaction
conditions. However, when the weak base Cs2CO3 is
employed, a much wider variety of functional groups are
tolerated. As shown in Table 4, substrates containing
methyl15 and ethyl esters or nitro groups are efficiently
coupled with a variety of amines. Although 4-bromo-
(14) Marcoux, J .-F.; Wagaw, S.; Buchwald, S. L. J . Org. Chem. 1997,
62, 1568-1569.
(15) Differences in the reactivity of methyl-4-bromobenzoate pur-
chased from different commercial sources were observed. Material
purchased from Aldrich (99% pure) gave satisfactory results; however,
use of material purchased from Lancaster (98% pure) resulted in
reactions which failed to go to completion and gave significantly
different product distributions. The 1H NMR spectra of the material
from these sources were identical.
(16) The reaction of 4-bromonitrobenzene with piperidine in DMF
in the absence of a palladium catalyst proceeded to completion in 28
h and afforded a 78% isolated yield of N-(4-nitrophenyl)piperidine.
(17) Reactions of the enolizable ketone, 4′-bromoacetophenone, were
only successful with 4-methylaniline. Attempts to couple this substrate
with morpholine or piperidine afforded only low yields (∼15% by GC)
of the desired product.

1148 J . Org. Chem., Vol. 65, No. 4, 2000
Ta ble 4. Ca ta lytic Am in a tion of Ar yl Br om id es Usin g Wea k Ba ses
Wolfe and Buchwald
a
Reaction conditions: 1.0 equiv of halide, 1.2 equiv of amine, 1.4 equiv of Cs2CO3, cat. Pd2(dba)3 or Pd(OAc)2, cat. BINAP (1.5 L/Pd),
toluene (0.25 M), 100 °C. A ) Pd2(dba)3/(S)-BINAP; B ) Pd(OAc)2/(S)-BINAP; C ) Pd(OAc)2/(()-BINAP. c Reaction run in 1,4-dioxane.
b
All yields reported are isolated yields (average of two runs) of compounds estimated to be g95% pure as judged by 1H NMR and either
d
GC analysis or combustion analysis. e K2CO3 used in place of Cs2CO3. f Base added last to the reaction mixture. Isolated yield from a
g
single experiment.

Pd/BINAP-Catalyzed Amination of Aryl Bromides
J . Org. Chem., Vol. 65, No. 4, 2000 1149
Sch em e 1
Sch em e 2
for Ra te-Lim itin g Oxid a tive Ad d ition . In many cases,
Pd(OAc)2 is an effective precatalyst and often provides
faster reactions than are observed when Pd2(dba)3 is
employed. This process also presumably proceeds through
a catalytic cycle involving Pd(0)-Pd(II) complexes as
intermediates. Studies were undertaken to determine
what was responsible for the initial reduction of Pd(OAc)2
to the active catalyst using 31P NMR.23 Mixing Pd(OAc)2
and (S)-BINAP in a 1/1.5 ratio in C6D6 resulted in the
formation of a complex identified as [(S)-BINAP]Pd-
(OAc)2,23 which was observed as a singlet at +26 ppm in
the 31P NMR spectrum;24 free BINAP was also observed.
Treatment of this complex with excess benzylamine did
not result in a change in the 31P NMR spectrum. Upon
addition of NaO-t-Bu (in the presence of excess benzyl-
amine), the color of the solution changed from yellow to
red and a new 31P NMR signal was observed at +27.3
ppm; at the same time, the signal for free (S)-BINAP
disappeared. This new complex possesses the same
chemical shift reported by Hayashi for (BINAP)2Pd,23,24
although it is possible that this complex is actually
(BINAP)PdLn (L ) amine, solvent), as use of a 1/1 ratio
of BINAP/Pd provided similar results.25 None of the
monophosphineoxide of BINAP was detected in the
reaction mixture; thus, the phosphine ligand is not
responsible for reduction of the Pd(II) precatalyst to the
active Pd(0) catalyst.23 It appears that the mixture of
amine and base causes reduction of the precatalyst,
presumably by a mechanism involving formation of a
Pd(amido)complex that then undergoes â-hydride elimi-
nation followed by reductive elimination (Scheme 2).
Mech a n istic Stu d ies
Ca ta lytic Cycle. We believe the catalytic cycle for this
process is similar to that postulated for many palladium-
catalyzed C-C bond-forming processes (Scheme 1).18
Mixing BINAP with Pd2(dba)3 initially leads to the
formation of the isolable complex (BINAP)Pd(dba) (2).19
This complex probably undergoes dissociation of a dba
ligand prior to oxidative addition of the aryl bromide to
form the isolable oxidative addition complex 3. However,
Amatore has shown that direct oxidative addition to (L-
L)Pd(dba) is possible.19 Coordination of the amine to 3,20
followed by deprotonation, would form amido complex 5,
which then undergoes reductive elimination to form the
desired product and to regenerate the Pd(0) catalyst.
Alternatively, Hartwig has recently demonstrated that
treatment of (DPPF)Pd(Ar)(O-t-Bu) with amine leads to
the formation of arylamine products.21 Thus, it is also
possible that the reaction proceeds via tert-butoxide
complex 6 when NaO-t-Bu is used as the base. Treatment
of 3 (Ar ) 4-t-BuPh) with an excess of benzylamine did
not lead to the detectable formation of an amine complex;
however, addition of NaO-t-Bu to this mixture afforded
the arylamine product. Both 2 and 3 were shown to
catalyze the coupling of amines with aryl bromides with
reaction rates, and product distributions similar to those
observed when mixtures of Pd2(dba)3 and BINAP were
employed. In contrast to what has been observed with
Pd/P(o-tol)3 complexes,1b,22 it is likely that all steps in the
catalytic cycle occur via 4-coordinate intermediates with-
out prior dissociation of a phosphine.
Addition of excess 5-bromo-m-xylene26a (10 equiv) to
the [(S)-BINAP]Pd0 reaction mixture did not produce any
(22) (a) Hartwig, J . F.; Paul, F. J . Am. Chem. Soc. 1995, 117, 5373-
5374. (b) Paul, F.; Patt, J .; Hartwig, J . F. J . Am. Chem. Soc. 1994,
116, 5969-5970. (c) Louie, J .; Hartwig, J . F. J . Am. Chem. Soc. 1995,
117, 11598-11599. (d) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc.
1995, 117, 4708-4709. (e) Louie, J .; Paul, F.; Hartwig, J . F. Organo-
metallics 1996, 15, 2794-2805. (f) Hartwig, J . F. Synlett 1997, 329-
340.
Use of P d (OAc)2 a s a P r eca ta lyst: Effect of th e
Or d er of Ad d ition on Rea ction Ra te a n d Evid en ce
(23) Hayashi has found that in asymmetric Heck arylations cata-
lyzed by Pd(OAc)2/BINAP the Pd(II) precatalyst is reduced to Pd(0)
by BINAP with concomitant oxidation of one of the phosphines. See:
Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 2177-2180.
(24) Our observed chemical shifts for these complexes differed from
those reported by Hayashi by ∼1 ppm; however, the chemical shift we
observed for BINAP also differed by ∼1 ppm from his value, suggesting
that our values agree with those reported by Hayashi, but there is a
discrepancy in the referencing of the spectra to external standards.
(25) This is supported by the fact that the same species is formed
regardless of the ratio of BINAP/Pd (ratios from 3/1 to 1/1 were
examined), although we cannot rule out the possibility that when a
ratio of <2/1 is employed not all of the palladium bears a phosphine
ligand.
(18) Farina, V. in Comprehensive Organometallic Chemistry, 2nd
ed.; Pergamon Press: Oxford, 1995; Vol. 12, pp 161-240.
(19) Amatore has reported detailed studies on (L-L)Pd(dba) com-
plexes. See: (a) Amatore, C.; Broeker, G.; J utand, A.; Khalil, F. J . Am.
Chem. Soc. 1997, 119, 5176-5185. (b) Amatore, C.; J utand, A. Coord.
Chem. Rev. 1998, 178-180, 511-528.
(20) Associative reactions of square-planar, d8 transition metal
complexes typically proceed via five-coordinate intermediates. See:
Collman, J . P.; Hegedus, L. S.; Norton, J . R.; Finke, R. G. Principles
and Applications of Organotransition Metal Chemistry; University
Science Books: Mill Valley, CA, 1987; Chapter 5.
(21) Mann, G.; Hartwig, J . F. J . Am. Chem. Soc. 1996, 118, 13109-
13110.

1150 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe and Buchwald
Ta ble 5
BINAP. Both (S)-BINAP and (()-BINAP gave similar
results, although it was necessary to heat the precatalyst
mixture when (()-BINAP was employed, due to the low
solubility of the (()-BINAP. Reactions which used Pd2-
(dba)3 as a precatalyst were much slower, and premixing
the catalyst did not affect reaction rates; (()-BINAP
provided reaction rates similar to those obtained with (S)-
BINAP.
Premixing the Pd(OAc)2/BINAP catalyst precursors
was particularly important for the reaction of aniline with
1-bromo-4-tert-butylbenzene. This reaction proceeded to
completion in high yield in <20 h if the BINAP and Pd-
(OAc)2 were premixed (eq 1). However, if the catalyst
catalyst and
ligand mixed
before addn
of other
relative
rate
catalyst
reagents
kobs (min-1
)
Pd2(dba)3/(()-BINAP
Pd2(dba)3/(S)-BINAP
Pd(OAc)2/(()-BINAP
Pd(OAc)2/(S)-BINAP
Pd2(dba)3/(()-BINAP
Pd(OAc)2/(()-BINAP
Pd2(OAc)2/(S)-BINAP
no
no
no
no
yes
yes
yes
0.017 ( 0.001
0.019 ( 0.001
0.044 ( 0.003
0.044 ( 0.005
0.021 ( 0.002
1.0 ( 0.1
1.1 ( 0.1
2.6 ( 0.2
2.6 ( 0.3
1.2 ( 0.1
0.175 ( 0.025 10.3 ( 1.5
0.159 ( 0.014 9.4 ( 0.8
new 31P NMR signals, and after heating to 40 °C for 20
min, 1H NMR analysis did not show formation of the
arylamine product. Heating this mixture to 80 °C also
did not produce new 31P NMR signals; however, after
heating for 10-15 min at this temperature, the aryl-
amine product was detected in the proton NMR, sug-
gesting that the resting state of the catalyst during the
amination of aryl bromides is a (BINAP)Pd0 species. This
result implies that the rate-limiting step in the catalytic
cycle is either oxidative addition of the aryl halide, or
dissociation of a ligand (amine, solvent, or BINAP) to
form (BINAP)Pd that then undergoes rapid oxidative
addition of the aryl halide.27
To more closely simulate the conditions of the catalytic
reactions, a mixture of Pd(OAc)2, (S)-BINAP (2 BINAP/
Pd),26b and excess NaO-t-Bu was dissolved in C6D6.
Analysis of this mixture by 31P NMR provided a surpris-
ing result; only a small amount of the (BINAP)Pd(OAc)2
complex had formed. Treatment of this mixture with
benzylamine led to the formation of a small peak at +27.3
ppm characteristic of the Pd(0) complex; however, the
majority of the BINAP remained uncomplexed to Pd,
suggesting that little active catalyst was being formed
under these conditions. These experiments led to the
discovery that significantly faster reactions occurred if
the BINAP was premixed with Pd(OAc)2 before the
addition of base to the reaction mixture. For example,
the reaction of 5-bromo-m-xylene with benzylamine using
the Pd(OAc)2/(S)-BINAP catalyst system (1 mol % Pd)
was complete in less than 10 min when the palladium
and ligand were mixed in toluene prior to the addition
of the other reagents. In comparison, when Pd(OAc)2 was
not mixed with the ligand in toluene before the amine
and base were added, the reaction proceeded to only 21%
conversion in the same amount of time and required over
2 h for all of the starting aryl halide to be consumed. Both
reactions gave similar ratios (>100/1) of product/reduced
arene side product, suggesting that the same active
catalyst was formed in both reactions, albeit in different
amounts. This reaction of 5-bromo-m-xylene with benz-
ylamine was examined for several different precatalyst
mixtures; the results are shown above in Table 5.
Reactions were fastest when Pd(OAc)2 was premixed with
precursors were not mixed prior to the addition of the
other reagents, the reaction did not proceeded to comple-
tion. This effect was also observed for the arylation of
aniline derivatives using a catalyst comprised of Pd-
(OAc)2/DPE-Phos.28 It is worth noting that the arylation
of primary anilines can also be accomplished if Pd2(dba)3
is substituted for palladium acetate; premixing the
catalyst does not affect the efficiency or rate of these
reactions (see below for discussion of this effect).
Premixing BINAP with palladium acetate before the
addition of cesium carbonate resulted in slightly higher
reaction rates, although this effect was less dramatic for
these reactions than for reactions which employed NaO-
t-Bu. For example, the reaction of methyl-3 bromoben-
zoate with morpholine proceeded to 87% conversion after
22 h with 1 mol % Pd(OAc)2/(()-BINAP when the catalyst
was not premixed. When a procedure was employed in
which the Pd(OAc)2 and (()-BINAP were mixed prior to
adding the other reagents, the above reaction proceeded
to completion in 22 h affording the desired product in
93% GC yield. Similar effects are observed for the
catalytic amination of aryl triflates using Cs2CO3 as the
base. For example, the reaction of 4-acetylphenyl triflate
with p-anisidine catalyzed by 3 mol % Pd(OAC)2/(()-
BINAP with THF as solvent at 65 °C stopped at 90%
conversion when the catalyst was not premixed; however,
this reaction proceeded to completion in 3 h when the
catalyst was premixed; 76% yield of the desired product
was obtained. Due to the increased solubility of (()-
BINAP in THF, it was not necessary to heat the pre-
catalyst mixture. In contrast to what was seen using
NaO-t-Bu, the efficiency of primary aniline arylations
was not substantially affected by the order of addition of
the reagents to the reaction mixture for reactions with
Cs2CO3 as base. For example, the reaction of 4-bro-
mobenzonitrile with p-toluidine proceeded to ∼25% con-
version in 1 h using 1 mol % Pd(OAc)2/(()-BINAP
regardless of the order in which reagents were added to
the reaction mixture; both reactions proceeded to comple-
tion in <18 h.
Exa m in a tion of th e Role of P -C Bon d Clea va ge
in th e Ca ta lytic P r ocess. As stated above, side prod-
(26) (a) This reaction was conducted using an aryl bromide rather
than an aryl triflate to avoid complications arising from NaO-t-Bu-
promoted triflate cleavage. (b) (S)-BINAP was used rather than (()-
BINAP due to the relatively low solubility of the racemate.
(28) DPE-Phos) 1, 1′-bis(diphenylphosphino)diphenyl ether: Sa-
dighi, J . P.; Harris, M. C.; Buchwald, S. L. Tetrahedron Lett. 1998,
39, 5327-5330.
(27) Hartwig has described similar NMR experiments. See ref 2d.

Pd/BINAP-Catalyzed Amination of Aryl Bromides
J . Org. Chem., Vol. 65, No. 4, 2000 1151
Sch em e 3
ucts are occasionally observed in Pd/BINAP-catalyzed
aminations of aryl bromides in which the amine has been
arylated with a phenyl group rather than the aryl group
from the substrate. These products usually form in small
amounts (<5%) when relatively high levels of the pal-
ladium catalyst are employed. As these side products
presumably arise from P-C bond cleavage of the phos-
phine ligand,13 it is possible that one of the phosphines
may be cleaved from the BINAP ligand to form 2-diphen-
ylphosphino-1,1′-binaphthyl29 (7) (Scheme 3). Our recent
results with bulky, electron-rich, monodentate phosphine
also suggested that some monophosphine ligands func-
tion well for a variety of catalytic amination reactions.2j
To determine whether the actual catalyst in this system
is the Pd/BINAP complex or a Pd complex of 7, we
prepared 7 and compared its reactivity to BINAP in the
reaction of 5-bromo-m-xylene with benzylamine. As
shown above in Scheme 3, the reaction proceeded to 98%
(average) conversion in >4 h with the Pd/(()-BINAP
catalyst, affording the desired product in 88% GC yield
after 20 h (100% conversion was obtained). In contrast,
use of 7 as a ligand provided only small amounts (∼2%
average) of the desired product in 4 h and gave a GC yield
of 5% (6% conversion) after 20 h. This experiment
suggests that palladium complexes of the bis(phosphine)
ligand are the catalytically active species in the reactions,
and while 7 may form under some conditions, it does not
appear to be important for catalysis.
In a separate experiment, the above reaction was
conducted using 5 mol % Pd2(dba)3 and 15 mol % (S)-
BINAP. Following completion of the reaction, the phos-
phine ligand was displaced from the metal by treatment
with an ethanolic solution of sodium cyanide. Analysis
of the mixture by 31P NMR showed no evidence for the
formation of 7 under these conditions; the only detectable
phosphorus-containing species were BINAP, BINAP-
(monooxide), and BINAP(bisoxide).30 Use of Pd(OAc)2 as
the precatalyst led to the formation of many phosphorus-
containing side products consistent with P-C bond
cleavage; however, the majority of the BINAP (∼70%)
remained unchanged after the reaction. It is difficult to
say what percentage of P-C bond cleavage occurred
during the reaction and what percentage occurred fol-
lowing consumption of the aryl bromide starting material;
no products resulting from P-C bond cleavage were
detected during the NMR experiments to ascertain the
resting state of the catalyst as described above.
Discu ssion
The efficiency of BINAP in the palladium-catalyzed
arylation of primary amines may result from its ability
to inhibit the formation of catalytically inactive palladium
bis(amine) aryl halide complexes11b and bridging amido
complexes,11c presumably through chelation of both phos-
phine groups of the ligand to the metal. This is high-
lighted by the differences in reactivity between BINAP
and 2-diphenylphosphino-1,1′-binaphthyl (7). The inef-
ficiency of 7 in the reaction of benzylamine with 5-bromo-
m-xylene is most likely due to the formation of bis(amine)-
complexes similar to those observed with other mono-
dentate phosphines.11b
We believe that structural features specific to BINAP
are also key to the success of this catalyst system.
Dissociation of one arm of a chelating ligand (dechelation)
could lead to increased amounts of â-hydride elimina-
tion;31 thus, the rigidity of the binaphthyl backbone and
the small bite angle32a of BINAP (92.7 °)32b relative to
DPPF (99.1 °)32c presumably lead to the formation of a
tight chelate. The large size of BINAP relative to other
chelating ligands also disfavors double arylation of the
(31) (a) Whitesides has demonstrated that â-hydride elimination in
platinum complexes requires an open coordination site. See: White-
sides, G. M.; Gaasch, J . F.; Stedronsky, E. R. J . Am. Chem. Soc. 1972,
94, 5258-5270. (b) â-hydride elimination of Pd(II) complexes may occur
either via 3-coordinate intermediates or via 4-coordinate intermediates.
In L2Pd(X)alkyl complexes (X ) OAc, phenoxide) â-hydride elimination
has been shown to occur predominantly through the 3-coordinate
pathway; however, in L2Pd(alkyl)2 complexes the major pathway
involves 4-coordinate intermediates. See: (c) Kawataka, F.; Kayaki,
Y.; Shimuzu, I.; Yamamoto, A. Organometallics 1994, 13, 3517-3524.
(d) Ozawa, F.; Ito, T.; Yamamoto, A. J . Am. Chem. Soc. 1980, 102,
6457-6463.
(32) (a) Bite angle is defined as the P-Pd-P angle; (b) Ozawa, F.;
Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi, K.;
Moriguchi, K. Organometallics 1993, 12, 4188-4196. (c) Hayashi, T.;
Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J . Am.
Chem. Soc. 1984, 106, 158-163.
(29) Uozumi, Y.; Suzuki, N.; Ogiwara, A.; Hayashi, T. Tetrahedron
1994, 50, 4293-4302.
(30) Phosphine oxides may form during the workup of the reaction.

1152 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe and Buchwald
primary amine substrate and should promote reductive
elimination to form the arylamine product.
the catalytic reactions; thus, faster reaction rates are
observed (due to the presence of larger amounts of the
active catalyst) when the Pd(OAc)2 and BINAP are mixed
before the amine and base are added. The rates of
reactions that did not employ preformed catalysts did not
increase with time, suggesting that the tert-butoxide
complexes are not slowly converted to catalytically active
species during the course of the reaction. The low
reactivity of primary anilines observed when the catalyst
precursors (palladium acetate, BINAP) are not premixed
may be due to a problematic reduction of the Pd(II)
precatalyst. The pathway by which Pd(II) is reduced to
Pd(0) when primary anilines are employed is not clear,
and this reduction may require prior coordination of the
ligand to the metal.
In conclusion, the Pd/BINAP catalyst system is highly
effective for the arylation of primary amine substrates.
A variety of substrate combinations are tolerated, includ-
ing amines that are branched or contain functional
groups such as olefins or acetals. Good results are also
obtained for the arylations of cyclic secondary amines,
although acyclic secondary amines often react poorly
under these conditions. A wide variety of functional
groups such as esters, nitriles, nitro groups, and enoliz-
able ketones are tolerated under the reaction conditions
when the mild base cesium carbonate is employed. In
some cases, reactions can be run at low catalyst loadings
(0.05 mol %) Pd. A combination of the chelating ability
of the phosphine groups, the rigidity of the ligand
backbone, and the small bite angle of the ligand are most
likely responsible for the utility of this ligand in catalytic
amination reactions. Either racemic or nonracemic BI-
NAP may be employed for the catalytic amination reac-
tions, and both function equally well. Despite the devel-
opment of several new catalysts for amination reactions,
BINAP continues to be the most generally efficacious
ligand for the arylation of primary amines with aryl
bromides and is highly effective for the transformation
of functionalized aryl halides.
The increased rates of reactions that employ Pd(OAc)2
instead of Pd2(dba)3 as the precatalyst, along with the
resting-state NMR experiments, support a mechanism
that involves rate-limiting oxidative addition of the aryl
bromide (for reactions of primary amine substrates).33
This is also supported by the fact that added dba
decreases the rate of the reaction. However, the fact that
bulky primary amines or secondary amines react much
more slowly than unbranched primary amines suggest
that the rate-limiting step of the reaction may be
substrate dependent. The relatively slow reactions ob-
served when Cs2CO3 is used in place of NaO-t-Bu also
suggests that the rate-limiting step of the catalytic cycle
changes when a weaker base is employed; it seems likely
that deprotonation is rate limiting in amination reactions
that employ weak bases.
The reasons for the increased efficiency of cesium
carbonate relative to other weak bases are not entirely
clear. Its increased solubility relative to other alkali
metal carbonates34 may play a role in its activity,
although none of the alkali metal carbonates are very
soluble in toluene or dioxane. The efficacy of cesium
carbonate relative to “stronger” organic bases such as
DBU may be related to its ionic character. Even though
the pKa of cesium carbonate is lower than that of DBU
in water,35 it is expected that a charged base would be
more strongly basic in a nonpolar solvent than in water.36
Moreover, in toluene formation of the ammonium salt
from DBU may be unfavorable.37
One possible explanation for the slower reaction rates
observed in reactions catalyzed by BINAP and palladium
acetate when the base is added without premixing the
catalyst is that the formation of Pd(O-t-Bu)n complexes
may inhibit the coordination of the BINAP ligand to the
metal due to the large size of the -O-t-Bu moiety. NMR
studies showed that a new complex forms upon reaction
of Pd(OAc)2 with NaO-t-Bu, and this complex does not
react at an appreciable rate with BINAP. Treatment of
this mixture with benzylamine led to the formation of a
small amount of “(BINAP)Pd0”; the signal for the pre-
sumed catalytically active species slowly increased upon
heating (in the absence of an aryl halide). It is likely that
the tert-butoxide complexes may undergo decomposition
to catalytically inactive species under the conditions of
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 E&R Microanalytical Labora-
tory Inc., Corona, NY, or by Atlantic Microlabs Inc., Norcross,
GA. All amines were purchased from commercial sources and
were purified either by distillation from CaH2 or by passing
through a short column of alumina. Aryl halides (except tert-
butyl-3-bromobenzoate) were purchased from commercial
sources and used without further purification. Toluene, ben-
zene, and ether were continuously refluxed and freshly
distilled from sodium or sodium benzophenone ketyl under
nitrogen or argon. tert-Butyl alcohol was purchased from
Mallinckrodt Chemical Co. and dried over 3 Å molecular
sieves. 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. Lithium tert-butoxide was purchased
from Aldrich Chemical Co. and stored under nitrogen in a
vacuum atmosphere glovebox. Ligand 7 was prepared accord-
ing to the previously published procedure29 and was character-
ized by 1H and 31P NMR and elemental analysis. Tris-
(dibenzylideneacetone)dipalladium(0), tri-o-tolylphosphine, and
(()-BINAP were purchased from Strem Chemical Co. and used
without further purification. Preparative flash chromatogra-
phy was performed on ICN Biomedicals Silitech 32-63d silica
(33) Amatore has previously shown dba to decrease the rate of
oxidative addition of aryl halides to Pd(0). See ref 15 and: Amatore,
C.; J utand, A.; Khalil, F.; M′Barki, M. A.; Mottier, L. Organometallics
1993, 12, 3168-3178.
(34) Although data for the solubility of alkali metal carbonates in
nonpolar solvents are not available, cesium carbonate is considerably
more soluble than potassium carbonate in water or methanol. The
solubility of cesium carbonate in water is 260.5 g/dL while that of
potassium carbonate is 112 g/dL. In methanol the solubilties of cesium
carbonate and potasssium carbonate are 56.1 g/100 g MeOH, and 6.2
g/100 g MeOH, respectively. See: (a) CRC Handbook of Chemistry and
Physics, 72nd ed.; Lide, D. R., Ed.; CRC Press: Boca Raton, 1991-
1992; 4-51, 4-85. (b) Stenger, V. A. J . Chem. Eng. Data 1996, 41, 1111-
1113.
(35) The pKa of carbonate is 10.33 in water; see: March, J . Advanced
Organic Chemistry, Reactions, Mechanisms, and Structure, 4th ed.;
J ohn Wiley and Sons: New York, 1992; Chapter 8. The pKa of DBU
has been measured or estimated to be 11.5-14.3 in water; see: (a)
Hermecz, I. In Advances in Heterocyclic Chemistry; Katritzky, A. R.,
Ed.; Academic Press: Orlando, 1987; Vol. 42, p 91. (b) Leffek, K. T.;
Pruszynski, P.; Thanapaalasingham, K. Can J . Chem. 1989, 67, 590-
595.
(36) Dyumaev, K. M.; Korolev, B. A. Russ. Chem. Rev. 1980, 49,
1021-1032.
(37) We thank Dr. Robert Singer for this suggestion.

Pd/BINAP-Catalyzed Amination of Aryl Bromides
J . Org. Chem., Vol. 65, No. 4, 2000 1153
gel. IR spectra reported in this paper for neat solids were
obtained by placing neat samples directly on the DiComp probe
of an ASI REACTIR in situ IR instrument. Yields refer to
isolated yields (average of two runs) of compounds estimated
to be ∼95% pure as determined by 1H NMR and either
capillary GC (known compounds) or combustion analysis (new
compounds). The procedures described in this section are
representative; thus, the yields may differ from those given
in Tables 1, 3, and 4.
P d [(R)-BINAP ](d ba ) (2). A purple solution of Pd2(dba)3 (72
mg, 0.08 mmol) and (R)-BINAP (100 mg, 0.16 mmol) in
benzene (5 mL) was stirred at room temperature for 2 h. The
resulting orange solution was filtered through Celite and
concentrated under vacuum to give an oily residue that was
dissolved in ether (5 mL). The precipitate that formed over 4
h was collected, washed with ether, and dried under vacuum
to give 2 (110 mg, 70%) as an orange solid: 1H NMR (300 MHz,
CD2Cl2, 25 °C) δ 7.82 (t, J ) 8.2 Hz), 7.69 (br), 7.55 (br), 7.48
(m), 7.37 (t, J ) 8.8 Hz), 7.21 (q, J ) 7.6 Hz), 7.11 (m), 7.0-
6.7 (br, m), 6.60 (t, J ) 7.4 Hz), 6.46 (t, J ) 6.5 Hz), 6.31 (t, J
) 6.9 Hz); 31P {1H} NMR (121 MHz, CDCl3, 25 °C) δ 25.8 (br
s), 24.6 (br s); IR (KBr, cm-1) 3051, 1641, 1587, 1498, 1474,
1436, 1332, 1207, 1092, 743, 695. Anal. Calcd for C61H46OP2-
Pd: C, 76.05; H, 4.81; P, 6.43. Found: C, 75.82; H, 4.62; P,
6.50.
(s, 1H), 6.24 (s, 2H), 3.48 (s, br, 1H), 3.08 (t, 2H, J ) 7.2 Hz),
2.23 (s, 6H), 1.62-1.29 (m, 8H), 0.90 (t, 3H, J ) 6.3 Hz); 13C
NMR (CDCl3, 75 MHz) δ 148.6, 138.7, 119.0, 110.6, 44.0, 31.6,
29.6, 26.8, 22.6, 21.4, 14.0; IR (neat, cm-1) 3409, 2955, 1601,
1188. Anal. Calcd for C14H23N: C, 81.89; H, 11.29. Found C,
81.78; H, 11.20.
N-Ben zyl-3,5-xylid en e (Ta ble 1, En tr y 2). The general
procedure using (S)-BINAP gave 177 mg (84%) of the title
compound as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ
7.38-7.25 (m, 5H), 6.39 (s, 1H), 6.29 (s, 2H), 4.30 (s, 2H), 3.89
(s, br, 1H), 2.23 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 148.3,
139.6, 138.8, 128.5, 127.5, 127.1, 119.5, 110.7, 48.3, 21.4; IR
(neat, cm-1) 3411, 3061, 1605, 1182. Anal. Calcd for C15H17N:
C, 85.26; H, 8.11. Found: C, 85.04; H, 8.25.
N-Ben zyl-3,5-xylid en e (Ta ble 1, En tr y 2). The general
procedure conducted on a 10 mmol scale using 0.025 mol %
Pd2(dba)3 and 0.075 mol % (S)-BINAP gave 1.66 g (79%) of
the title compound as a colorless oil. See above for NMR data.
N-Cycloh exyl-3,5-xylid en e (Ta ble 1, En tr y 3).39 The
general procedure using (S)-BINAP gave 172 mg (85%) of the
title compound as a white solid: mp 49.7-51.6 °C (lit. mp 50-
52 °C);39 1H NMR (CDCl3, 300 MHz) δ 6.32 (s, 1H), 6.22 (s,
2H), 3.42 (s, br, 1H), 3.19-3.29 (m, 1H), 2.22 (s, 6H), 2.08-
2.00 (m, 2H), 1.78-1.60 (m, 3H), 1.42-1.08 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 147.4, 138.7, 118.8, 111.0, 51.5, 33.5, 25.9,
25.0, 21.4; IR (KBr, cm-1) 3396, 2928, 1603, 1338.
[(R)-BINAP ]P d (4-ter t-bu tylp h en yl)(Br ) (3). A solution
of BINAP (100 mg, 0.16 mmol) and {Pd[P(o-tolyl)3](p-C6H4-
N-ter t-Bu tyl-3,5-xylid en e (Ta ble 1, En tr y 4).40 The gen-
eral procedure using 2 mol % Pd2(dba)3, 6 mol % (()-BINAP,
and a reaction temperature of 100 °C gave 137 mg (76%) of
the title compound as a yellow oil. This material contained
3% N-tert-butylaniline as judged by GC analysis: 1H NMR
(CDCl3, 300 MHz) δ 6.41 (s, 1H), 6.39 (s, 2H), 2.23 (s, 6 H),
1.32 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 146.7, 138.3, 120.1,
115.3, 51.4, 30.2, 21.6; IR (KBr, cm-1) 3405, 2968, 1602, 1224.
N-(2-Eth ylm or p h olin o)-3,5-xylid en e (Ta ble 1, En tr y 5).
The general procedure using (S)-BINAP gave 193 mg (82%)
of the title compound as a colorless oil: 1H NMR (CDCl3, 300
MHz) δ 6.38 (s, 1H), 6.29 (s, 2H), 4.20 (s, br, 1H), 3.72 (t, 4H,
J ) 5.0 Hz), 3.15 (t, 2H, J ) 6.0 Hz), 2.62 (t, 2H, J ) 6.0 Hz),
2.46 (m, 4H), 2.24 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 148.4,
11a
CMe3)(µ-Br)}2 (100 mg, 0.16 mmol) in benzene (16 mL) was
stirred at room temperature under argon for 1.5 h. The solvent
was evaporated under vacuum to afford an oily solid that was
dissolved in ether (20 mL). A white precipitate formed quickly
and was collected, washed with ether, and dried under vacuum
to give 3 (76 mg, 50%) as a yellow-white solid: mp 178 °C dec;
1H NMR (C6DC6, 300 MHz, 25 °C) δ 8.15-8.05 (m, 3H), 7.92-
7.78 (m, 4H), 7.76-7.55 (br, 2H), 7.42-7.39 (m, 1H), 7.27-
7.15 (m, 8H), 7.12-6.91 (m, 6H), 6.81-6.75 (m, 4H), 6.66-
6.53 (m, 2H), 6.50-6.42 (m, 1H), 6.40-6.30 (m, 3H), 6.30-
6.20 (m, 2H), 1.24 (s, 9H); 31P {1H} NMR (C6DC6, 121 MHz,
25 °C) δ 27.9 (d, J ) 38.1 Hz), 12.1 (d, J ) 38.0 Hz); IR (KBr,
cm-1) 3053, 2956, 1560, 1500, 1479, 1436, 808, 696. Anal. Calcd
for C54H45P2PdBr: C, 68.84; H, 4.81. Found: C, 68.78; H, 5.00.
t-Bu tyl 3-Br om oben zoa te38 To a solution of lithium tert-
butoxide (401 mg, 5.0 mmol) in tert-butyl alcohol (7 mL) was
slowly added 3-bromobenzoyl chloride (0.66 mL, 5.0 mmol) in
ether (4 mL). The solution was allowed to stir at room
temperature for 18 h, diluted with ether (20 mL), and poured
into a separatory funnel. The solution was washed with brine
(3 × 5 mL), and the organic layer was dried over anhydrous
magnesium sulfate, filtered, and concentrated. The crude
product was purified further by flash chromatography on silica
gel using 2% ethyl acetate/hexane as the eluant to afford 760
mg (59%) of the title compound as a colorless oil: 1H NMR
(CDCl3, 300 MHz) δ 8.11 (t, 1H, J ) 1.1 Hz), 7.94-7.89 (m,
1H), 7.67-7.62 (m, 1H),7.29 (t, 1H, J ) 7.7 Hz), 1.59 (s, 9H);
13C NMR (CDCl3, 75 MHz) δ 164.3, 135.3, 133.9, 132.4, 129.7,
128.0, 122.2, 81.6, 28.1; IR (neat, cm-1) 2978, 1715, 1368, 1160;
GC/MS (m/z) 258, 256, 185, 183.
138.7, 119.2, 110.7, 66.8, 57.0, 53.2, 39.8, 21.4; IR (neat, cm-1
)
3382, 2955, 1602, 1120. Anal. Calcd for C14H22N2O: C, 71.76;
H, 9.46. Found: C, 71.91; H, 9.44.
N-(4-Cya n op h en yl)h exyla m in e (Ta ble 1, En tr y 6). The
general procedure using (S)-BINAP gave 196 mg (97%) of the
1
title compound as a white solid: mp 35.1-35.7 °C; H NMR
(CDCl3, 300 MHz) δ 7.43-7.39 (m, 2H), 6.56-6.51 (m, 2H),
4.16 (s, br, 1H), 3.14 (m, 2H), 1.65-1.29 (m, 8H), 0.90 (t, 3H,
J ) 6.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 151.5, 133.4, 120.6,
111.8, 97.6, 43.0, 31.3, 28.8, 26.5, 22.4, 13.8; IR (KBr, cm-1
)
3382, 2930, 2212, 1612, 1530, 1173. Anal. Calcd for C13H18N2:
C, 77.18; H, 8.97. Found: C, 77.35; H, 9.02.
N-(4-Cya n op h en yl)h exyla m in e (Ta ble 1, En tr y 6). The
general procedure conducted on a 10 mmol scale using 0.025
mol % Pd2(dba)3 and 0.075 mol % (S)-BINAP gave 1.95 g (97%)
of the title compound as a white solid. See above for NMR data.
2-(3-N-Ben zyla n ilin o)-1,4-d ioxola n e (Ta ble 1, En tr y 7).
The general procedure using (S)-BINAP gave 213 mg (84%)
of the title compound as a colorless oil: 1H NMR (CDCl3, 300
MHz) δ 7.35-7.25 (m, 5H), 7.18 (t, 1H, J ) 7.2 Hz), 6.84 (d,
1H, J ) 7.8 Hz), 6.78 (s, 1H), 6.63 (d, 1H, J ) 6.9 Hz), 5.75 (s,
1H), 4.34 (br, 3H), 4.12-3.95 (m, 4H); 13C NMR (CDCl3, 75
MHz) δ 148.1, 139.2, 138.8, 129.0, 128.3, 127.2, 126.9, 115.2,
113.2, 110.5, 103.6, 64.9, 47.9; IR (neat, cm-1) 3404, 3060, 1611,
1494, 1094. Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71.
Found: C, 75.54; H, 6.67.
Gen er a l P r oced u r e for Ar yla tion of P r im a r y Am in es.
A Schlenk flask was charged with aryl halide (1.0 mmol),
amine (1.1-1.2 mmol), sodium tert-butoxide (1.4 mmol), tris-
(dibenzylideneacetone)dipalladium(0) (0.0025 mmol, 0.5 mol
% Pd), BINAP (0.0075 mmol), and toluene (2 mL) under argon.
The flask was immersed in an 80 °C oil bath with stirring until
the starting material had been completely consumed as judged
by GC analysis. The solution was then allowed to cool to room
temperature, taken up in ether (15 mL), filtered, and concen-
trated. The crude product was then purified further by flash
chromatography on silica gel.
ter t-Bu tyl-3-(N-ben zyla m in o)ben zoa te (Ta ble 1, En tr y
8). The general procedure using (S)-BINAP gave 201 mg (71%)
1
of the title compound as a white solid: mp 73.6-75.4 °C; H
N-Hexyl-3,5-xylid en e (Ta ble 1, En tr y 1). The general
procedure using (S)-BINAP gave 176 mg (86%) of the title
compound as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 6.35
NMR (CDCl3, 300 MHz) δ 7.38-7.26 (m, 7H), 7.19 (t, 1H, J )
(39) (a) Katritzky, A. R.; Lloyd, J . M.; Patel, R. C Chem. Scr. 1981,
18, 256-265. (b) Toma, C.; Balaban, A. T. Tetrahedron: Suppl. 1966,
7, 9-25.
(40) Vernaudon, P.; Rahoharison, H. G.; Roussel, C. B. Chem. Soc.
Fr. 1987, 205-211.
(38) (a) Frye, S. V.; J ohnson, M. C.; Valvano, N. L. J . Org. Chem.
1991, 56, 3750-3752. (b) Hodgson, P. K. G.; Meakins, G. D.; Willbe,
C. J . Chem. Soc., Perkin Trans. 2 1978, 853-855.

1154 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe and Buchwald
7.7 Hz), 6.76 (dd, 1H, J ) 2.4 Hz, 7.6 Hz), 4.36 (s, 2H), 4.15 (s,
br, 1H), 1.57 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 166.0, 147.9,
139.0, 132.8, 128.9, 128.5, 127.4, 127.2, 118.4, 116.5, 113.4,
80.5, 48.0, 28.0; IR (KBr, cm-1) 3359, 3030, 1694, 1603, 1298,
1116. Anal. Calcd for C18H21NO2: C, 76.3; H, 7.47. Found: C,
76.59; H, 7.32.
N-Hexyl-2-m eth yl-4-m eth oxya n ilin e (Ta ble 1, En tr y 9).
The general procedure using (S)-BINAP gave 207 mg (94%)
of the title compound as a colorless oil: 1H NMR (CDCl3, 300
MHz) δ 6.71-6.69 (m, 2H), 6.57-6.53 (m, 1H), 3.74 (s, 3H),
3.12 (s, Br, 1H), 3.09 (t, 2H, J ) 7.2 Hz), 2.13 (s, 3H), 1.67-
1.30 (m, 8H), 0.90 (t, 3H, J ) 6.6 Hz); 13C NMR (CDCl3, 75
MHz) δ 151.4, 140.7, 123.5, 116.8, 111.5, 110.7, 55.6, 44.7, 31.6,
29.6, 26.9, 22.6, 17.6, 14.0; IR (neat, cm-1) 3414, 2928, 1514,
1225, 1051. Anal. Calcd for C14H23NO: C, 75.97; H, 10.47.
Found: C, 75.93; H, 10.45.
136.7, 129.1, 128.7, 126.9, 121.2, 117.1, 113.3, 112.6, 55.5, 39.0;
IR (neat, cm-1) 3060, 1602, 1260, 1027. Anal. Calcd for C14H15
NO: C, 78.84; H, 7.09. Found: C, 78.96; H, 7.22.
-
2-Meth oxy-N-m eth yld ip h en yla m in e (Ta ble 3, En tr y 1).
The general procedure B using 1.0 mol % Pd2(dba)3 and (()-
BINAP gave 143 mg (61%) of the title compound as a colorless
oil. See above for NMR data.
2-(Dim eth yla m in o)-N-m eth yld ip h en yla m in e (Ta ble 3,
En tr y 2).41 The general procedure A using 0.5 mol % Pd2(dba)3
gave 143 mg (63%) of the title compound as a colorless oil: 1H
NMR (CDCl3, 300 MHz) δ 7.21-7.09 (m, 4H), 6.98 (dd, 1H, J
) 1.5, 8.1 Hz), 6.87 (dt, 1H, J ) 1.5, 7.8 Hz), 6.75-6.70 (m,
3H), 3.17 (s, 3H), 2.73 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ
149.2, 148.5, 139.0, 129.2, 128.7, 126.1, 121.1, 118.2, 117.0,
113.5, 42.1, 37.1; IR (neat, cm-1) 2941, 1602, 1138.
2-(Dim eth yla m in o)-N-m eth yld ip h en yla m in e (Ta ble 3,
En tr y 2).41 The general procedure B using 1.0 mol % Pd2(dba)3
and (()-BINAP gave 147 mg (65%) of the title compound as a
colorless oil. See above for NMR data.
N-Meth yl-N-p h en yl-2,5-xylid en e (Ta ble 3, En tr y 3). The
general procedure A gave 201 mg (95%) of the title compound
as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.19-7.14 (m,
3H), 7.01-6.95 (m, 2H), 6.72-6.67 (m, 1H), 6.54-6.51 (m, 2H),
3.20 (s, 3H), 2.30 (s, 3H), 2.09 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 149.1, 146.6, 137.1, 133.4, 131.1, 128.9, 128.7, 127.1,
116.6, 112.7, 38.9, 20.8, 17.3; IR (neat, cm-1) 2920, 1597, 1340.
Anal. Calcd for C15H17N: C, 85.26; H, 8.11. Found: C, 85.37;
H, 8.03.
N-(2-Isop r op ylp h en yl)a m in oa ceta ld eh yd e Dieth yl Ac-
eta l (Ta ble 1, En tr y 10). The general procedure using (()-
BINAP gave 232 mg (92%) of the title compound as a colorless
oil: 1H NMR (CDCl3, 300 MHz) δ 7.15 (d, 1H, J ) 7.5 Hz),
7.09 (d, 1H, J ) 7.5 Hz), 6.75 (t, 1H, J ) 7.3 Hz), 6.64 (d, 1H,
J ) 7.9 Hz), 4.76 (t, 1H, J ) 5.7 Hz), 4.00 (s, br, 1H), 3.80-
3.50 (m, 4H), 3.28 (d, 2H, J ) 5.7 Hz), 2.95-2.80 (m, 1H),
1.26-1.22 (m, 12 H); 13C NMR (CDCl3, 75 MHz) δ 144.6, 132.5,
126.7, 125.0, 117.6, 110.7, 100.8, 62.2, 46.3, 27.2, 22.2, 15.4;
IR (neat, cm-1) 3432, 2972, 1509, 1061. Anal. Calcd for C15H26
NO2: C, 71.67; H, 10.02. Found: C, 71.59; H, 10.03.
-
N-(4-t-Bu tylp h en yl)-s-bu tyla m in e (Ta ble 1, En tr y 11).
The general procedure using 1 mol % Pd2(dba)3, 3 mol % (()-
BINAP, and a reaction temperature of 100 °C gave 167 mg
(81%) of the title compound as a colorless oil: 1H NMR (CDCl3,
300 MHz) δ 7.19 (d, 2H, J ) 8.7 Hz), 6.53 (d, 2H, J ) 8.6 Hz),
3.40-3.28 (m, 2H), 1.60-1.45 (m, 2H), 1.27 (s, 9H), 1.15 (d,
3H, J ) 6.2 Hz), 0.94 (t, 3H, J ) 7.4 Hz); 13C NMR (CDCl3, 75
MHz) δ 145.3, 139.4, 126.0, 112.7, 49.9, 33.8, 31.6, 29.8, 20.4,
10.4; IR (neat, cm-1) 3405, 2961, 1613, 1192. Anal. Calcd for
N-Meth yl-N′-(2,5-xylyl)p ip er a zin e (Ta ble 3, En tr y 4).
The general procedure A gave 197 mg (97%) of the title
compound as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.05
(d, 1H, J ) 7.5 Hz), 6.83-6.78 (m, 2H), 2.94 (t, 4H, J ) 4.8
Hz), 2.58 (s, br, 4H), 2.30 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H); 13
C
NMR (CDCl3, 75 MHz) δ 151.2, 135.9, 130.7, 129.1, 123.6,
119.6, 55.6, 51.5, 46.1, 21.1, 17.3; IR (neat, cm-1) 2937, 1505,
1150. Anal. Calcd for C13H20N2: C, 76.42; H, 9.87. Found: C,
76.31; H, 9.71.
N-Meth yl-N′-(2,5-xylyl)p ip er a zin e (Ta ble 3, En tr y 4).
The general procedure B using 1 mol % Pd2(dba)3 and (()-
BINAP gave 199 mg (98%) of the title compound as a colorless
oil. See above for NMR data.
N-Meth yl-N′-(2,5-xylyl)p ip er a zin e (Ta ble 3, En tr y 4).
The general procedure A conducted on a 10 mmol scale using
0.025 mol % Pd2(dba)3 and 0.075 mol % (S)-BINAP gave 1.91
g (94%) of the title compound as a colorless oil. See above for
NMR data.
C
14H23N: C, 81.89; H, 11.29. Found: C, 81.83; H, 11.27.
N-Ben zyl-2,6-xylid en e (Ta ble 1, En tr y 12). The general
procedure using (()-BINAP, 1 mL/mmol halide of toluene as
solvent, and a reaction temperature of 100 °C gave 188 mg
(89%) of the title compound as a colorless oil: 1H NMR (CDCl3,
300 MHz) δ 7.40-7.26 (m, 5H), 7.01 (d, 2H, J ) 7.3 Hz), 6.85
(t, 1H, J ) 7.8 Hz), 4.11 (s, 2H), 3.21 (s, br, 1H), 2.07 (S, 6H);
13C NMR (CDCl3, 75 MHz) δ 145.8, 140.4, 129.8, 128.8, 128.5,
127.9, 127.2, 122.1, 52.8, 18.4; IR (neat, cm-1) 3366, 2945, 1475,
1216. Anal. Calcd for C15H17N: C, 85.26; H, 8.11. Found: C,
85.10; H, 8.06.
N-(4-ter t-Bu tylp h en yl)p yr r olid in e (Ta ble 3, En tr y 5).4a
The general procedure B using 0.25 mol % Pd2(dba)3 and 0.75
mol % (()-BINAP gave 161 mg (79%) of the title compound as
a white solid: mp 38-40 °C (lit.4a mp 38-39 °C); 1H NMR
(CDCl3, 300 MHz) δ 7.27 (d, 2H, J ) 8.7 Hz), 6.53 (d, 2H, J )
8.7 Hz), 3.30-3.22 (m, 4H), 2.01-1.95 (m, 4H), 1.29 (s, 9H).
N-(4-ter t-Bu tylp h en yl)m or p h olin e (Ta ble 3, En tr y 6).4d
The general procedure A using (()-BINAP gave 203 mg (93%)
of the title compound as a white solid: mp 60-61 °C (lit.4d
Gen er a l P r oced u r es for Ar yla t ion of Secon d a r y
Am in es. Meth od A. No Solven t. An oven-dried glass vial
was charged with aryl halide (1.0 mmol), amine (1.2 mmol),
sodium tert-butoxide (1.4 mmol), tris(dibenzylideneacetone)-
dipalladium(0) (0.0025 mmol, 0.5 mol %), and BINAP (0.0075
mmol). The vial was flushed with a stream of argon and tightly
capped. The mixture was immersed in an oil bath and heated
to 80 °C with stirring until the starting material had been
completely consumed as judged by GC analysis. The mixture
was allowed to cool to room temperature, taken up in ether
(15 mL), filtered, and concentrated. The crude product was
then purified further by flash chromatography on silica gel.
Meth od B. With Solven t. A Schlenk flask was charged
with aryl halide (1.0 mmol), amine (1.2 mmol), sodium tert-
butoxide (1.4 mmol), tris(dibenzylideneacetone)dipalladium-
(0) (0.0025-0.01 mmol, 0.5-2 mol %), BINAP (0.0075-0.03
mmol), and toluene (2-9 mL) under argon. The flask was
immersed in an oil bath and heated to 80 °C with stirring until
the starting material had been completely consumed as judged
by GC analysis. The mixture was allowed to cool to room
temperature, taken up in ether (15 mL), filtered, and concen-
trated. The crude product was then purified further by flash
chromatography on silica gel.
1
mp 59 °C); H NMR (CDCl3, 300 MHz) δ 7.30 (d, 2H, J ) 8.9
Hz), 6.87 (d, 2H, J ) 8.9 Hz), 3.86 (t, 4H, J ) 4.7 Hz), 3.14 (t,
4H, J ) 4.9 Hz), 1.30 (s, 9H).
Gen er a l P r oced u r e for Ca ta lytic Am in a tion w ith
Cesiu m Ca r bon a te a s Ba se. An oven-dried Schlenk flask
was charged with cesium carbonate that had been finely
ground with a mortar and pestle (1.4 equiv) in a nitrogen-filled
glovebox. The flask was capped with a rubber septum and
removed from the glovebox. The flask was then charged with
Pd2(dba)3 or Pd(OAc)2 and BINAP (see Table 4) and purged
with argon. The aryl bromide (1.0 equiv), the amine (1.2 equiv),
and toluene (2-4 mL/mmol halide) were added, and the
mixture was heated to 100 °C with stirring until the starting
material had been consumed as judged by GC analysis. The
mixture was cooled to room temperature, diluted with ether
(20 mL), filtered, and concentrated. The crude product was
2-Meth oxy-N-m eth yl-d ip h en yla m in e (Ta ble 3, En tr y
1). The general procedure A gave 172 mg (77%) of the title
compound as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ
7.23-7.14 (m, 4H), 7.00-6.94 (m, 2H), 6.74-6.63 (m, 3H), 3.78
(s, 3H), 3.22 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 155.9, 149.3,
(41) Pilgram, K. H.; Skiles, R. D. Phosphorous Sulfur 1988, 36, 117-
124.

Pd/BINAP-Catalyzed Amination of Aryl Bromides
J . Org. Chem., Vol. 65, No. 4, 2000 1155
then purified by flash chromatography on silica gel. A reaction
that employed cesium carbonate that had been finely ground
in the air and stored in a desiccator outside of the glovebox
gave results comparable to the analogous reaction that em-
ployed cesium carbonate from the glovebox.
a yellow solid: mp 102-103 °C; 1H NMR (CDCl3, 300 MHz) δ
7.45 (d, 2H, J ) 9.0 Hz), 7.16 (d, 2H, J ) 8.5 Hz), 7.06 (d, 2H,
J ) 8.3 Hz), 6.89 (d, 2H, J ) 9.0 Hz), 5.95 (s, br, 1H), 2.35 (s,
3H); 13C NMR (CDCl3, 75 MHz) δ 148.5, 137.0, 133.8, 133.5,
130.0, 121.9, 120.0, 114.2, 100.5, 20.9; IR (KBr, cm-1) 3334,
2211, 1597, 1514. Anal. Calcd for C14H12N2: C, 80.74; H, 5.81.
Found: C, 80.65; H, 5.91.
N-(4-Nitr op h en yl)p ip er id in e (Ta ble 4, En tr y 1).42 The
general procedure gave 87 mg (84%) of the title compound as
1
a yellow solid: mp 95 °C (lit.42 mp 104 °C); H NMR (CDCl3,
N-(2,5-Xylyl)p yr r olid in e (Ta ble 4, En tr y 9).45 The gen-
eral procedure gave 82 mg (93%) of the title compound as a
colorless oil: 1H NMR (CDCl3, 300 MHz) δ 6.99 (d, 2H, J )
7.5 Hz), 6.69 (s, 1H), 6.64 (d, 1H, J ) 7.5 Hz), 3.15-3.20 (m,
4H), 2.29 (s, 3H), 2.28 (s, 3H), 1.93-1.89 (m, 4H).
N -(1-Mo r p h o lin o e t h y l)-3-c h lo r o -4-n it r o -6-m e t h y l-
a n ilin e (Ta ble 4, En tr y 10). The general procedure gave 108
mg (72%) of the title compound as a yellow solid: mp 104-
105 °C; 1H NMR (CDCl3, 300 MHz) δ 7.89 (s, 1H), 6.53 (s, 1H),
5.21 (s, br, 1H), 3.72 (t, 4H, J ) 4.6 Hz), 3.24 (q, 2H, J ) 5.1
Hz), 2.72 (t, 2H, J ) 6.2 Hz), 2.46 (t, 4H, J ) 4.7 Hz), 2.14 (s,
3H); 13C NMR (CDCl3, 75 MHz) δ 150.4, 135.0, 128.5, 128.1,
120.1, 110.8, 67.0, 55.8, 53.0, 39.0, 16.6; IR (KBr, cm-1) 3352,
2815, 1561, 1526, 1312, 1112; GC/MS (m/z) 301, 299. Anal.
Calcd for C13H18N3O3Cl: C, 52.09; H, 6.05. Found: C, 52.33;
H, 6.28.
300 MHz) δ 8.09 (d, 2H, J ) 9.3 Hz), 6.79 (d, 2H, J ) 9.9 Hz),
3.50 (m, 4H), 1.75-1.65 (m, 6H); 13C NMR (CDCl3, 75 MHz) δ
154.6, 137.0, 125.9, 112.1, 48.3, 25.3, 24.2; IR (KBr, cm-1) 2942,
1508, 1450, 1311, 1248, 1200, 1109. Anal. Calcd for C11H14
N2O2: C, 64.06; H, 6.84. Found: C, 64.19; H, 6.72.
-
Meth yl (4-n -Hexyla m in o)ben zoa te (Ta ble 4, En tr y 2).
The general procedure gave 88 mg (75%) of the title compound
as a white solid: mp 93-94 °C; 1H NMR (CDCl3, 300 MHz) δ
7.85 (d, 2H, J ) 8.7 Hz), 6.53 (d, 2H, J ) 8.7 Hz), 4.01 (s, br,
1H), 3.85 (s, 3H) 3.15 (t, 2H, J ) 6.9 Hz), 1.70-1.50 (m, 3H),
1.45-1.28 (m, 5H), 0.90 (t, 3H, J ) 6.6 Hz); 13C NMR (CDCl3,
75 MHz) δ 167.1, 152.0, 131.4, 117.8, 111.1, 51.5, 43.4, 31.6,
29.3, 26.8; IR (KBr, cm-1) 3060, 1703, 1609, 1181. Anal. Calcd
for C13H21NO2: C, 71.46; H, 8.99. Found: C, 71.47; H, 9.11.
N-Meth yl-N-ben zyl(4-ca r bom eth oxy)a n ilin e (Ta ble 4,
En tr y 3). The general procedure gave 87 mg (68%) of the title
N-Ben zyl-3-ch lor o-4-cya n oa n ilin e (Ta ble 4, En tr y 11).
The general procedure gave 102 mg (84%) of the title com-
pound as a white solid: mp 91 °C; 1H NMR (CDCl3, 300 MHz)
δ 7.40-7.27 (m, 6H), 6.65 (d, 1H, J ) 2.3 Hz), 6.48 (dd, 1H, J
) 8.6 Hz, 2.4 Hz), 4.67 (s, br, 1H), 4.36 (d, 2H, J ) 4.6 Hz);
13C NMR (CDCl3, 75 MHz) δ 151.7, 138.1, 137.0, 134.7, 128.9,
1
compound as a white solid: mp 67-68 °C; H NMR (CDCl3,
300 MHz) δ 7.88 (d, 2H, J ) 9.0 Hz), 7.32-7.26 (m, 3H), 7.20-
7.10 (m, 2H), 6.69 (d, 2H, J ) 9.0 Hz), 4.62 (s, 2H), 3.84 (s,
3H), 3.11 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 167.2, 152.6,
137.7, 131.3, 128.7, 127.1, 126.4, 117.3, 110.8, 56.0, 51.5, 38.7;
IR (KBr, cm-1) 2948, 1702, 1608, 1181. Anal. Calcd for C16H17
NO2: C, 75.27; H, 6.71. Found: C, 75.38; H, 6.88.
-
127.8, 127.2, 117.4, 112.5, 111.0, 100.0, 47.6; IR (KBr, cm-1
)
3356, 2216, 1603; GC/MS (m/z) 244,242. Anal. Calcd for
C
14H11N2Cl: C, 69.28; H, 4.57. Found: C, 69.21; H, 4.52.
N-(3-Ca r bom eth oxyp h en yl)m or p h olin e (Ta ble 4, En -
tr y 4). The general procedure gave 97 mg (87%) of the title
compound as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.58
(s, 1H), 7.54 (d, 1H, J ) 6.9 Hz), 7.33 (t,1H, J ) 8.1 Hz), 7.09
(dd, 1H, J ) 7.5 Hz, 1.8 Hz), 3.91 (s, 3H), 3.87 (t, 4H, J ) 4.5
Hz), 3.21 (t, 4H, J ) 5.1 Hz); 13C NMR (CDCl3, 75 MHz) δ
167.1, 151.0, 130.8, 129.0, 120.8, 119.8, 116.2, 66.7, 52.1, 49.0;
N-(4-Acetylp h en yl)-p-tolu id in e (Ta ble 4, En tr y 12).46
The general procedure gave 82 mg (73%) of the title compound
as an orange solid: mp 108 °C (lit.46 mp 115 °C); 1H NMR
(CDCl3, 300 MHz) δ 7.84 (d, 2H, J ) 9.0 Hz), 7.16 (d, 2H, J )
8.3 Hz), 7.08 (d, 2H, J ) 8.5 Hz), 6.91 (d, 2H, J ) 8.8 Hz),
5.98 (s, br, 1H), 2.52 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 196.1, 149.0, 137.7, 133.1, 130.4, 129.8, 128.1, 121.3,
113.6, 26.1, 20.9; IR (KBr, cm-1) 3325, 1649, 1565, 1177. Anal.
Calcd for C15H15NO: C, 77.97; H, 6.71. Found: C, 80.19; H,
6.88.
N-Met h yl-N-b en zyl-4-for m yla n ilin e (Ta b le 4, E n t r y
13).47 The general procedure gave 59 mg (52%) of the title
compound as a white solid: mp 53 °C (lit.47 mp 63 °C); 1H NMR
(CDCl3, 300 MHz) δ 9.73 (s, 1H), 7.71 (d, 2H, J ) 9.1 Hz),
7.33-7.26 (m, 3H), 7.17 (d, 2H, J ) 6.8 Hz), 6.75 (d, 2H, J )
9.0 Hz), 4.66 (s, 2H), 3.16 (s, 3H); 13C NMR (CDCl3, 75 MHz)
δ 189.9, 153.7, 137.0, 131.9, 128.7, 127.2, 126.2, 125.5, 111.1,
55.9, 38.9; IR (KBr, cm-1) 2374, 1660, 1591, 1108. Anal. Calcd
for C15H15NO: C, 79.97; H, 6.71. Found: C, 80.19; H, 6.95.
N-(2-Ch lor p h en yl)-m -n itr oa n ilin e (Ta ble 4, En tr y 14).
The general procedure using 1 mol % Pd2(dba)3 and 3 mol %
(()-BINAP (the product was isolated by recrystallization from
methanol instead of by chromatography) gave 196 mg (79%)
of the title compound as a yellow solid: mp 93-94 °C; 1H NMR
(CDCl3, 250 MHz) δ 8.05-7.95 (m, 1H), 7.82-7.75 (m, 1H),
7.50-7.30 (m, 5H), 6.99-6.93 (m, 1H), 6.24 (s, br, 1H); 13C
NMR (CDCl3, 75 MHz) δ 149.2, 143.5, 138.1, 130.1, 127.7,
123.7, 123.6, 122.8, 117.9, 116.1, 112.1; IR (neat, cm-1) 3397,
3061, 1532, 1336; GC/MS (m/z) 250, 248. Anal. Calcd for C12H9-
ClN2O2: C, 57.96; H, 3.65. Found: C, 58.14; H, 3.72.
IR (neat, cm-1) 2954, 1721, 1601, 1122. Anal. Calcd for C11H15
NO3: C, 65.14; H, 6.83. Found: C, 65.03; H, 6.79.
-
N-(2-Ca r bom eth oxyp h en yl)-p-a n sid in e (Ta ble 4, En tr y
5).43 The general procedure gave 115 mg (89%) of the title
compound as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 9.26
(s, br, 1H), 7.93 (d, 1H, J ) 8.1 Hz), 7.25 (t, 1H, J ) 7.8 Hz),
7.17 (d, 2H, J ) 8.7 Hz), 6.96 (d, 1H, J ) 8.1 Hz), 6.90 (d, 2H,
J ) 8.7 Hz), 6.65 (t, 1H, J ) 6.9 Hz), 3.90 (s, 3H), 3.82 (s, 3H);
13C NMR (CDCl3, 75 MHz) δ 168.8, 156.5, 149.4, 134.0, 133.2,
125.8, 116.0, 114.5, 113.2, 110.7, 55.5, 51.7; IR (neat, cm-1
)
3324, 2950, 1682, 1084. Anal. Calcd for C15H15NO3: C, 70.02;
H, 5.88. Found: C, 70.28; H, 5.95.
N-Meth yl-N-(4-ca r beth oxyp h en yl)a n ilin e (Ta ble 4, En -
tr y 6).44 The general procedure gave 114 mg (89%) of the title
compound as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.86
(d, 2H, J ) 8.4 Hz), 7.41-7.36 (m, 2H), 7.22-7.19 (m, 3H),
6.77 (d, 2H, J ) 8.7 Hz), 4.29 (q, 2H, J ) 7.2 Hz), 3.36 (s, 3H),
1.36 (t, 3H, J ) 6.9 Hz); 13C NMR (CDCl3, 75 MHz) δ 166.5,
152.3, 147.4, 130.8, 129.6, 125.6, 125.1, 119.5, 113.8, 60.2, 40.2,
14.5; IR (neat, cm-1) 2949, 1682, 1600, 1172, 1109. Anal. Calcd
for C16H17NO2: C, 75.27; H, 6.71. Found: C, 75.17; H, 6.51.
N-(4-Cya n op h en yl)p ip er id in e (Ta ble 4, En tr y 7).42 The
general procedure gave 77 mg (83%) of the title compound as
a white solid: mp 45 °C (lit.42 mp 56 °C); 1H NMR (CDCl3,
300 MHz) δ 7.45 (d, 2H, J ) 9.0 Hz), 6.83 (d, 2H, J ) 9.0 Hz),
3.88-3.28 (m, 4H), 1.70-1.60 (m, 6H); 13C NMR (CDCl3, 75
MHz) δ 153.4, 133.3, 120.2, 113.9, 98.8, 48.4, 25.3, 24.3; IR
(KBr, cm-1) 2938, 2217, 1605, 1124. Anal. Calcd for C12H14N2:
C, 77.38; H, 7.58. Found: C, 77.55; H, 7.41.
Gen er a l P r oced u r e for P a lla d iu m -Ca ta lyzed Am in a -
tion Usin g P d (OAc)2/(()-BINAP (P r em ixed Ca ta lyst). An
oven-dried Schlenk flask was purged with argon and charged
with (()-BINAP (9.3 mg, 0.0075 mmol, 1.5 mol %), and capped
with a rubber septum. The flask was purged with argon and
toluene (1 mL) was added. The mixture was heated to 80 °C
with stirring until the BINAP dissolved (∼1 min). The solution
N-(4-Cya n op h en yl)-p-tolu id in e (Ta ble 4, En tr y 8). The
general procedure gave 84 mg (81%) of the title compound as
(42) Verardo, G.; Giumanini, A. G.; Favret, G.; Strazzolini, P.
Synthesis 1991, 447-450.
(43) Legrand, L.; Lozac′h, N. Bull. Chem. Soc. Fr. 1969, 1173-1182.
(44) Guram, A. S.; Buchwald, S. L. J . Am. Chem. Soc. 1994, 116,
7901-7902.
(45) Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119,
6054-6058.
(46) Itier, J .; Casadevall, A. Bull. Chem. Soc. Fr. 1969, 2342-2355.
(47) Hora, I. M.; Gupta, V.; Ittyerah, P. I. J . Indian. Chem. Soc.
1972, 49, 901-905.

1156 J . Org. Chem., Vol. 65, No. 4, 2000
Wolfe and Buchwald
was cooled to room temperature, the septum was removed, and
Pd(OAc)2 (2.2 mg, 0.01 mmol, 1 mol %) was added. The flask
was recapped with the septum and then purged with argon
(for ∼30 s), and toluene (0.2 mL) was added to rinse the Pd
from the sides of the flask. The mixture was stirred at room
temperature for ∼1 min, the aryl halide (1.0 mmol) and the
amine (1.2 mmol) were added, the septum was removed, and
NaO-t-Bu was added. The flask was recapped with the septum
and then purged with argon, and additional toluene (0.8 mL)
was added. 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, filtered, and concentrated in
vacuo. The crude product was then purified by flash chroma-
tography on silica gel.
Gen er a l P r oced u r e for R ea ct ion s E m p loyin g (S)-
BINAP in Wh ich th e Ca ta lyst Wa s P r em ixed An oven-
dried Schlenk flask equipped with a stirbar and a rubber
septum was attached to a ReactIR in situ IR instrument and
purged with argon. The flask was charged with Pd2(dba)3 or
Pd(OAc)2 (0.5 mol % Pd), (S)-BINAP (11.7 mg, 0.0188 mmol,
0.75 mol %), and toluene (2.5 mL). The mixture was stirred at
room temperature for ∼1 min, and then 5-bromo-m-xylene
(0.34 mL, 2.5 mmol) and benzylamine (3.0 mmol) were added
through the septum. The septum was removed, NaO-t-Bu (336
mg, 3.5 mmol) was added, and the flask was capped with the
septum and then was purged with argon. Additional toluene
(2.5 mL) and dodecane (0.575 mL) were added, and a thermo-
couple was inserted into the flask through the septum. The
mixture was stirred at room temperature, and the IR acquisi-
tion was begun. After five scans (2.5 min), the flask was
immersed in an 85 °C oil bath; typically, the internal temper-
ature of the reactions were ∼78 °C. An aliquot (∼30 µL) was
removed via syringe after 10 scans, and the conversion was
analyzed by GC in order to accurately correlate absorbance
with concentration. The IR acquisition was continued until the
starting aryl halide had been completely consumed.
Gen er a l P r oced u r e for Rea ction s Em p loyin g (()-
BINAP in Wh ich th e Ca ta lyst Wa s P r em ixed . An oven-
dried Schlenk flask equipped with a stirbar, and a rubber
septum was attached to a ReactIR in situ IR instrument. It
was purged with argon, charged with (()-BINAP (11.7 mg,
0.0188 mmol, 1.5 mol %), and capped with a rubber septum.
The flask was purged with argon, and toluene (2.5 mL) was
added. The mixture was heated to 80 °C with stirring until
the BINAP dissolved (∼1 min). The mixture was cooled to room
temperature, the septum was removed, and the Pd2(dba)3 or
Pd(OAc)2 was added. The flask was capped with the septum
and stirred at room temperature for ∼1 min, and then
5-bromo-m-xylene (0.34 mL, 2.5 mmol) and benzylamine (3.0
mmol) were added through the septum. The septum was
removed, NaO-t-Bu (336 mg, 3.5 mmol) was added, and the
flask was capped with the septum and then was purged with
argon. Additional toluene (2.5 mL) and dodecane (0.575 mL)
were added, and a thermocouple was inserted into the flask
through the septum. The mixture was stirred at room tem-
perature, and the IR acquisition was begun. After five scans
(2.5 min), the flask was immersed in an 85 °C oil bath; typically
the internal temperature of the reactions were ∼78 °C. An
aliquot (∼30 µL) was removed via syringe after 10 scans, and
the conversion was analyzed by GC in order to accurately
correlate absorbance with concentration. The IR acquisition
was continued until the starting aryl halide had been com-
pletely consumed.
N-Ben zyl-3,5-xylid en e (Ta ble 1, En tr y 2). The general
procedure gave 189 mg (90%) of the title compound as a
colorless oil. See above for NMR data.
N-(4-ter t-Bu tylp h en yl)a n ilin e (Ta ble 1, En tr y 13).48 The
general procedure was conducted in a resealable Schlenk flask
and gave the 211 mg (94%) of the title compound as a white
solid: mp 64-67 °C (lit.48 mp 66-67 °C); 1H (250 MHz, CDCl3)
δ_7.31-7.21 (m, 4H), 7.03 (d, 4H, J ) 8.4 Hz), 6.89 (t, 1H, J
) 7.3 Hz); 5.62 (s, br, 1H), 1.31 (s, 9H); 13C δ 1441., 143.6,
129.2, 126.1, 120.3, 118.1, 117.0, 34.1, 31.4; IR (neat, cm-1
)
3388, 2962, 1594. Anal. Calcd for C16H19N: C, 85.28; H, 8.50.
Found: C, 84.98; H, 8.52.
N-Allyl-4-p h en yla n ilin e (Ta ble 1, En tr y 14).49 The gen-
eral procedure using 1.5 equiv allylamine gave 174 mg (83%)
of the title compound as a white solid: mp 66-68 °C (lit.49 mp
1
55-57 °C); H NMR (CDCl3, 250 MHz) δ 7.53 (d, 2H, J ) 7.3
Hz), 7.45-7.35 (m, 4H), 7.27-7.22 (m, 1H), 6.69 (d, 2H, J )
6.71 Hz), 6.03-5.93 (m 1H), 5.31 (d, 1H, J ) 17.1 Hz), 5.19 (d,
1H, J ) 10.3 Hz), 3.90 (s, br, 1H), 3.83 (d, 2H, J ) 5.3 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 147.4, 141.2, 135.3, 1304., 128.6,
127.9, 126.2, 126.0, 116.3, 113.2, 46.5; IR (neat, cm-1) 3408,
3027, 2825, 1611, 1160. Anal. Calcd for C15H15N: C, 86.08; H,
7.12. Found: C, 85.68; H, 7.15.
N-(3-Ca r bom eth oxyp h en yl)-3,5-xylid en e (Ta ble 4, En -
tr y 15). The general procedure using Cs2CO3 as the base gave
220 mg (86%) of the title compound as a white solid: mp 107-
109 °C; 1H NMR (CDCl3, 250 MHz) δ 7.68 (s, 1H), 7.55 (d, 1H,
J ) 7.04 Hz), 7.34-7.25 (m, 2H), 6.72 (s, 2H), 6.63 (s, 1H),
5.62 (S, br, 1H), 3.90 (s, 3H), 2.28 (s, 6H); 13C NMR (CDCl3,
75 MHz) δ 167.1, 143.7, 142.2, 139.0, 131.2, 129.2, 123.5, 121.4,
121.3, 118.2, 116.2, 52.1, 21.3; IR (neat, cm-1) 3362, 2949, 1714,
1583, 1309. Anal. Calcd for C16H16NO2: C, 75.23; H, 6.71.
Found: C, 75.19; H, 6.72.
N-Meth yl-N-ben zyl-(4-ca r bom eth oxy)a n ilin e (Ta ble 4,
En tr y 3). The general procedure using Cs2CO3 as the base
gave 219 mg (86%) of a white solid: mp 67-68 °C. See above
for NMR data.
An a lysis of Da ta for Rela tive Ra te Exp er im en ts. The
IR data were obtained in the form of absorbance vs time. The
following formula was used to transform the absorbance data
into a measure of aryl bromide concentration:
P r oced u r es for th e Rela tive Ra te Exp er im en ts Sh ow n
in Ta ble 5. Gen er a l P r oced u r e for Rea ction s w ith ou t
P r em ixin g t h e Ca t a lyst . An oven-dried Schlenk flask
equipped with a stirbar and a rubber septum was attached to
a ReactIR in situ IR instrument and purged with argon. The
flask was charged with Pd2(dba)3 or Pd(OAc)2 (0.5 mol % Pd),
(S)- or (()-BINAP (11.7 mg, 0.0188 mmol, 0.75 mol %), and
NaO-t-Bu (336 mg, 3.5 mmol). The flask was purged with
argon and toluene (5 mL), dodecane (0.575 mL), 5-bromo-m-
xylene (0.34 mL, 2.5 mmol), and benzylamine (3.0 mmol). A
thermocouple was inserted into the flask through the septum.
The mixture was stirred at room temperature, and the IR
acquisition was begun. After five scans (2.5 min), the flask was
immersed in an 85 °C oil bath; typically the internal temper-
ature of the reactions were ∼78 °C. An aliquot (∼30 µL) was
removed via syringe after 10 scans, and the conversion was
analyzed by GC in order to accurately correlate absorbance
with concentration. The IR acquisition was continued until the
starting aryl halide had been completely consumed.
Time was measured starting from the point at which the flask
was immersed in the oil bath. Plots of [ArBr] vs tTime gave
exponential graphs. Plots of ln[ArBr] vs time gave straight
lines; the slopes of these lines are reported as the observed
rates (k) for the reactions. All experiments were conducted at
least two times; the results were averaged. The errors were
estimated by taking the average of the differences of the
individual runs from the median. The relative rates were
determined by setting the rate of the slowest reaction to 1 and
scaling the other results accordingly.
(48) Craig, D. J . Am. Chem. Soc. 1935, 57, 195-198.
(49) Bartoli, G.; Marcantoni, E.; Bosco, M.; Dalpozzo, R. Tetrahedron
Lett. 1988, 29, 2251-2254.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 58160) and the National Cancer

Pd/BINAP-Catalyzed Amination of Aryl Bromides
J . Org. Chem., Vol. 65, No. 4, 2000 1157
Institute (Training grant NCI No. CI T32CA09112) for
financial support of this work. We also acknowledge
Pfizer, Merck, and Novartis for additional unrestricted
support. J .P.W. is grateful for fellowships from the
Organic Division of the American Chemical Society
sponsored by Schering-Plough and from Boehringer-
Ingelheim. We thank Pfizer, Inc., for a generous gift of
(S)-BINAP, which was used in a portion of this work.
J O9916986