Palladium-catalyzed N-arylation of bis(ortho-substituted aryl)amines: An efficient method for preparing sterically congested triarylamines

Article abstract of DOI:10.1055/s-0030-1258125

Bis(ortho-substituted aryl)amines were arylated on the nitrogen atom with various haloarenes in high yields using the palladium catalyst, which was generated from palladium(II) acetate and tri(tert-butyl)phosphine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258125

LETTER
1819
Palladium-Catalyzed N-Arylation of Bis(ortho-substituted aryl)amines:
an Efficient Method for Preparing Sterically Congested Triarylamines
N-Arylation of
B
y
is(ortho-subs
o
tituted
a
ryl)
i
a
Department of Chemistry, Graduate School of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Fax +81(92)6422572; E-mail: rkuwano@chem.kyushu-univ.jp
b
Tosoh Organic Chemical Co., Ltd., 4988 Kaisei-cho, Shunan, Yamaguchi 746-0006, Japan
Received 15 May 2010
L5 was the most effective among 2-(dialkylphosphino)bi-
aryl ligands (entries 5–8).2b,13 The tert-butyl group on the
phosphorus is preferable to cyclohexyl for the arylation of
2a. However, prolongation of the reaction time to 24
hours resulted in no change of the yield of 3a in the reac-
tion using the biarylphosphines L5.
Abstract: Bis(ortho-substituted aryl)amines were arylated on the
nitrogen atom with various haloarenes in high yields using the pal-
ladium catalyst, which was generated from palladium(II) acetate
and tri(tert-butyl)phosphine.
Key words: amination, arylation, cross-coupling, homogeneous
catalysis, palladium
The observation suggests that the L5-ligated palladium
catalyst has a limited lifetime in the catalytic amination of
haloarenes with 2a. The ligands bearing a di(tert-bu-
tyl)phosphino group, Q-Phos,5a cBRIDP,14 cataCXium®
A,15 and (t-Bu)3P,4,16 were found to enable sterically con-
gested 2a to couple with aryl bromide with high efficiency
(entries 9–12). In particular, the (t-Bu)3P–palladium cata-
lyst successfully produced 3a in 86% yield at three hours.
Triarylamine is an important structural motif, which is of-
ten seen in organic electronic devices, for example, hole
transport or organic photovoltaic materials.1 An access to
the framework is the cross-coupling of diarylamines with
halobenezenes using palladium2 or copper catalyst.3 In
particular, the former catalyst is applicable to the amina-
tions of a broad range of haloarenes, which include unre-
active chloroarenes.4,5 As for diarylamine substrates, the
palladium-catalyzed cross-coupling is compatible with
various functional groups on the para position in the aro-
matic ring.4,6 Only a few mono-ortho-substituted diaryl-
amines are known to couple with haloarenes by palladium
catalysis.7 However, the carbon–nitrogen bond formation
between aryl halides and bis(ortho-substituted ar-
yl)amines has not been reported previously. The installa-
tion of methyl groups at the ortho positions in fluorescent
triarylamines is known to cause blue shifts of the emission
as well as enhancement of the fluorescent intensity.8
Herein, we report that the N-arylation of bis(ortho-substi-
tuted aryl)amine proceeds in the presence of a (t-
Bu)3P-ligated palladium catalyst. The catalytic carbon–
nitrogen bond formation affords a variety of sterically
congested triarylamines in high yields.
Effects of other reaction parameters were investigated in
the reaction using (t-Bu)3P ligand. The cross-coupling of
1a with 2a was scarcely affected by the reaction solvent.
Choice of base is crucial for the carbon–nitrogen bond
formation. Little or no formation of 3a was observed in
the reaction using bases other than NaO(t-Bu) (entries 13–
16). As for palladium precursors, Pd(OAc)2 was compara-
ble to Pd(dba)2 (entry 17). The loading of (t-Bu)3P–palla-
dium catalyst was reduced to 1 mol% without a significant
loss of catalyst efficiency (entry 18). Furthermore, the re-
action produced the coupling product in 91% isolated
yield when it was carried out at 120 °C (entry 19).17
The optimized catalyst in hand was applied to the amina-
tion of a range of bromoarenes with diarylamine 2a
(Table 2). As with 1a, p-bromotoluene (1b) was coupled
with 2a in high yield (entry 1). The catalytic N-arylation
of 2a was not hampered by the substituent at the meta po-
sition of the electrophilic substrate (entries 2 and 3). The
o-methyl group of 1e or 1f significantly obstructed the
carbon–nitrogen bond formation, but the sterically con-
gested triarylamines, 3e and 3f could be obtained in pure
form from the palladium-catalyzed reactions (entries 4
and 5). Electron-donating or -withdrawing substituents on
bromoarenes 3g–i scarcely affected the formation of tri-
arylamine (entries 6–8). However, alkoxycarbonyl group
caused no formation of the desired coupling product.
Bis(o-methylaryl)amines 2b and 2c were also arylated
with 1a by (t-Bu)3P–Pd(OAc)2 catalyst (entries 9 and 10).
It is noteworthy that electron-rich 2c was coupled with
ortho-substituted 1e or 1f to form tris(ortho-substituted
aryl)amine 3l or 3m in good yield (entries 11 and 12). The
methoxy group of 2c might accelerate the amination of
(aryl)(bromo)palladium(II) intermediate.
We evaluated a series of ligands, which are known to be
effective for the palladium-catalyzed amination of aryl
halides, for the reaction between bromobenzene (1a) and
bis(2-methylphenyl)amine (2a) with 5 mol% palladium
loading in toluene at 80 °C for three hours (Table 1). No
cross-coupling of 1a with 2a was observed in the reaction
using a chelate bisphosphine ligand, such as DPPF9 or
BINAP10 (entries 1 and 2). The desired cross-coupling
was observed with
a
bulky and electron-rich
proazaphosphatrane11 or N-heterocyclic carbene12 ligand,
but 3a was obtained in low yield (entries 3 and 4). Ligand
SYNLETT 2010, No. 12, pp 1819–1824
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258125; Art ID: U03710ST
© Georg Thieme Verlag Stuttgart · New York

1820
R. Kuwano et al.
LETTER
Table 1 Optimization of Reaction Conditionsa
Me
Me
Me
cat. [Pd]—ligand
+
HN
N
Br
base, toluene
80 °C, 3 h
Me
1a
2a
3a
ligands:
Fe
i-Pr
N+
i-Pr
i-Bu
N
PR1
2
i-Bu
i-Bu
L2 R1 = Cy, R2 = H
P
N
N
N
PPh2
PPh2
L3 R1 = Cy, R2 = 2,4,6-(i-Pr)3
L4 R1 = t-Bu, R2 = H
PPh2
PPh2
–
BF4
R2
L5 R1 = t-Bu, R2 = 2,6-(MeO)2
i-Pr i-Pr
N
L1
SIPr⋅HBF4
DPPF
BINAP
P(t-Bu)2
Fe
Ph
Ph
Ph
Ph
Q-Phos
Ph
Ph
Me
Pn-Bu
cataCXium®
A
2
Ph
P(t-Bu)2
cBRIDP
Entry
[Pd]
Ligand
DPPFd
Base
Yield (%)c
(mol%)b
1
2
3
4
5
6
7
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
NaO(t-Bu)
NaO(t-Bu)
NaO(t-Bu)
NaO(t-Bu)
NaO(t-Bu)
NaO(t-Bu)
NaO(t-Bu)
0
0
rac-BINAPd
L1
9
SIPr·HBF4
18
10
20
41
L2
L3
L4
8
9
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(dba)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
L5
NaO(t-Bu)
NaO(t-Bu)
NaO(t-Bu)
NaO(t-Bu)
NaO(t-Bu)
KOHe
44
73
74
85
86
9
Q-Phos
cBRIDP
cataCXium®
(t-Bu)3P
(t-Bu)3P
(t-Bu)3P
(t-Bu)3P
(t-Bu)3P
(t-Bu)3P
(t-Bu)3P
(t-Bu)3P
10
11
12
13
14
15
16
17f
18f
19f,g
A
K3PO4
0
Cs2CO3
2
K2CO3
0
NaO(t-Bu)
NaO(t-Bu)
NaO(t-Bu)
87
79
91h
a Reactions were conducted in toluene (0.5 mL) at 80 °C. The ratio of 1a/2a (0.20 mmol)/NaO(t-Bu)/[Pd]/ligand was 110:100:150:5:10 unless
otherwise noted.
b Catalyst loading is in parentheses.
c GC yield (average of two runs).
d The ratio of [Pd]/ligand is 1:1.
e The reaction was conducted in the presence of C14H29NMe3Br (3.0 mol% to 2a).
Synlett 2010, No. 12, 1819–1824 © Thieme Stuttgart · New York

LETTER
N-Arylation of Bis(ortho-substituted aryl)amines
1821
Table 2 Amination of Bromoarenes 1 with Diarylamines 2a
R2
R2
Me
Me
Pd(OAc)2 (1.0 mol%),
(t-Bu)3P (2.0 mol%)
R1
R1
Br +
Me
HN
N
NaO(t-Bu),
toluene, 120 °C
1
Me
R2
R2
2
3
Entry
1 R1 =
2 R2 =
Time (h)
Product 3
Yield (%)b
Me
Me
Me
N
1
1b 4-Me
2a H
2a H
2a H
2a H
2a H
2a H
2a H
2
92
3b
Me
Me
N
2
3
4
5
6
7
1c 3-Me
2
2
91
89
35
17
80
97
Me
Me
3c
Me
N
1d 3,5-Me2
Me
Me
Me
3d
N
Me
1e 2-Me
2
Me
3e
Me
Me
Me
Me
N
1f 2,6-Me2
1g 4-MeO
1h 3-MeO
24
3f
Me
Me
MeO
N
2
3g
MeO
Me
N
2
Me
3h
Synlett 2010, No. 12, 1819–1824 © Thieme Stuttgart · New York

1822
R. Kuwano et al.
LETTER
Table 2 Amination of Bromoarenes 1 with Diarylamines 2a (continued)
R2
R2
Me
Me
Me
Pd(OAc)2 (1.0 mol%),
R1
R1
(t-Bu)3P (2.0 mol%)
Br +
Me
HN
N
NaO(t-Bu),
toluene, 120 °C
1
R2
R2
2
3
Entry
1 R1 =
2 R2 =
Time (h)
Product 3
Yield (%)b
Me
Me
F3C
N
8
1i 4-F3C
2a H
2
84
3i
Me
Me
Me
N
9
1a H
2b 5-Me
2
2
91
97
73
60
Me
3j
Me
Me
10
1a H
2c 4-MeO
2c 4-MeO
2c 4-MeO
N
MeO
OMe
OMe
OMe
3k
Me
Me
Me
11c
1e 2-Me
15
24
N
MeO
3l
Me
Me
Me
Me
12d
1f 2,6-Me2
N
MeO
3m
a Reactions were conducted in toluene (2.0 mL) at 120 °C. The ratio of 1/2 (1.0 mmol)/NaO(t-Bu)/Pd(OAc)2/(t-Bu)3P was 110:100:150:1:2
unless otherwise noted.
b Isolated yield.
c The ratio of 1/2 was 1.5:1.
d The ratio of 1/2 was 1.2:1.
Aryl chlorides 4 were also coupled with the bis(ortho-sub- thylphenyl)amine 3e could be obtained from the arylation
stituted aryl)amines by the (t-Bu)3P–palladium catalyst of 2a with 2-chlorotoluene (4d). The reaction of 4d was
(Table 3). The aminations of non-, para-, or meta-sub- comparable in the yield of 3e to that of bromoarene 1e.
stitued chlorobenzenes 4a–c with 2a produced the corre-
sponding triarylamines 3a–c in 87–89% yields (entries 1–
The present N-arylation of bis(o-methylaryl)amines 2
proceeds through a typical mechanism of palladium-cata-
3). However, the reactions of the chloroarenes required a
lyzed cross-coupling of haloarenes with amines
longer reaction time for the complete conversion of 2a
(Scheme 1). The catalytic cycle starts from the oxidative
than those of the corresponding bromoarenes. Tris(o-me-
addition of haloarenes to (t-Bu)3P–palladium(0) species
Synlett 2010, No. 12, 1819–1824 © Thieme Stuttgart · New York

LETTER
N-Arylation of Bis(ortho-substituted aryl)amines
1823
A.18 The resulting (aryl)(halo)palladium(II) B undergoes In summary, bis(ortho-substituted aryl)amines were ary-
ligand exchange with tert-butoxide to form palladium lated on their nitrogen atoms with bromo- or chloroarenes
alkoxide C.19 The alkoxo ligand in C abstracts the proton in high yields by using the (t-Bu)3P–Pd(OAc)2 catalyst.
from 2 and is replaced by diarylamido ligand. The reduc- The catalytic carbon–nitrogen bond formation produced a
tive elimination from (amido)(aryl)palladium(II) D pro- variety of sterically congested triarylamines in high
duces the triarylamine 3 and regenerates the palladium(0) yields. The arylation of bis(ortho-substituted aryl)amines
A.20 The oxidative addition is believed to be the rate- is applicable to the preparation of sterically congested
controlling step in the typical palladium-catalyzed amina- tris(ortho-substituted aryl)amines.
tion of haloarene.21 However, electron-rich bromoarene
1g exhibited reactivity comparable to electron-deficient 1i
in the catalytic amination with 2a.22 This observation sug-
gests that the substitution of alkoxo with amido ligand
controls the rate of the cross-coupling of 1 with 2. The two
o-methyl groups may hinder the interaction between pal-
ladium and amine substrate. As for the amination of o-
bromotoluene, the electron-rich diarylamine 2c was trans-
formed to the desired triarylamine in higher yield than 2a
(entries 4 vs. 11 in Table 2).23 The formation of (ami-
do)palladium D might be facilitated by the methoxy
groups of 2c, which enhance the nucleophilicity of the ni-
trogen atom.24
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was partly supported by KAKENHI (No. 19685008) and
a Grant-in-Aid for the Global COE Program, ‘Science for Future
Molecular Systems’ from MEXT.
References and Notes
(1) Representative reviews: (a) Shirota, Y. J. Mater. Chem.
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Landeros, F.; Hartwig, J. F. In The Chemistry of Anilines;
Rappoport, Z., Ed.; Wiley Interscience: New York, 2007,
455. (b) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed.
2008, 47, 6338.
Table 3 Amination of Chloroarenes 4 with Diarylamine 2aa
Me
Pd(OAc)2 (1.0 mol%)
(t-Bu)3P (2.0 mol%)
R
R
+ 2a
Cl
N
NaO(t-Bu), toluene
120 °C, 24 h
4
Me
(3) (a) Liu, Y.-H.; Chen, C.; Yang, L.-M. Tetrahedron Lett.
2006, 47, 9275. (b) Nandurkar, N. S.; Bhanushali, M. J.;
Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett. 2007, 48,
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K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(5) (a) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F.
J. Org. Chem. 2002, 67, 5553. (b) Kuwano, R.;
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Hartwig, J. F.; O’Keeffe, M.; Yaghi, O. M. J. Am. Chem.
Soc. 2001, 123, 11482. (b) Jin, Z.; Lucht, B. L. J. Am. Chem.
Soc. 2005, 127, 5586. (c) Yan, X. Z.; Pawlas, J.; Goodson,
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(d) Fukuzaki, E.; Nishide, H. J. Am. Chem. Soc. 2006, 128,
996.
3
Entry
4 R =
Product 3
Yield (%)b
1
2
3
4
4a H
3a
3b
3c
3e
88
87
89
36
4b 4-Me
4c 3-Me
4d 2-Me
a Reactions were conducted in toluene (2.0 mL) at 120 °C for 24 h.
The ratio of 4/2a (1.0 mmol)/NaO(t-Bu)/Pd(OAc)2/(t-Bu)3P was
110:100:150:1:2 unless otherwise noted.
b Isolated yield.
Ar22N–Ar1
Pd(0)L
A
Ar1X
1 or 4
3
(7) (a) Plater, M. J.; McKay, M.; Jackson, T. J. Chem. Soc.,
Perkin Trans. 1 2000, 2695. (b) Yano, M.; Furuya, T.;
Yonezawa, M.; Tatsumi, M.; Oyama, M.; Sato, K.; Takui, T.
Polyhedron 2005, 24, 2121. (c) Nishide, Y.; Osuga, H.;
Iwata, K.; Tanaka, K.; Sakamoto, H. Bull. Chem. Soc. Jpn.
2008, 81, 1322.
Ar22N Pd(II)L
X
Pd(II)L
Ar1
Ar1
D
B
t-BuOH
NaO(t-Bu)
(8) Chen, C.-T.; Chiang, C.-L.; Lin, Y.-C.; Chan, L.-H.; Huang,
C.-H.; Tsai, Z.-W.; Chen, C.-T. Org. Lett. 2003, 5, 1261.
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7217.
(10) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215.
Ar22NH
t-BuO
Pd(II)L
Ar1
NaX
L = (t-Bu)3P
X = Br or Cl
2
C
Scheme 1 A possible mechanism of arylation of 2 with halobenzenes
(11) Urgaonkar, S.; Nagarajan, M.; Verkade, J. G. Org. Lett.
2003, 5, 815.
Synlett 2010, No. 12, 1819–1824 © Thieme Stuttgart · New York

1824
R. Kuwano et al.
LETTER
(12) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.;
Hartwig, J. F. Org. Lett. 2000, 2, 1423.
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Na2SO4, and then evaporated under reduced pressure. The
residue was purified with a flash column chromatography
(EtOAc–hexane) to give the desired triarylamine 3.
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(22) The competitive experiment using an equimolar mixture of
1g and 1i afforded 3g and 3i by a ratio of 48:52. See details
in the Supporting Information.
(23) The competitive experiment using an equimolar mixture of
2a and 2c afforded 3a and 3k by a ratio of 32:68. See details
in the Supporting Information.
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Soc. 2003, 125, 16347.
(17) Typical Procedure for the N-Arylation of Bis(ortho-
substituted aryl)amines 2
Under a nitrogen atmosphere, a haloarene 1 or 4 (1.5 mmol)
was added to a mixture of (t-Bu)3P (4.1 mg, 20 mmol),
Pd(OAc)2 (2.2 mg, 10 mmol), NaOt-Bu (144 mg, 1.5 mmol),
and a diarylamine 2 (1.0 mmol) in toluene (2.0 mL). The
reaction mixture was stirred at 120 °C for 2–24 h, cooled to
r.t., diluted with H2O, and then extracted with EtOAc. The
combined organic layer was washed with brine, dried over
Synlett 2010, No. 12, 1819–1824 © Thieme Stuttgart · New York

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