Efficient palladium-catalyzed amination of aryl chlorides using dicyclo-hexylamino[(2,6-dimethyl)morpholino]phenylphosphine as a PN2 ligand

Article abstract of DOI:10.1055/s-0028-1083337

The palladium-catalyzed amination of aryl chlorides with various amines is accomplished using dicyclohexyl- amino[(2,6-dimethyl)morpholino]phenylphosphine as a bulky electron-rich monoaryl phosphine ligand. The optimized reaction conditions required the use of 1 mol% each of catalyst and ligand. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083337

PAPER
815
Efficient Palladium-Catalyzed Amination of Aryl Chlorides Using Dicyclo-
hexylamino[(2,6-dimethyl)morpholino]phenylphosphine as a PN2 Ligand
Efficient
Palla
o
dium-Cataly
n
g
onof
A
ryl
C
-
hloridesEun Park,a Seung Beom Kang,a Kwang-Ju Jung,a Ju-Eun Won,a Sang-Gyeong Lee,*b Yong-Jin Yoon*a
a
Department of Chemistry & Environmental Biotechnology National Core Research Center, Research Institute of Natural Science,
Graduate School for Materials and Nanochemistry, Gyeongsang National University, Jinju 660-701, Korea
b
Department of Chemistry & Research Institute of Natural Science, Graduate School for Materials and Nanochemistry, Gyeongsang
National University, Jinju 660-701, Korea
Fax +82(55)7610244; E-mail: yjyoon@gnu.ac.kr
Received 16 September 2008; revised 14 October 2008
aryl chlorides. The amination of aryl chlorides with
amines, however, did not occur when using ligands 3 and
4. In order to increase the efficacy of these ligands for the
amination of aryl chlorides, we designed ligand 1 as a
novel stable monoaryl-based PN2 ligand containing a di-
cyclohexylamino group as an electron-rich and sterically
hindered alkyl group (Figure 1).
Abstract: The palladium-catalyzed amination of aryl chlorides
with various amines is accomplished using dicyclohexyl-
amino[(2,6-dimethyl)morpholino]phenylphosphine as a bulky elec-
tron-rich monoaryl phosphine ligand. The optimized reaction
conditions required the use of 1 mol% each of catalyst and ligand.
Key words: Buchwald–Hartwig amination, palladium-catalyzed
amination, PN2 ligand, palladium, C–N coupling
O
O
O
An important accomplishment in the field of catalysis has
been the discovery of the palladium-catalyzed carbon–
nitrogen bond-forming process commonly known as the
Buchwald–Hartwig amination reaction.1 The palladium-
catalyzed formation of C–N bonds is also a rapidly ex-
panding area of research.1a,2 Since the first general proce-
dures were discovered,3 efforts have been made towards
increasing the substrate scope and efficiency. Although
the use of alternative bases or solvents can be beneficial,
electronic and steric tuning of the supporting ligand has
the most impact on increasing the efficacy and reactivity
in these processes.1c,2 A major advance in this field was
the ability to activate the notoriously unreactive but rela-
tively cheap aryl chlorides. Not surprisingly, a plethora of
catalyst systems featuring a palladium-bound ligand are
now available for accomplishing the aforementioned
transformation with aryl chlorides. Typically, electron-
rich sterically hindered ligands belonging to the trialkyl-
phosphine,4–6 ferrocenyldialkylphosphine,7 aryldialkyl-
phosphine,8–10 phosphinous acid,11 palladacycle,12,13
heterocyclic carbene14–16 or triaminophosphine (PN3)1d,17–20
classes have been investigated for these reactions. While
several ligands exhibiting improved abilities in assisting
palladium-catalyzed aryl aminations are now available, a
general solution has not been achieved for the metal-cata-
lyzed aryl aminations of all substrates. Thus, as part of our
ongoing efforts to develop efficient methods for the ami-
nation of aryl chlorides, we attempted to design a novel
and efficient ligand for this purpose. In a previous paper,21
we reported dimorpholinophenylphosphine (3) and
di(2,6-dimethylmorpholino)phenylphosphine (4) as effi-
cient ligands for the Suzuki–Miyaura coupling reaction of
N
N
N
N
N
N
P
P
P
O
1
2
3
O
O
N
N
N
N
N
N
P
P
P
4
6
5
Figure 1 Bulky electron-rich ligands used in the amination of aryl
chlorides
We also selected ligands 5 and 6 as monophenyl-based
PN2 ligands for the Buchwald–Hartwig amination reac-
tion. Ligand 6 is commercially available, and ligands 222
and 3–5 were prepared by literature methods.21,23 Ligand
1 was synthesized from dichlorophenylphosphine (7) un-
der similar conditions. Herein, we report our results on the
amination of aryl chlorides with various amines using
ligand 1 as a novel PN2 ligand.
Reaction of dichlorophenylphosphine (7) with dicyclo-
hexylamine (8) and then 2,6-dimethylmorpholine (10) in
the presence of triethylamine in refluxing dichlo-
romethane gave a mixture of ligands 1 and 11 which was
separated by silica gel column chromatography
(Scheme 1). The structures of compounds 1 and 11 were
established by X-ray crystallographic analysis,24,25 and IR
SYNTHESIS 2009, No. 5, pp 0815–0823
x
x
.
x
x
.2
0
0
9
Advanced online publication: 27.01.2009
DOI: 10.1055/s-0028-1083337; Art ID: F19708SS
© Georg Thieme Verlag Stuttgart · New York

816
S. E. Park et al.
PAPER
O
N
N
P
Cl
N
P
HN
O
10
Cl
Cl
1
Et3N
+
P
HN
CH2Cl2
Et3N
CH2Cl2
O
O
N
P
8
9
7
N
11
Scheme 1 Synthesis of ligands 1 and 11
and NMR spectroscopy. According to X-ray crystallo-
graphic data, compound 1 is the R-form (Figure 2),
whereas compound 11 is the S-form (Figure 3). Ligand 1
was oxidized to compound 11 under our reaction condi-
tions by aerial oxidation (according to TLC studies).
When this reaction was carried out under an argon atmo-
sphere, only ligand 1 was obtained in 85% yield.
Figure 3 ORTEP diagram of ligand 11
Table 1 Screening of Ligandsa
Cl
NH2
PdCl2, ligand,
KOt-Bu
+
toluene, reflux
N
H
Entry
Ligand
Time (h)
Yield (%)b
Figure 2 ORTEP diagram of ligand 1
1
2
3
4
5
6
7
1
7
96
47
90
–
Initial reaction of chlorobenzene with aniline using palla-
dium chloride (1 mol%), ligand 1 (1 mol%), potassium
tert-butoxide (1.35 equiv) in toluene at reflux gave the
product of coupling in 96% isolated yield (entry 1,
Table 1). We also evaluated the efficiency of ligands 2–6
and 11 under the same conditions. Amination of chlo-
robenzene with aniline using ligand 2 or 11 afforded the
expected coupling product in 90% and 47% yield, respec-
tively. In contrast, the coupling reaction did not take place
when ligands 3–6 were used. Therefore, we selected 1 as
the ligand for this coupling reaction.
11
2
24
24
24
24
24
24
3
4
–
5
–
6
–
a Reaction conditions: PhCl (5.0 mmol, 1 equiv), PhNH2 (5.5 mmol,
1.1 equiv), ligand (0.05 mmol, 1 mol%), KOt-Bu (6.75 mmol, 1.35
equiv), PdCl2 (0.05 mmol, 1 mol%), toluene (30 mL), reflux.
b Isolated yield after silica gel column chromatography.
Next, we investigated the effect of various palladium
compounds on the reaction between chlorobenzene and
Synthesis 2009, No. 5, 815–823 © Thieme Stuttgart · New York

PAPER
Efficient Palladium-Catalyzed Amination of Aryl Chlorides
817
aniline. Among the palladium compounds explored, pal- Toluene was found to be the best solvent among those in-
ladium chloride gave the fastest reaction rate and excel- vestigated (toluene, 1,4-dioxane, EtOAc, MeCN, THF
lent yields; Pd2(dba)3 and Pd(OAc)2 were also suitable and n-hexane) (Table 4). We next optimized the amount
catalysts (entries 1–3, Table 2). However, reaction using of catalyst and ligand required for the coupling of chlo-
Pd(dpa)2 gave the coupled product in 71% yield after 31 h robenzene and aniline. The following system proved to be
(entry 4, Table 2). The coupling reaction did not occur the best: chlorobenzene (1 equiv), aniline (1.1 equiv),
when 10% Pd/C was used as the catalyst.
palladium chloride (1 mol%), ligand 1 (1 mol%), potassi-
um tert-butoxide (1.35 equiv) in toluene (entry 3,
Table 5).
Table 2 Screening of Palladium Catalystsa
Cl
NH2
Pd catalyst, 1
KOt-Bu
Table 4 Screening of Solventsa
+
Cl
NH2
PdCl2, 1
KOt-Bu
toluene, reflux
N
H
+
Yield (%)b
solvent, reflux
N
H
Entry
Pd catalyst
Pd2(dba)3
PdCl2
Time (h)
1
2
3
4
5
8
89
96
87
71
–
Entry
Solvent
toluene
1,4-dioxane
EtOAc
Time (h)
Yield (%)b
7
1
2
3
4
5
6
7
96
95
–
Pd(OAc)2
Pd(dpa)2
10% Pd/C
10
31
24
8
10
10
12
12
MeCN
–
a Reaction conditions: PhCl (5.0 mmol, 1.0 equiv), PhNH2 (5.5 mmol,
1.1 equiv), ligand 1 (0.05 mmol, 1 mol%), KOt-Bu (6.75 mmol, 1.35
equiv), Pd catalyst (0.05 mmol, 1 mol%), toluene (30 mL), reflux.
b Isolated yield after silica gel column chromatography.
THF
–
n-hexane
–
a Reaction conditions: PhCl (5.0 mmol, 1.0 equiv), PhNH2 (5.5 mmol,
1.1 equiv), ligand 1 (0.05 mmol, 1 mol%), KOt-Bu (6.75 mmol, 1.35
equiv), PdCl2 (0.05 mmol, 1 mol%), solvent (30 mL), reflux.
b Isolated yield after silica gel column chromatography.
We investigated a variety of bases and solvents for the
aforementioned coupling reaction catalyzed by the palla-
dium chloride and ligand 1 system. Among the bases ex-
plored, potassium tert-butoxide gave the best result (entry
1, Table 3) whilst Cs2CO3, K2HPO4, Na2CO3, K2CO3,
Et3N and DMAP failed to provide complete conversion
even after 20 hours (entries 2–7, Table 3).
Table 5 Optimization of the Amount of Ligand and Catalyst for the
Coupling Reactiona
Cl
NH2
PdCl2, 1
KOt-Bu
+
Table 3 Screening of Basesa
toluene, reflux
N
H
Cl
NH2
PdCl2, 1
Entry
Ligand 1
(mol%)
PdCl2
(mol%)
Time (h)
Yield (%)b
base
+
toluene, reflux
N
H
1
2
3
4
5
6
7
8
1
0.5
1
8
83
Entry
Base
Time (h)
Yield (%)b
0.5
1
14
6
40
1
2
3
4
5
6
7
KOt-Bu
Cs2CO3
K2HPO4
Na2CO3
K2CO3
Et3N
7
96
1
96
20
20
20
20
20
20
trace
trace
12c
–
2
1
12
18
18
7
44c
24d
19d
62c
72c
5
1
10
1
1
2
13c
–
1
3
5
a Reaction conditions: PhCl (5.0 mmol, 1.0 equiv), PhNH2 (5.5 mmol,
1.1 equiv), ligand 1, KOt-Bu (6.75 mmol, 1.35 equiv), PdCl2, toluene
(30 mL), reflux.
DMAP
a Reaction conditions: PhCl (5.0 mmol, 1.0 equiv), PhNH2 (5.5 mmol,
1.1 equiv), ligand 1 (0.05 mmol, 1 mol%), base (6.75 mmol, 1.35
equiv), PdCl2 (0.05 mmol, 1 mol%), toluene (30 mL), reflux.
b Isolated yield after silica gel column chromatography.
c Unreacted starting materials were also recovered.
b Isolated yield after silica gel column chromatography.
c Homocoupling product of PhCl was also obtained.
d Unreacted starting materials were also recovered.
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818
S. E. Park et al.
PAPER
With the optimized conditions in hand, we next evaluated The coupling of chlorobenzene with alkylamines such as
the scope of the coupling of aryl chlorides with various benzylamines or phenethylamine using our optimized
amines (Table 6). Chlorobenzenes containing electron- system gave the corresponding mono- and double-
donating groups such as methyl and methoxy underwent coupled products, except for 1-phenylethanamine and cy-
rapid coupling with aniline (entries 1 and 2, Table 6), clohexylamine (entries 10–14, Table 6), whereas the cou-
whereas the coupling reaction of 1-chloro-4-nitrobenzene pling reaction of chlorobenzenes with arylamines
containing an electron-withdrawing group was slow afforded only the mono-coupled products (entries 1–9,
(entry 3, Table 6). The coupling of 2-chloroquinoline with Table 6). The coupling reaction of chlorobenzene with
aniline using our system also gave the corresponding C– morpholine, piperidine, n-butylamine and tert-butylamine
N coupling product in 60% yield (entry 8, Table 6).
under our optimized conditions gave the corresponding
C–N coupled products (entries 15–18, Table 6) in moder-
ate to excellent yields.
Table 6 Palladium-Catalyzed Amination of Aryl Chloridesa
PdCl2, 1
KOt-Bu
R1R2NH
ArNR1R2
+
ArCl
toluene, reflux
Entry
1
Aryl chloride
Amine
Time (h)
12
Product
Yield (%)b
74c
H
Me
N
Me
Cl
NH2
NH2
NH2
NH2
H
MeO
O2N
NC
Cl
MeO
O2N
NC
N
2
3
4
5
6
7
5
48
10
8
79
8c
H
Cl
N
H
Cl
N
89
89
84
88
H
N
Cl
Me
NH2
Me
MeO
Cl
PhO
Me
NH2
MeO
NH
OPh
Me
22
13
NH2
MeO
Cl
MeO
NH
NH2
NH2
8
9
18
24
60
N
N
H
Cl
N
N
H
N
N
Cl
30c
N
N
NH2
H
Cl
N
10
5
45
34
N
Synthesis 2009, No. 5, 815–823 © Thieme Stuttgart · New York

PAPER
Efficient Palladium-Catalyzed Amination of Aryl Chlorides
819
Table 6 Palladium-Catalyzed Amination of Aryl Chloridesa (continued)
PdCl2, 1
KOt-Bu
R1R2NH
ArNR1R2
+
ArCl
toluene, reflux
Entry
Aryl chloride
Amine
Time (h)
Product
Yield (%)b
H
N
NH2
Cl
11
32
22
20
N
NH2
12
13
18
5
60
47
Cl
Cl
H
N
NH
NH2
26
N
H
N
14
15
16
17
18
2
35
4
78
72
90
73
60
Cl
Cl
Cl
Cl
Cl
NH2
O
NH
O
N
N
NH
n-BuNH2
t-BuNH2
10
18
NH(n-Bu)
NH(t-Bu)
a Reaction conditions: aryl chloride (5.0 mmol, 1.0 equiv), amine (5.5 mmol, 1.05 equiv), ligand 1 (0.05 mmol, 1 mol%), KOt-Bu (6.75 mmol,
1.35 equiv), PdCl2 (0.05 mmol, 1 mol%), toluene (30 mL), reflux.
b Isolated yield after silica gel column chromatography.
c Unreacted starting materials were also recovered.
The structures of all the products were established by IR high temperature, and is prepared easily from cheap and
and 1H and 13C NMR spectroscopy and elemental analy- commercially available dichlorophenylphosphine.
sis.
In conclusion, we have demonstrated the efficiency of
ligand 1 as a new, asymmetric PN2 ligand for the palladi-
um-catalyzed amination of aryl chlorides. Ligand 1 toler-
ates a wide variety of aryl and aliphatic amines and
promotes formation of the corresponding N-aryl and N,N-
diarylamines. It is stable in air and in organic solvents at
Melting points were determined with a Thomas-Hoover capillary
apparatus and are uncorrected. The 1H and 13C NMR spectra were
recorded on a Bruker FT-NMR DRX 300 spectrometer at 300 MHz
and 75 MHz, respectively, with chemical shift (d) values reported in
ppm relative to an internal standard (TMS). IR spectra were ob-
tained on an Hitachi 270-50 or a Mattson Genesis Series FT-IR
spectrophotometer. Elemental analyses were performed with a
Synthesis 2009, No. 5, 815–823 © Thieme Stuttgart · New York

820
S. E. Park et al.
PAPER
Perkin-Elmer 240C apparatus. X-ray diffraction data were obtained
using a Bruker SMART diffractometer equipped with a graphite
monochromated MoKa (l = 0.71073 Å) radiation source and a
CCD detector. Open-bed column chromatography was carried out
on silica gel (70–230 mesh, Merck) using gravity flow. Ligand 6 is
commercially available, and ligands 2–5 were prepared by literature
methods.21,23
1H NMR (300 MHz, CDCl3): d = 1.00–1.28 (m, 10 H), 1.49–1.88
(m, 16 H), 2.64–2.74 (m, 4 H), 3.18 (dd, J = 2.7, 2.4 Hz, 2 H), 3.94–
4.03 (m, 2 H), 7.24–7.63 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 17.9, 25.7, 26.6, 26.8, 36.0, 53.5,
53.6, 66.4, 67.1, 127.3, 128.19, 128.23, 131.1, 131.3, 141.6, 141.7.
Anal. Calcd for C24H39N2O2P: C, 68.87; H, 9.39; N, 6.69. Found: C,
68.91; H, 9.43; N, 6.72.
Ligands 1 and 11
C–N Coupling Reaction of Amines and Aryl Chlorides; General
Procedure
Method A: A solution of dicyclohexylamine (8) (3.35 g, 18.5
mmol) and Et3N (2.06 g, 20.4 mmol) in CH2Cl2 (10 mL) was slowly
added dropwise to dichlorophenylphosphine (7) (3 g, 16.8 mmol) in
CH2Cl2 (100 mL) with stirring at room temperature. The mixture
was stirred for 30 min at r.t. Next, a solution of 2,6-dimethylmor-
pholine (10) (2.06 g, 20.4 mmol) and Et3N (2.06 g, 20.4 mmol) in
CH2Cl2 (10 mL) was slowly added. The resulting mixture was heat-
ed at reflux for 26 h until 1-chloro-N,N-dicyclohexyl-1-phenylphos-
phine (9) had been consumed (TLC monitoring). After evaporating
the solvent under reduced pressure, the resulting residue was tritu-
rated with n-hexane (100 mL), filtered and washed with n-hexane.
The combined filtrate was evaporated under reduced pressure. The
resulting residue was purified by open-bed silica gel column chro-
matography (n-hexane–EtOAc, 10:1). Fractions containing the
ligand 1 [Rf = 0.66 (n-hexane–EtOAc, 5:1)] were combined and
evaporated under reduced pressure to give pure compound 1 in 70%
yield; mp 132–136 °C. Fractions containing compound 11 [Rf =
0.62 (n-hexane–EtOAc, 5:1)] were combined and evaporated under
reduced pressure to give pure dicyclohexylamino[(2,6-dimeth-
yl)morpholino]phenylphosphine oxide (11) in 10% yield; mp 161–
165 °C.
A solution of aryl chloride (5 mmol), amine (5.5 mmol), PdCl2 (1
mol%), ligand 1 (1 mol%) and KOt-Bu (6.7 mmol, 1.35 equiv) in
anhydrous toluene (30 mL) was heated at reflux until all the starting
chloride had been consumed (TLC monitoring). The reaction mix-
ture was then cooled to r.t., filtered through a pad of Celite-545, and
washed with EtOAc. The filtrate was evaporated under reduced
pressure and the resulting residue was purified by flash chromatog-
raphy on silica gel (n-hexane–EtOAc, 5:1) to afford the correspond-
ing C–N coupled product.
Diphenylamine
Mp 53–54 °C (Lit.26 mp 52–53 °C); Rf = 0.57 (n-hexane–EtOAc,
3:1).
IR (KBr): 3392, 3318, 1602, 1486, 1324, 740 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.60 (br s, 1 H, NH, D2O exch.),
6.87–6.93 (m, 2 H), 7.01–7.04 (m, 4 H), 7.19–7.26 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 118.0, 121.1, 129.4, 143.3.
Anal. Calcd for C12H11N: C, 85.17; H, 6.55; N, 8.28. Found: C,
85.20; H, 6.57; N, 8.30.
Method B: A solution of dicyclohexylamine (8) (3.35 g, 18.5
mmol) and Et3N (2.06 g, 20.4 mmol) in CH2Cl2 (10 mL) was slowly
added dropwise to dichlorophenylphosphine (7) (3 g, 16.8 mmol) in
CH2Cl2 (100 mL) with stirring at room temperature under an argon
atmosphere. The mixture was refluxed for 30 min after which a so-
lution of 2,6-dimethylmorpholine (10) (2.06 g, 20.4 mmol) and
Et3N (2.06 g, 20.4 mmol) in CH2Cl2 (10 mL) was slowly added un-
der an argon atmosphere. The resulting reaction mixture was re-
fluxed for 20 h. After evaporating the solvent under reduced
pressure, the resulting residue was triturated with n-hexane (100
mL), filtered and washed with n-hexane. The combined filtrate was
evaporated under reduced pressure and the resulting residue was pu-
rified by open-bed silica gel column chromatography (n-hexane–
EtOAc, 10:1). Fractions containing ligand 1 [Rf = 0.66 (n-hexane–
EtOAc, 5:1)] were combined and evaporated under reduced pres-
sure to give pure compound 1 in 85% yield.
4-Methyl-N-phenylaniline
Mp 87–88 °C; Rf = 0.74 (n-hexane–EtOAc, 5:1).
IR (KBr): 3400, 3010, 2912, 1596, 1508, 1304, 744 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.29 (s, 3 H), 5.55 (br s, 1 H, NH,
D2O exch.), 6.84–6.89 (m, 1 H), 6.97–7.00 (m, 4 H), 7.06–7.08 (m,
2 H), 7.19–7.25 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 20.7, 117.0, 119.0, 120.4, 129.3,
129.9, 131.0, 140.4, 144.0.
Anal. Calcd for C13H13N: C, 85.21; H, 7.15; N, 7.64. Found: C,
85.24; H, 7.18; N, 7.67.
4-Methoxy-N-phenylaniline
Mp 99–100 °C (Lit.27 mp 101–102 °C); Rf = 0.48 (n-hexane–
EtOAc, 2:1).
Dicyclohexylamino[(2,6-dimethyl)morpholino]phenylphos-
phine (1)
IR (KBr): 3428, 3056, 2992, 2950, 1600, 1502, 1300, 1242, 1038,
744 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.79 (s, 3 H), 5.46 (br s, 1 H, NH,
D2O exch.), 6.80–6.91 (m, 5 H), 7.05–7.08 (m, 2 H), 7.18–7.23 (m,
2 H).
13C NMR (75 MHz, CDCl3): d = 55.6, 114.7, 115.7, 119.6, 122.2,
129.3, 135.8, 145.2, 155.4.
IR (KBr): 3422, 3068, 3050, 2969, 2925, 2848, 2818, 1447, 1372,
1316, 1233, 1162, 1138, 1111, 1077, 1051, 1006, 970 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.07–1.28 (m, 12 H), 1.54–1.61
(m, 6 H), 1.70–1.84 (m, 10 H), 2.64–2.72 (m, 4 H), 3.15–3.19 (m, 2
H), 7.23–7.26 (m, 1 H), 7.30–7.38 (m, 2 H), 7.54–7.64 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 17.9, 18.0, 18.9, 19.0, 25.8, 26.6,
26.8, 35.5, 35.9, 52.3, 52.4, 53.4, 53.5, 53.7, 56.3, 56.7, 66.9, 67.1,
72.9, 73.0, 73.2, 127.20, 127.22, 127.27, 127.29, 128.13, 128.17,
128.23, 131.1, 131.3, 141.3, 141.4, 141.7.
Anal. Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C,
78.38; H, 6.60; N, 7.05.
4-Anilinobenzonitrile
Mp 134–135 °C; Rf = 0.08 (n-hexane–EtOAc, 5:1).
Anal. Calcd for C24H39N2OP: C, 71.61; H, 9.77; N, 6.96. Found: C,
71.65; H, 9.81; N, 6.99.
IR (KBr): 3246, 2248, 1634, 1600, 1390, 1098 cm–1.
Dicyclohexylamino[(2,6-dimethyl)morpholino]phenylphos-
phine oxide (11)
1H NMR (300 MHz, CDCl3): d = 4.81 (br s, 1 H, NH, D2O exch.),
6.95–6.99 (m, 2 H), 7.04–7.10 (m, 1 H), 7.36–7.43 (m, 4 H), 7.81–
7.84 (m, 2 H).
IR (KBr): 3049, 2849, 1715, 1447, 1371, 1149, 1113, 1003, 968,
901, 746, 700, 494 cm–1.
Synthesis 2009, No. 5, 815–823 © Thieme Stuttgart · New York

PAPER
Efficient Palladium-Catalyzed Amination of Aryl Chlorides
821
13C NMR (75 MHz, CDCl3): d = 121.5, 123.2, 128.2, 128.7, 129.6,
130.5, 134.2, 136.6, 149.3.
Anal. Calcd for C20H19N: C, 87.87; H, 7.01; N, 5.12. Found: C,
87.80; H, 7.05; N, 5.17.
Anal. Calcd for C13H10N2: C, 80.39; H, 5.19; N, 14.42. Found: C,
80.38; H, 5.19; N, 14.39.
N-(1-Phenylethyl)aniline
Colorless oil; Rf = 0.74 (n-hexane–EtOAc, 5:1).
N-Phenylquinolin-2-amine
Mp 162–163 °C; Rf = 0.78 (n-hexane–EtOAc, 2:1).
IR (KBr): 3426, 3056, 3044, 2996, 1606, 1504, 1320, 750, 698
cm–1.
IR (KBr): 3443, 3057, 3045, 1593, 1504, 1423, 1344, 1328, 1294,
823, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.00 (br s, 1 H, NH, D2O exch.),
7.14–7.91 (m, 11 H).
13C NMR (75 MHz, CDCl3): d = 111.9, 120.7, 123.1, 123.2, 124.2,
126.7, 127.6, 129.3, 129.9, 137.8, 140.4, 147.8, 154.7.
1H NMR (300 MHz, CDCl3): d = 1.69 (d, J = 6.7 Hz, 3 H, CH3), 4.21
(br s, 1 H, NH, D2O exch.), 4.69 (q, J = 6.7 Hz, 1 H) 6.72–6.76 (m,
2 H), 6.89–6.92 (m, 1 H), 7.30–7.60 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 25.2, 53.7, 113.6, 117.5, 126.1,
127.1, 128.7, 128.9, 145.5, 147.6.
Anal. Calcd for C14H15N: C, 85.24; H, 7.66; N, 7.10. Found: C,
85.21; H, 7.64; N, 7.09.
Anal. Calcd for C15H12N2: C, 81.79; H, 5.49; N, 12.72. Found: C,
81.78; H, 5.47; N, 12.71.
N-(2-Phenylethyl)aniline
Mp 46–47 °C; Rf = 0.65 (n-hexane–EtOAc, 2:1).
N-Benzylaniline
Mp 83–85 °C; Rf = 0.65 (n-hexane–EtOAc, 10:1).
IR (KBr): 3405, 3082, 3052, 3023, 2927, 2856, 1599, 1504, 1318,
1261, 1179, 748, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.36 (t, J = 7.0 Hz, 2 H), 3.84 (t,
J = 7.0 Hz, 2 H), 4.09 (br s, 1 H, NH, D2O exch.), 7.08 (d, J = 7.7
Hz, 2 H), 7.23 (t, J = 7.3 Hz, 1 H), 7.66–7.75 (m, 5 H), 7.79–7.84
(m, 2 H).
IR (KBr): 3417, 3082, 3052, 3024, 2919, 2850, 1601, 1504, 1451,
1322, 1269, 1253, 749, 694 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.84 (br s, 1 H, NH, D2O exch.),
4.23 (s, 2 H), 6.56 (d, J = 8.7 Hz, 2 H), 6.68 (t, J = 7.5 Hz, 1 H),
7.09–7.15 (m, 2 H), 7.23–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 48.4, 113.0, 117.4, 127.4, 127.7,
128.8, 129.4, 139.6, 139.6, 148.3.
13C NMR (75 MHz, CDCl3): d = 35.7, 45.3, 113.3, 117.7, 126.7,
128.9, 129.1, 129.6, 139.7, 148.3.
Anal. Calcd for C14H15N: C, 85.24; H, 7.66; N, 7.10. Found: C,
85.25; H, 7.69; N, 7.13.
Anal. Calcd for C13H13N: C, 85.21; H, 7.15; N, 7.64. Found: C,
85.25; H, 7.20; N, 7.70.
N-Phenyl-N-(2-phenylethyl)aniline
Mp 46–47 °C; Rf = 0.71 (n-hexane–EtOAc, 2:1).
N-Benzyl-N-phenylaniline
Mp 84–86 °C; Rf = 0.71 (n-hexane–EtOAc, 10:1).
IR (KBr): 3082, 3023, 2927, 2861, 1587, 1494, 1360, 1241, 1176,
745, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.95 (t, J = 7.8 Hz, 2 H), 3.93 (t,
J = 7.8 Hz, 2 H), 6.92–6.92 (m, 6 H), 7.17–7.31 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 33.8, 54.1, 121.0, 126.4, 127.2,
128.5, 128.6, 128.9, 129.0, 129.4, 139.5, 147.8.
IR (KBr): 3077, 3054, 3022, 2921, 2850, 1584, 1494, 1449, 1355,
1255, 1231, 747, 694 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.96 (m, 2 H), 6.86–6.92 (m, 2 H),
7.05 (d, J = 8.7 Hz, 4 H), 7.17–7.32 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 56.5, 120.8, 125.5, 123.7, 127.0,
128.4, 128.7, 129.4, 130.1, 139.4, 148.2.
Anal. Calcd for C20H19N: C, 87.87; H, 7.01; N, 5.12. Found: C,
87.90; H, 7.11; N, 5.18.
Anal. Calcd for C19H17N: C, 87.99; H, 6.61; N, 5.40. Found: C,
88.01; H, 6.65; N, 5.43.
4-Phenylmorpholine
N-(4-Methylbenzyl)aniline
Mp 38–40 °C; Rf = 0.67 (n-hexane–EtOAc, 5:1).
Mp 51–53 °C (Lit.26 mp 51–54 °C); Rf = 0.55 (n-hexane–EtOAc,
5:1).
IR (KBr): 3413, 3085, 3039, 3011, 2913, 1600, 1509, 1434, 1321,
1266, 1174, 740, 685, 474 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.28 (s, 3 H), 3.80 (br s, 1 H, NH,
D2O exch.), 4.14 (s, 2 H), 6.52 (d, J = 7.8 Hz, 2 H), 6.67 (t, J = 7.5
Hz, 1 H), 7.07–7.19 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 21.5, 48.3, 113.2, 117.8, 127.8,
129.6, 129.7, 136.8, 137.1, 148.6.
IR (KBr): 3416, 3062, 2970, 2865, 2826, 1600, 1494, 1444, 1222,
1110, 920, 864 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.12–3.16 (m, 4 H), 3.83–3.86 (m,
4 H), 6.85–6.92 (m, 3 H), 7.23–7.30 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 49.4, 67.0, 115.7, 120.1, 129.2,
151.3.
Anal. Calcd for C10H13NO: C, 73.59; H, 8.03; N, 8.58. Found: C,
73.60; H, 8.01; N, 8.55.
Anal. Calcd for C14H15N: C, 85.24; H, 7.66; N, 7.10. Found: C,
85.27; H, 7.70; N, 7.13.
N-Cyclohexylaniline
Liquid; Rf = 0.78 (n-hexane–EtOAc, 5:1).
N-(4-Methylbenzyl)-N-phenylaniline
Deep green oil; Rf = 0.63 (n-hexane–EtOAc, 5:1).
IR (KBr): 3399, 3049, 3017, 2927, 2851, 1600, 1502, 1259, 747,
691 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.05–1.42 (m, 6 H), 1.66–1.67 (m,
1 H), 1.71–1.77 (m, 2 H), 2.00–2.06 (m, 2 H), 3.36 (br s, 1 H, NH,
D2O exch.), 6.68 (d, J = 7.8 Hz, 2 H), 6.76 (t, J = 7.5 Hz, 1 H), 7.22–
7.25 (m, 2 H).
IR (KBr): 3040, 2919, 2855, 1682, 1592, 1494, 1310, 748, 692
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.29 (s, 3 H), 4.94 (s, 2 H), 6.90
(t, J = 7.2 Hz, 2 H), 7.04–7.10 (m, 6 H), 7.17–7.23 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 21.2, 56.1, 120.8, 121.4, 126.6,
129.3, 136.2, 136.4, 148.2.
Synthesis 2009, No. 5, 815–823 © Thieme Stuttgart · New York

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S. E. Park et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 25.1, 26.1, 33.6, 51.7, 113.2, 116.9,
129.3, 147.5.
N-(Pyrimidin-4-yl)aniline
Liquid; Rf = 0.34 (n-hexane–EtOAc, 3:1).
Anal. Calcd for C12H17N: C, 82.23; H, 9.78; N, 7.99. Found: C,
82.27; H, 9.81; N, 8.01.
IR (KBr): 3287, 2923, 2852, 1684, 1599, 1519, 1494, 1442, 751
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.01 (t, J = 14.4 Hz, 1 H), 7.32–
7.37 (m, 3 H), 7.43–7.46 (m, 2 H), 7.96 (d, J = 2.7 Hz, 1 H), 8.09–
8.11 (m, 1 H), 8.23 (d, J = 1.5 Hz, 1 H).
1-Phenylpiperidine
Liquid; Rf = 0.74 (n-hexane–EtOAc, 5:1).
IR (KBr): 3059, 2932, 2852, 2803, 1633, 1597, 1497, 1447, 1382,
1235, 1128, 754, 691 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.48–1.55 (m, 2 H), 1.62–1.70 (m,
4 H), 3.09 (t, J = 5.7 Hz, 4 H), 6.78 (t, J = 7.5 Hz, 1 H), 6.89 (d, J =
8.4 Hz, 2 H), 7.20 (t, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 120.3, 123.5, 129.4, 133.1, 134.6,
139.4, 141.9, 152.5.
Anal. Calcd for C10H9N3: C, 70.16; H, 5.30; N, 24.54. Found: C,
70.19; H, 5.38; N, 24.58.
13C NMR (75 MHz, CDCl3): d = 24.6, 26.1, 50.9, 116.7, 119.4,
129.2, 152.5.
Acknowledgment
Anal. Calcd for C11H15N: C, 81.94; H, 9.38; N, 8.69. Found: C,
82.00; H, 9.40; N, 8.71.
This study was financially supported by a grant from the Korean
Science and Engineering Foundation (KOSEF) to the Environmen-
tal Biotechnology National Core Research Center (Grant No.: R15-
2003-012-02001-0).
4-Methoxy-N-(4-phenoxyphenyl)aniline
Mp 81–82 °C; Rf = 0.55 (n-hexane–EtOAc, 5:1).
IR (KBr): 3422, 3047, 2952, 1594, 1508, 1490, 1240, 1130, 820
cm–1.
References
1H NMR (300 MHz, CDCl3): d = 3.77 (s, 3 H), 5.39 (br s, 1 H, NH,
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D2O exch.), 6.81–7.05 (m, 11 H), 7.25–7.32 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 55.6, 114.8, 117.6, 117.8, 120.8,
121.3, 122.4, 129.6, 136.6, 141.2, 149.9, 155.1, 158.6.
Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C,
78.30; H, 5.89; N, 4.80.
4-Methoxy-N-(4-methylphenyl)aniline
Mp 81–83 °C; Rf = 0.60 (n-hexane–EtOAc, 5:1).
IR (KBr): 3396, 3028, 1588, 1500 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.27 (s, 3 H), 3.78 (s, 3 H), 5.36
(br s, 1 H, NH, D2O exch.), 6.81–6.85 (m, 4 H), 6.98–7.04 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 20.5, 55.6, 114.7, 116.6, 121.1,
129.4, 129.8, 136.7, 142.5, 154.9.
Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C,
78.80; H, 7.10; N, 6.56.
(3) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348. (b) Driver, M. S.;
Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
(4) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett.
1998, 39, 617.
N-Butylaniline
Liquid; Rf = 0.63 (n-hexane–EtOAc, 5:1).
(5) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K.
H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(6) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807.
(7) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F.
J. Org. Chem. 2002, 67, 5553.
(8) Wolfe, J. P.; Tomori, J.; Sadighi, J. P.; Yin, J.; Buchwald, S.
L. J. Org. Chem. 2000, 65, 1158.
IR (KBr): 3406, 3081, 3050, 3019, 2956, 2928, 2867, 1602, 1505,
1476, 1429, 1374, 1319, 1262, 1177, 1149, 747, 691 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93 (m, 3 H), 1.19–1.57 (m, 6 H),
3.53 (s, 1 H), 6.54–6.65 (m, 3 H), 7.11–7.16 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.1, 20.5, 31.8, 43.9, 112.9, 117.3,
121.1, 121.2, 129.3, 148.6.
(9) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Kalpars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(10) Bei, X.; Uno, T.; Norris, J.; Turner, H. W.; Guram, A. S.;
Petersen, J. L. Organometallics 1999, 18, 1840.
(11) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66,
8677.
(12) Schnyder, A.; Indolese, A. F.; Studer, M.; Blaser, H.-U.
Angew. Chem. Int. Ed. 2002, 41, 3668.
(13) Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413.
(14) Viciu, M. S.; Kissling, R. M.; Stevens, E. D.; Nolan, S. P.
Org. Lett. 2002, 4, 2229.
Anal. Calcd for C10H15N: C, 80.48; H, 10.13; N, 9.39. Found: C,
80.51; H, 10.19; N, 9.42.
N-(tert-Butyl)aniline
Liquid; Rf = 0.47 (n-hexane–EtOAc, 5:1).
IR (KBr): 3050, 2971, 2931, 2908, 2869, 1599, 1496, 1220, 746,
693 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 (s, 9 H), 3.58 (s, 1 H), 6.73–
6.78 (m, 3 H), 7.12–7.18 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 30.1, 51.6, 117.7, 118.5, 128.9,
146.8.
(15) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.;
Hartwig, J. F. Org. Lett. 2000, 2, 1423.
(16) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org.
Chem. 2001, 66, 7729.
Anal. Calcd for C10H15N: C, 80.48; H, 10.13; N, 9.39. Found: C,
80.50; H, 10.17; N, 9.40.
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Efficient Palladium-Catalyzed Amination of Aryl Chlorides
823
(17) Urgaonkar, S.; Nagarajan, M.; Verkade, J. G. Tetrahedron
Lett. 2002, 43, 8921.
(18) Urgaonkar, S.; Nagarajan, M.; Verkade, J. G. J. Org. Chem.
2003, 68, 452.
(19) Urgaonkar, S.; Nagarajan, M.; Verkade, J. G. Org. Lett.
2003, 5, 815.
(20) Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135.
(21) Cho, S. D.; Kim, H. K.; Yim, H. S.; Kim, M. R.; Lee, J. K.;
Kim, J. J.; Yoon, Y. J. Tetrahedron 2007, 63, 1345.
(22) Mohan, T.; Sudheendra Rao, M. N.; Aravamudan, G.
Tetrahedron Lett. 1989, 30, 4871.
method: full matrix least squares on F2, data/restraints/
parameters = 5495/0/253, goodness-of-fit on F2 = 1.147,
final R indices [I > 2s(I)]: R1 = 0.0781, wR2 = 0.1620, R
indices (all data): R1 = 0.0966, wR2 = 0.1700, largest diff.
peak and hole: 0.560 and –0.440 eÅ–3.
(25) Crystal data for 11 (CCDC 716141): C24H39N2O2P, formula
weight = 418.54, wavelength = 0.71073 Å, crystal system =
tetragonal, space group = P4 (3), unit cell dimensions: a =
11.6762 (7) Å, b = 11.6762 (7) Å, c = 17.0457 (15) Å, a =
90°, b = 90°, g = 90°, volume = 2323.9 (3) Å3, Z = 4,
density(calcd) = 1.196 mg/m3, absorption coefficient =
0.140 mm–1, F(000) = 912, crystal size = 0.30 × 0.20 × 0.20
mm3, q range for data collection = 1.74 to 25.99°, index
ranges = –14 £ h £ 14, –14 £ k £ 12, –18 £ l £ 21, reflections
collected = 13286, independent reflections = 4071 [R(int) =
0.0456], completeness to q = 25.99° (100%), absorption
correction = none, refinement method = full matrix least
squares on F2, data/restraints/parameters = 4071/1/262,
goodness-of-fit on F2 = 1.238, final R indices [I > 2s(I)] =
R1 = 0.1017, wR2 = 0.2859, R indices (all data): R1 =
0.1065, wR2 = 0.2917, absolute structure parameter = 0.0(3),
largest diff. peak and hole: 0.555 and –0.589 eÅ–3.
(26) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2005, 70,
8107.
(23) Oishi, T.; Yoshimi, Y.; Kato, T.; Mukai, K. Japan Patent JP
56161310, 1981; Chem. Abstr. 1982, 97, 2256.
(24) Crystal data for ligand 1 (CCDC 716140): C24H39N2OP,
formula weight = 402.54, wavelength = 0.71073 Å, crystal
system = monoclinic, space group = P2/n, unit cell
dimensions: a = 16.3520 (9) Å, b = 8.1675 (5) Å, c = 17.9629
(10) Å, a = 90°, b = 100.8710 (10)°, g = 90°, volume =
2356.0(2) Å3, Z = 4, density(calcd) = 1.135 mg/m3,
absorption coefficient = 0.133 mm–1, F(000) = 880, crystal
size = 0.50 × 0.40 × 0.20 mm3, q range for data collection =
1.87 to 28.27°, index ranges: –21 £ h £ 21, –10 £ k £ 9, –23
£ l £ 21, reflections collected = 14447, independent
reflections = 5495 [R(int) = 0.0611], completeness to q =
28.27° (94%), absorption correction = none, refinement
(27) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198.
Synthesis 2009, No. 5, 815–823 © Thieme Stuttgart · New York