The use of palladium chloride as a precatalyst for the amination of aryl bromides

Article abstract of DOI:10.1139/v01-152

The use of palladium chloride as a precatalyst for the amination of aryl bromides is reported. To overcome the poor solubility of palladium chloride in commonly used solvents, a procedure was developed in which PdCl₂ was preheated with neat amine in the presence of a phosphine ligand before the addition of the other reaction components. This protocol is effective for a broad range of substrate combinations using several types of phosphine ligands.

Full text of DOI:10.1139/v01-152

1799
The use of palladium chloride as a precatalyst for
the amination of aryl bromides
Xiao-Xiang Zhang, Michele C. Harris, Joseph P. Sadighi, and
Stephen L. Buchwald
Abstract: The use of palladium chloride as a precatalyst for the amination of aryl bromides is reported. To overcome
the poor solubility of palladium chloride in commonly used solvents, a procedure was developed in which PdCl2 was
preheated with neat amine in the presence of a phosphine ligand before the addition of the other reaction components.
This protocol is effective for a broad range of substrate combinations using several types of phosphine ligands.
Key words: palladium chloride, amination, aryl bromide, phosphine ligand.
Résumé : On démontre l’utilité du chlorure de palladium comme précatalyseur pour l’amination de bromures d’aryle.
Pour surmonter la piètre solubilité du chlorure de palladium dans les solvants normalement utilisés, on a mis au point
une procédure dans laquelle le PdCl2 est préchauffé avec de l’amine pure, en présence d’un ligand phosphine, avant
l’addition des autres réactifs. Ce protocole est efficace pour un large spectre de combinaisons de substrats faisant appel
à plusieurs types de ligands phosphines.
Mots clés : chlorure de palladium, amination, bromure d’aryle, ligand phosphine.
[Traduit par la Rédaction] Zhang et al. 1805
Introduction
demonstrated that PdCl2 is an efficient palladium source for
the arylation of primary anilines and other amines with aryl
bromides (eq. [1]); the results are summarized in Tables 1
and 2.
The palladium-catalyzed amination of aryl halides and
triflates has proven to be a useful method for the formation
of carbon–nitrogen bonds and has found numerous applica-
tions (1), including the synthesis of natural products (2), bio-
logically and pharmaceutically important compounds (3),
and new ligands and materials (4). A variety of amines can
be coupled with aryl halides and aryl triflates when a palla-
dium precatalyst is combined with an appropriate phosphine
ligand (5–9, and for the use of other electron-rich bulky
phosphine ligands for amination reactions, see ref. 10).
We have commonly employed Pd2(dba)3 and Pd(OAc)2 as
precatalysts in our C–N bond-forming protocol. Although
PdCl2 is readily available and cheaper than Pd(OAc)2 and
Pd2(dba)3, it hasn’t found wide application in Pd-catalyzed
cross-coupling methodology, due to its insolubility in com-
monly used solvents. We have found that when PdCl2 and a
suitable ligand are preheated in the neat amine prior to the
addition of other reaction components until a homogeneous
solution was obtained, the coupling reactions proceed
smoothly (for a recent report that described the use of PdCl2
for amination, see ref. 11). Using this new protocol, we have
R1
R2
R1
R2
PdCl2/Ligand
Base
+
H
Br
N
N
[1]
R3
R3
The chelating ligand bis[2-(diphenylphosphino)phenyl]
ether (DPEphos) has been recently demonstrated to be an ef-
fective ligand for the palladium-catalyzed aryl amination re-
action (6, 12). Most of the reactions with PdCl2 were carried
out using DPEphos as the supporting ligand. Typically, reac-
tions were performed in toluene at 80 or 100°C using 0.5
mol% PdCl2 (L/Pd = 1.5) in the presence of 1.4 equiv. of
base, NaO-t-Bu. The PdCl2 and DPEphos were first heated
with the arylamine under an inert atmosphere to generate a
clear solution, followed by sequential addition of aryl bro-
mide and the base. Using this procedure, most reactions pro-
ceed to completion in ?18 h. The results (Table 1) indicate
that the combination of PdCl2 and DPEphos is as active as
Pd(OAc)2–DPEphos (6) or Pd(OAc)2–BINAP (5) for the
amination of the examples listed.
Both para- and otho-substituted anilines can been effi-
ciently coupled with electron-neutral or electron-rich bro-
mides (Table 1, entries 1–4). As was the case for the
Pd(OAc)2–DPEphos system (6), the combination of PdCl2
and a chelating phosphine can be used to effect couplings of
highly steric substrates. For example, the sterically de-
manding 2,6-diisopropylaniline can be coupled with 2-
methylbromobenzene in 96% yield (Table 1, entry 10).
When 4-bromochlorobenzene was used (Table 1, entry 9),
2,6-diisopropylaniline was chemoselectively coupled with
Received April 2, 2001. Published on the NRC Research Press
Web site at http://canjchem.nrc.ca on November 19, 2001.
Dedicated with respect and affection to Professor Victor
Snieckus; a great chemist and worthy role model.
X.-X. Zhang, M.C. Harris, J.P. Sadighi, and S.L.
Buchwald.1 Department of Chemistry, Massachusetts Institute
of Technology, Cambridge, MA 02139, U.S.A.
1Corresponding author (telephone: (617) 253-1885; fax: (617)
253-3297; e-mail: sbuchwal@mit.edu).
Can. J. Chem. 79: 1799–1805 (2001)
© 2001 NRC Canada
DOI: 10.1139/cjc-79-11-1799

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Can. J. Chem. Vol. 79, 2001
Table 1. Catalytic amination of aryl bromides using PdCl2 and bisphosphine ligands.
Yieldb
(%)
mol %
PdCl2
Ligand
(L/Pd)
Timea
(h)
Entry
1
Product
Amine
Bromide
MeO
OMe
DPEphos
(1.5)
H
N
Me
Me
NH
2
0.5
3
97
Me
Me
Br
Me
Me
H
N
DPEphos
(1.5)
NH
Br
2
3
4
5
0.5
0.5
0.5
0.5
17
98
2
Me
Me
Me
Me
OMe
OMe
OMe
H
N
DPEphos
(1.5)
Br
Br
17
4
97
93
92
87
NH
2
Me
Me
Me
Me
MeO Me
H
N
DPEphos
(1.5)
NH
2
Me
O
Me
N
Br
Me
NH
Xantphos
(1.5)
O
4
H
O
H
O
Me
Me
H
N
BINAP
(1.5)
Ph
NH
Ph
Br
0.5
1.0
0.5
3
18
18
6
7
2
Me
Me
DPEphos
(1.5)
85c
97
Ph NH
2
Br
Ph
Ph N
Ph
Et
2
Me
Me
Me
Et
H
N
DPEphos
(1.5)
Me
NH
Me
8
2
Br
Me
iPr
iPr
H
N
98c
DPEphos
(1.5)
9
Br
Cl
0.5
0.5
5.0
18
18
18
NH
Cl
2
2
iPr
iPr
iPr
iPr Me
Me
H
N
DPEphos
(1.5)
96c
91c
10
11
NH
Br
iPr
iPr
Me
iPr
iPr Me
H
N
DPEphos
(1.5)
Br
NH
2
Me
iPr
iPr Me
Note: Reactions were run at 80°C with ArBr (1.0 equiv.), Ar>NH2 (1.2 equiv.), NaO-t-Bu (1.4 equiv.), cat. PdCl2, and
cat. ligand. Concentration: 2 mL toluene per mmol ArBr.
aReaction times have not been optimized.
1
bYields represent isolated yields (average of two runs) of compounds estimated to be >95% pure by H NMR, GC, and
for new compounds, combustion analysis.
the bromide. With a higher catalyst loading (5 mol%), a very
hindered diarylamine was prepared in 91% yield from the
coupling of 2,6-diisopropylaniline with 2-bromo-m-xylene
(Table 1, entry 11). Secondary anilines (Table 1, entries 5
and 7) and benzyl amine (entry 6) are also suitable coupling
partners under similar reaction conditions.
In addition to DPEphos, PdCl2 can also be used with a
number of other commonly employed phosphine ligands for
© 2001 NRC Canada

Zhang et al.
1801
Table 2. Catalytic amination of aryl bromides using PdCl2 and monophosphine ligands.
Yieldc
(%)
Liganda
(L/Pd)
Timeb
mol %
PdCl2
Entry
1
Product
Amine
Bromide
(h)
MeO
Br
OMe
N
1
(1.5)
NH
1.0
43
65
OMe
OMe
OMe
H
N
Ph
NH2
1
(1.5)
Ph
Br
Br
2
3
1.0
1.0
23
21
93
83
OMe
1
(1.5)
n-Bu
(n-Bu)2NH
N
n-Bu
Me
Me
Me
Et
N
Et
NH
1
(1.5)
Br
0.5
4
28
72
Me
H
N
1
(1.5)
Br
t-Bu
O
N
t-Bu
1.0
3.0
5
6
21
28
93
O
H
N
2
(1.5)
74d
Br
CN
O
N
CN
O
Note: Reactions were run at 80°C with ArBr (1.0 equiv.), Ar>NH2 (1.2 equiv.), NaO-t-Bu (1.4 equiv.), cat. PdCl2, and cat.
ligand. Concentration: 2 mL toluene per mmol ArBr.
a1: 2-(di-tert-butylphosphino)biphenyl; 2: 2-(dicyclohexylphosphino)biphenyl.
bReaction times have not been optimized.
1
cYields represent isolated yields (average of two runs) of compounds estimated to be >95% pure by H NMR, GC, and
for new compounds, combustion analysis.
dThe reaction was conducted at 100°C using K3PO4 as the base and DME as the solvent.
catalyzing C–N bond forming reactions, as is shown for the
bisphosphine ligands Xantphos (Table 1, entry 5) and
BINAP (entry 6) as well as for biphenyl-based electron-
rich bulky monophosphine ligands (Fig. 1) (9) 2-(di-tert-
butylphosphino)biphenyl (1) and 2-(dicyclohexylphos-
phino)-biphenyl (2) (Table 2). By applying the combination
of PdCl2 and 1 or 2, secondary cyclic amines such as
pyrrolidine and morpholine can be effectively coupled with
electron-rich (Table 2, entry 1), -neutral (entry 5), and -poor
(entry 6) aryl bromides to afford the corresponding desired
products in good to excellent yields. Acyclic primary (Ta-
ble 2, entry 2) and secondary (entry 3) amines as well as N-
ethylaniline (entry 4) are also suitable for coupling with aryl
bromides. When the weak base K3PO4 was used instead of
NaO-t-Bu, 4-bromobenzonitrile was successfully coupled
with morpholine to give N-(4-cyanophenyl)-morpholine in
good yield in DME at 100°C using a combination of PdCl2
(3.0 mol%) and 2 (Table 2, entry 6).
the use of PdCl2 as a precatalyst in the amination of aryl
bromides is comparable with Pd(OAc)2 and Pd2(dba)3 when
the common bisphosphine ligands are applied. However, at
present, it is less effective when the biphenyl-based electron-
rich bulky monophosphine ligands are employed. This causes
it to be ineffective for the amination of aryl chlorides, as indi-
cated by our preliminary results. The reason for these limita-
tions will be the subject of future research in our laboratory.
Experimental
General
All reactions were carried out under an argon atmosphere
in oven-dried glassware. Elemental analyses were performed
by Atlantic Microlabs Inc., Norcross, GA. Toluene was dis-
tilled under nitrogen from molten sodium. Aryl halides were
purchased from commercial sources and were used without
further purification. Amines were purchased from commer-
cial sources and were passed through alumina before use.
DPEphos and Xantphos were prepared as previously de-
scribed (6, 7). Palladium chloride, rac-BINAP, 1, and 2 were
purchased from Strem Chemical company. Sodium tert-
In conclusion, we have demonstrated a procedure to use
PdCl2 in the amination of aryl bromides. This protocol was
successfully applied with several different phosphine ligands
and substrate combinations. In general, the effectiveness of
© 2001 NRC Canada

1802
Can. J. Chem. Vol. 79, 2001
Fig. 1. Structures of chelating ligands and biphenyl-based electron-rich bulky monophosphine ligands.
PPh2
PPh2
Me
Me
PPh2
PPh2
O
O
P(tBu)2
PCy2
PPh2
PPh2
DPEphos
Xantphos
BINAP
1
2
butoxide was purchased from Aldrich; the bulk of this mate-
rial 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. Pro-
ton and carbon nuclear magnetic resonance spectra (1H and
13C NMR) were recorded on a Varian Mercury 300 spec-
trometer and referenced with respect to TMS internal stan-
dard. Infrared spectra were obtained using a PerkinElmer
1600 Series FT-IR spectrometer. Samples were prepared as
films on NaCl plate by evaporating CHCl3 solutions. High-
resolution mass spectroscopy (HRMS) was performed by the
MIT Department of Chemistry Instrumentation Facility on a
Finnigan MAT system 8200 double-focusing sector mass
spectrometer using electron impact (EI) ionization tech-
nique. Yields in Tables 1 refer to isolated yields (average of
two runs) of compounds estimated to be >95% pure as deter-
mined by 1H NMR and GC analysis or combustion analysis.
(film, cm–1): 3411, 3022, 2937, 2862, 2834, 1600, 1519,
1243, 740. H NMR (300 MHz, CDCl3) d: 7.21–7.18 (m,
1H), 7.09–7.02 (m, 4H), 6.86–6.75 (m, 3H), 6.05 (s, 1H),
3.85 (s, 3H), 2.29 (s, 3H). 13C NMR (75 MHz, CDCl3) d:
147.9, 139.9, 133.9, 131.1, 129.9, 120.9, 119.7, 119.3,
113.8, 110.4, 55.7, 21.0.
1
N-(p-Tolyl)-2,5-dimethylaniline (Table 1, entry 2) (13)
The general procedure was used for the coupling of p-
toluidine with 2-bromo-p-xylene, using DPEphos as the
supporting ligand and a reaction time of 17 h. The title com-
pound was obtained as an orange solid (414 mg, 98%): mp
49–50°C. EI-HRMS calcd. for C15H17N: 211.1361; found:
211.1356 (M+). IR (film, cm–1): 3414, 3020, 2917, 2862,
1610, 1577, 1526, 1511, 814, 800. 1H NMR (300 MHz,
CDCl3) d: 7.06 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 7.5 Hz,
1H), 6.98 (s, 1H), 6.89 (d, J = 8.1 Hz, 2H), 6.68 (d, J =
7.5 Hz, 1H), 5.23 (s, 1H), 2.29 (s, 3H), 2.24 (s, 3H), 2.19 (s,
3H). 13C NMR (75 MHz, CDCl3) d: 141.9, 141.2, 136.5,
130.7, 130.4, 129.9, 124.0, 121.9, 118.8, 118.0, 21.5, 21.0,
17.7.
General procedure
Arylamine (2.40 mmol), PdCl2 (1.8 mg, 0.010 mmol,
0.5 mol%), and bisphosphine (0.015 mmol, 0.75 mol%)
were placed in a dried, resealable Schlenk tube, which was
fitted with a Teflon screwcap, evacuated, and backfilled with
argon. The tube was sealed, and its contents were heated at
80°C until a clear solution formed (ca. 30 min). The tube
was then cooled to room temperature, and the Teflon
screwcap was replaced with a rubber septum. Toluene
(2 mL) was added via syringe, followed by aryl bromide
(2.00 mmol). The resulting solution was stirred for a few
seconds, then the septum was removed. Sodium tert-
butoxide was added, then the septum was replaced. An addi-
tional portion of toluene (2 mL) was added to wash into the
reaction any base adhering to the side of the tube. The tube
was purged with argon for 3 min, then the septum was re-
placed with the Teflon screwcap. The tube was sealed, and
its contents were heated at 80°C with stirring until the start-
ing aryl bromide was completely consumed as judged by GC
analysis. The reaction mixture was then cooled to room tem-
perature, taken up in diethyl ether (50 mL), and washed with
brine (30 mL). The resulting solution was dried over anhy-
drous potassium carbonate, filtered, and concentrated in
vacuo. The crude product was purified by flash column
chromatography on silica gel.
N-(2-Methoxyphenyl)-3,5-dimethylaniline (Table 1, entry
3) (6)
The general procedure was used for the coupling of o-
anisidine with 5-bromo-m-xylene, using DPEphos as the
supporting ligand and a reaction time of 17 h. The title com-
pound was obtained as a pale yellow oil (443 mg, 97%). EI-
HRMS calcd. for C15H17NO: 227.1310; found: 227.1304
(M+). IR (film, cm–1): 3411, 3024, 3001, 2939, 2916, 2855,
2833, 1590, 1520, 1494, 1463, 829, 742. 1H NMR
(300 MHz, CDCl3) d: 7.30–7.27 (m, 1H), 6.87–6.82 (m,
3H), 6.77 (s, 2H), 6.58 (s, 1H), 6.06 (s, 1H), 3.84 (s, 3H),
2.27 (s, 3H), 2.26 (s, 3H). 13C NMR (75 MHz, CDCl3) d:
148.2, 142.7, 139.0, 133.2, 123.1, 120.9, 119.7, 116.4,
114.9, 110.5, 55.8, 21.7.
N-(2-Methoxyphenyl)-2,5-dimethylaniline (Table 1, entry
4) (6, 9c)
The general procedure was used for the coupling of o-
anisidine with 2-bromo-p-xylene, using DPEphos as the
supporting ligand and a reaction time of 4 h. The title com-
pound was isolated as a white solid (424 mg, 93%): mp
88.5–90.5°C. EI-HRMS calcd. for C15H17NO: 227.1310;
found: 227.1306 (M+). IR (film, cm–1): 3409, 3061, 3042,
3003, 2962, 2930, 2833, 1560, 1573, 740. 1H NMR
(300 MHz, CDCl3) d: 7.12 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H),
7.01 (dd, J = 6.9, 2.4 Hz, 1H), 6.88–6.77 (m, 3H), 6.75 (d,
J = 7.6 Hz, 1H), 5.82 (s, 1H), 3.87 (s, 3H), 2.27 (s, 3H),
2.21 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 148.0, 140.6,
N-(p-Tolyl)-o-anisidine (Table 1, entry 1) (13)
The general procedure was used for coupling p-toluidine
with 2-bromoanisole, using DPEphos as the supporting
ligand and a reaction time of 3 h. The title compound was
isolated as a colorless oil (413 mg, 97%). EI-HRMS calcd.
for C14H15NO: 213.1154; found: 213.1158 (M+). IR
© 2001 NRC Canada

Zhang et al.
1803
136.4, 134.0, 130.8, 126.3, 123.1, 120.9, 120.3, 119.2,
114.5, 110.4, 55.8, 21.5, 17.7.
3H). 13C NMR (75 MHz, CDCl3) d: 143.9, 136.0, 135.7,
135.2, 129.3, 128.3, 127.9, 126.9, 118.0, 111.8, 24.5, 21.2,
18.5, 13.5.
2-[3-(N-Methylanilino)phenyl]-1,3-dioxolane (Table 1,
entry 5)
2,6-Diisopropyl-4>-chlorodiphenylamine (Table 1, entry 9)
(6)
The general procedure was used for the coupling of N-
methylaniline with 2-(3-bromophenyl)-1,3-dioxolane, using
Xantphos as the supporting ligand and a reaction time of
4 h. The title compound was isolated as a colorless oil
(470 mg, 92%). EI-HRMS calcd. for C16H17NO2: 255.1259;
found: 255.1264 (M+). IR (film, cm–1): 3058, 3035, 2950,
2884, 2815, 1609, 1595, 1585, 1496, 696. 1H NMR
(300 MHz, CDCl3) d: 7.29–7.21 (m, 3H), 7.12 (m, 1H),
7.06–6.92 (m, 5H), 5.73 (s, 1H), 4.12–3.96 (m, 4H), 3.31 (s,
3H). 13C NMR (75 MHz, CDCl3) d: 149.1, 148.9, 139.0,
129.3, 129.2, 121.7, 121.0, 120.9, 119.1, 117.8, 103.9, 65.4,
40.5. Anal. calcd. for C16H17NO2: C 75.27, H 6.71; found:
C 75.36, H 6.75.
The general procedure was used for the coupling of 2,6-
diisopropylaniline with 4-bromochlorobenzene, using
DPEphos as the supporting ligand and a reaction time of
18 h. The reaction was conducted at 100°C. The title com-
pound was isolated as a red-orange oil (564 mg, 98%). EI-
HRMS calcd. for C18H22ClN: 287.1441; found: 287.1447
(M+). IR (film, cm–1): 3412, 2962, 2928, 2867, 1600, 1587,
1493, 1466, 1304, 817. 1H NMR (300 MHz, CDCl3) d:
7.31–7.19 (m, 3H), 7.06 (d, J = 9.0 Hz, 2H), 6.38 (d, J =
9.0 Hz, 2H), 5.11 (s, 1H), 3.14 (sept, J = 6.8 Hz, 2H), 1.13
(d, J = 6.8 Hz, 12H). 13C NMR (75 MHz, CDCl3) d: 147.6,
146.9, 134.8, 129.2, 127.7, 124.1, 122.3, 114.1, 28.5, 24.1.
N-(3,5-Dimethylphenyl)-benzylamine (Table 1, entry 6)
(14)
2,6-Diisopropyl-2>-methyldiphenylamine (Table 1, entry 10)
(6)
The general procedure was used for the coupling of
benzylamine with 5-bromo-m-xylene, using rac-BINAP as
the supporting ligand and a reaction time of 3 h. The title
compound was isolated as a colorless oil (368 mg, 87%). EI-
HRMS calcd. for C15H17N: 211.1361; found: 211.1354
(M+). IR (film, cm–1): 3409, 3027, 2915, 2856, 1603, 1512,
The general procedure was used for the coupling of 2,6-
diisopropylaniline with 2-methylbromobenzene, using
DPEphos as the supporting ligand and a reaction time of
18 h. The reaction was conducted at 100°C. The title com-
pound was isolated as a light-orange oil (511 mg, 96%). EI-
HRMS calcd. for C19H25N: 267.1987; found: 267.1982
(M+). IR (film, cm–1): 3425, 2961, 2926, 2867, 1606, 1585,
1500, 1464, 1442, 746. 1H NMR (300 MHz, CDCl3) d:
7.31–7.19 (m, 3H), 7.11 (dd, J = 7.5, 1.2 Hz, 1H), 6.93 (td,
J = 7.5, 1.2 Hz, 1H), 6.65 (td, J = 7.5, 1.2 Hz, 1H), 6.11 (dd,
J = 7.5, 1.2 Hz, 1H), 4.89 (s, 1H), 3.10 (sept, J = 6.9 Hz,
2H), 2.33 (s, 3H), 1.16 (d, J = 6.9 Hz, 6H), 1.11 (d, J =
6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3) d: 147.3, 146.1,
135.8, 130.2, 127.2, 127.1, 123.9, 121.4, 117.6, 111.5, 28.5,
25.0, 23.3, 17.9.
1
1494, 1473, 1452, 1337, 1182, 821. H NMR (300 MHz,
CDCl3) d: 7.35–7.21 (m, 5H), 6.36 (s, 1H), 6.25 (s, 2H),
4.26 (s, 2H), 3.84 (br s, 1H), 2.21 (s, 6H). 13C NMR
(75 MHz, CDCl3) d: 148.4, 139.7, 139.0, 128.7, 127.6,
127.2, 119.7, 110.8, 48.5, 21.8.
4-(Diphenylamino)biphenyl (Table 1, entry 7) (15)
The general procedure was used for the coupling of
diphenylamine with 4-bromobiphenyl, using DPEphos as the
supporting ligand and a reaction time of 18 h. The reaction
was conducted at 100°C with 1.0 mol% PdCl2 and 1.5 mol%
DPEphos. The title compound was isolated as white crystals
(553 mg, 86%): mp 111–112°C. EI-HRMS calcd. for
C24H19N: 321.1518; found: 321.1509 (M+). IR (film, cm–1):
2,6-Diisopropyl-2>,6>-dimethyldiphenylamine (Table 1,
entry 11) (6, 9c)
The general procedure was used for the coupling of 2,6-
diisopropylaniline with 2-bromo-m-xylene, except that the
reaction was carried out at 100°C, using 5 mol% PdCl2 and
7.5 mol% DPEphos. The title compound was isolated as a
red-brown oil (514 mg, 91%). EI-HRMS calcd. for C20H27N:
281.2144; found: 281.2150 (M+). IR (film, cm–1): 3433,
1
3058, 3030, 1589, 1519, 1485, 1280, 747, 693. H NMR
(300 MHz, CDCl3) d: 7.58–7.52 (m, 2H), 7.48–7.36 (m,
4H), 7.31–7.20 (m, 5H), 7.12 (d, J = 7.5 Hz, 6H), 7.01 (t,
J = 7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) d: 147.7,
147.2, 140.7, 135.2, 129.4, 128.8, 127.9, 126.9, 126.8,
124.5, 124.0, 123.0.
1
2961, 2927, 2867, 1596, 1472, 1446, 1333, 795. H NMR
(300 MHz, CDCl3) d: 7.15–7.07 (m, 3H), 6.92 (d, J =
7.5 Hz, 2H), 6.70 (t, J = 7.5 Hz, 1H), 4.78 (s, 1H), 3.14
(sept, J = 6.9 Hz, 2H), 1.97 (s, 6H), 1.11 (d, J = 6.9 Hz,
12H). 13C NMR (75 MHz, CDCl3) d: 144.2, 143.2, 138.9,
129.6, 125.7, 124.9, 123.4, 119.7, 28.3, 23.8, 19.7.
2,4,6-Trimethyl-2>-ethyldiphenylamine (Table 1, entry 8)
(6)
The general procedure was used for the coupling of 2,4,6-
trimethylaniline with 2-ethylbromobenzene, using DPEphos
as the supporting ligand and a reaction time of 18 h. The ti-
tle compound was isolated as a tan solid (465 mg, 97%): mp
74–75°C. EI-HRMS calcd. for C17H21N: 239.1674; found:
239.1678 (M+). IR (film, cm–1): 3384, 2965, 2912, 1601,
N-(2-Methoxyphenyl)pyrrolidine (Table 2, entry 1)
The general procedure was used for the coupling of
pyrrolidine with 2-bromoanisole, using 1 as the supporting
ligand and a reaction time of 43 h. The title compound was
isolated as a colorless liquid (0.216 g, 61%). IR (film, cm–1):
1
1582, 1505, 1496, 1454, 1252, 744. H NMR (300 MHz,
1
CDCl3) d: 7.12 (dd, J = 7.2, 1.5 Hz, 1H), 6.94 (td, J = 7.5,
1.2 Hz, 1H), 6.93 (s, 2H), 6.71 (td, J = 7.5, 1.2 Hz, 1H),
6.13 (dd, J = 7.2, 1.5 Hz, 1H), 4.96 (s, 1H), 2.67 (q, J =
7.8 Hz, 2H), 2.30 (s, 3H), 2.13 (s, 6H), 1.35 (t, J = 7.8 Hz,
3060, 2960, 2830, 1504, 1232, 730. H NMR (300 MHz,
CDCl3) d: 6.90–6.85 (m, 3H), 6.82–6.78 (m, 1H), 3.84 (s,
3H), 3.30–3.26 (m, 4H), 1.95–1.91 (m, 4H). 13C (75 MHz,
CDCl3) d: 150.6, 140.0, 121.3, 119.8, 115.6, 111.7, 55.7,
© 2001 NRC Canada

1804
Can. J. Chem. Vol. 79, 2001
1
50.6, 24.8. Anal. calcd. for C11H15NO: C 74.54, H 8.53;
found: C 74.30, H 8.52.
2217, 1606, 1116. H NMR (300 MHz, CDCl3) d: 7.53 (d,
J = 8.7 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 3.88–3.85 (m,
4H), 3.31–3.27 (m, 4H). 13C (75 MHz, CDCl3) d: 153.6,
133.6, 120.0, 114.2, 101.1, 66.6, 47.4. Anal. calcd. for
C11H12N2O: C 70.19, H 6.43; found: C 69.93, H 6.27.
N-(3-Methoxyphenyl)-benzylamine (Table 2, entry 2)
The general procedure was used for the coupling of
benzylamine with 3-bromoanisole, using 1 as the supporting
ligand and a reaction time of 23 h. The title compound was
isolated as a yellow liquid (0.397 g, 93%). IR (film, cm–1):
Acknowledgments
1
2970, 2917, 1590, 1495, 692. H NMR (300 MHz, CDCl3)
This work was supported in part by grants from the Office
of Naval Research and the National Institutes of Health
(GM58160). M.C.H. is grateful to the National Cancer Insti-
tute for support under training grant NCI CI (T32C
A09 112).
d: 7.40–7.27 (m, 5H), 7.08 (t, J = 8.1 Hz, 1H), 6.31–6.25
(m, 2H), 6.21–6.19 (m, 1H), 4.32 (s, 2H), 4.10 (br s, 1H),
3.75 (s, 3H). 13C (75 MHz, CDCl3) d: 160.9, 149.7, 139.4,
130.1, 128.7, 127.6, 127.4, 106.1, 102.7, 98.9, 55.2, 48.4.
Anal. calcd. for C14H15NO: C 78.84, H 7.09; found:
C 78.76, H 7.01.
References
N-(3-Methoxyphenyl)-di-n-butylamine (Table 2, entry 3)
The general procedure was used for the coupling of di-n-
butylamine with 3-bromoanisole, using 1 as the supporting
ligand and a reaction time of 21 h. The title compound was
isolated as a yellow liquid (0.415 g, 88%). IR (film, cm–1):
1. (a) J.P. Wolfe, S. Wagaw, J.-F. Marcoux, and S.L. Buchwald.
Acc. Chem. Res. 31, 805 (1998); (b) J.F. Hartwig. Angew.
Chem. Int. Ed. 37, 2046 (1998); (c) B.Y. Yang and S.L.
Buchwald. J. Organomet. Chem. 576, 125 (1999).
2. (a) F. He, B.M. Foxman, and B.B. Snider. J. Am. Chem. Soc.
120, 6417 (1998); (b) G.J. Tanoury, C.H. Senanayake, R. Hett,
A.M. Kuhn, D.W. Kessler, and S.A. Wald. Tetrahedron Lett.
39, 6845 (1998).
3. (a) E.A. Harwood, S.T. Sigurdsson, N.B.F. Edfeldt, B.R. Reid,
and P.B. Hopkins. J. Am. Chem. Soc. 121, 5081 (1999);
(b) M.K. Lakshman, J.C. Keeler, J.H. Hilmer, and J.Q. Martin.
J. Am. Chem. Soc. 121, 6090 (1999); (c) S. Wagaw, B.H.
Yang, and S.L. Buchwald. J. Am. Chem. Soc. 121, 10251
(1999); (d) O.J. Plante, S.L. Buchwald, and P.H. Seeberger. J.
Am. Chem. Soc. 122, 7148 (2000).
4. (a) L.-C. Liang, R.R. Schrock, W.M. Davis, and D.H.
McConville. J. Am. Chem. Soc. 121, 5797 (1999); (b) R.A.
Singer, J.P. Sadighi, and S.L. Buchwald. J. Am. Chem. Soc.
120, 213 (1998); (c) J.P. Sadighi, R.A. Singer, and S.L.
Buchwald. J. Am. Chem. Soc. 120, 4960 (1998); (d) X.-X.
Zhang, J.P. Sadighi, T.W. Mackewitz, and S.L. Buchwald. J.
Am. Chem. Soc. 122, 7606 (2000); (e) X.-X. Zhang and S.L.
Buchwald. J. Org. Chem. 65, 8027 (2000).
1
2956, 2871, 1609, 1500, 1204, 746. H NMR (300 MHz,
CDCl3) d: 7.10 (t, J = 8.1 Hz, 1H), 6.29–6.25 (m, 1H),
6.21–6.18 (m, 2H), 3.78 (s, 3H), 3.24 (t, J = 7.8 Hz, 4H),
1.61–1.51 (m, 4H), 1.40–1.28 (m, 4H), 0.95 (t, J = 6.9 Hz,
6H). 13C (75 MHz, CDCl3) d: 161.0, 149.7, 129.9, 105.1,
99.7, 98.4, 55.2, 51.0, 29.6, 20.5, 14.2. Anal. calcd. for
C15H25NO: C 76.55, H 10.71; found: C 76.40, H 10.59.
N-(3,5-Dimethylphenyl)-N-ethylaniline (Table 2, entry 4)
The general procedure was used for the coupling of N-
ethylaniline with 5-bromo-m-xylene, using 1 as the support-
ing ligand and a reaction time of 28 h. The title compound
was isolated as a yellow liquid (0.308 g, 68%). IR (film, cm–1):
1
3415, 3027, 2834, 1614, 1162. H NMR (300 MHz, CDCl3)
d: 7.27–7.21 (m, 2H), 6.96–6.90 (m, 3H), 6.64–6.63 (m,
3H), 3.75 (q, J = 7.2 Hz, 2H), 2.26 (s, 6H), 1.21 (t, J =
7.2 Hz, 3H). 13C (75 MHz, CDCl3) d: 148.0, 147.7, 139.0,
129.3, 123.6, 120.5, 120.3, 119.5, 46.6, 21.6, 12.9. Anal.
calcd. for C16H19N: C 85.29, H 8.50; found: C 85.39,
H 8.49.
5. J.P. Wolfe and S.L. Buchwald. J. Org. Chem. 65, 1144 (2000).
6. J.P. Sadighi, M.C. Harris, and S.L. Buchwald. Tetrahedron
Lett. 39, 5327 (1998).
7. Y. Guari, D.S. van Es, J.N.H. Reek, P.C.J. Kamer, and
P.W.N.M. van Leeuwen. Tetrahedron Lett. 40, 3789 (1999).
8. M.S. Driver and J.F. Hartwig. J. Am. Chem. Soc. 118, 7217
(1996).
N-(4-tert-Butylphenyl)morpholine (Table 2, entry 5)
The general procedure was used for the coupling of
morpholine with 1-bromo-4-tert-benzene, using 1 as the sup-
porting ligand and a reaction time of 21 h. The title com-
pound was isolated as a yellow solid (0.403 g, 92%): mp
9. (a) D.W. Old, J.P. Wolfe, and S.L. Buchwald. J. Am. Chem.
Soc. 120, 9722 (1988); (b) J.P. Wolfe and S.L. Buchwald.
Angew. Chem. Int. Ed. 38, 2413 (1999); (c) J.P. Wolfe, H.
Tomori, J.P. Sadighi, J. Yin, and S.L. Buchwald. J. Org. Chem.
65, 1158 (2000); (d) J.P. Wolfe, R.A. Singer, B.H. Yang, and
S.L. Buchwald. J. Am. Chem. Soc. 121, 9550 (1999); (e) J.M.
Fox, X. Huang, A. Chieffi, and S.L. Buchwald. J. Am. Chem.
Soc. 122, 1360 (2000); (f) A. Aranyos, D.W. Old, A.
Kiyomori, J.P. Wolfe, J.P. Sadighi, and S.L. Buchwald. J. Am.
Chem. Soc. 121, 4369 (1999).
10. (a) M. Nishiyama, T. Yamamoto, and Y. Koie. Tetrahedron
Lett. 39, 617 (1998); (b) T. Yamamoto, M. Nishiyama, and Y.
Koie. Tetrahedron Lett. 39, 2367 (1998); (c) B.C. Hamann and
J.F. Hartwig. J. Am. Chem. Soc. 120, 7369 (1998); (d) J.F.
Hartwig, M. Kawatsura, S.I. Hauck, K.H. Shaughnessy,
and L.M. Alcazar-Roman. J. Org. Chem. 64, 5575 (1999).
11. V. Bavetsias and E.A. Henderson. J. Chem. Res.-S, 418 (2000).
1
53–55°C. IR (film, cm–1): 2958, 2853, 1612, 1118. H NMR
(300 MHz, CDCl3) d: 7.31 (d, J = 8.7 Hz, 2H), 6.86 (d, J =
9.0 Hz, 2H), 3.87–3.84 (m, 4H), 3.15–3.12 (m, 4H), 1.30 (s,
9H). 13C (75 MHz, CDCl3) d: 149.0, 142.9, 126.1, 115.5,
67.1, 49.7, 34.1, 31.6. Anal. calcd. for C14H21NO: C 76.67,
H 9.65; found: C 76.56, H 9.57.
N-(4-Cyanophenyl)morpholine (Table 2, entry 6)
The general procedure was used for the coupling of
morpholine with 4-bromobenzonitrile, using 2 as the sup-
porting ligand, K3PO4 as the base, DME as the solvent, and
a reaction time of 28 h. The reaction was conducted at
100°C. The title compound was isolated as a yellow solid
(0.287 g, 76%): mp 73–75°C. IR (film, cm–1): 2980, 2831,
© 2001 NRC Canada

Zhang et al.
1805
12. B.C. Hamann and J.F. Hartwig. J. Am. Chem. Soc. 120, 3694
14. J.P. Wolfe, S. Wagaw, and S.L. Buchwald. J. Am. Chem. Soc.
(1998).
118, 7215 (1996).
13. R.J. Sundberg and K.B. Sloan. J. Org. Chem. 38, 2052
15. J. Piccard and F. de Montmollin. Helv. Chim. Acta, 6, 1011
(1973).
(1923).
© 2001 NRC Canada