Sterically Hindered Amination of Aryl Chlorides Catalyzed by a New Carbazolyl-Derived P,N-Ligand-Composed Palladium Complex

Article abstract of DOI:10.1055/s-0037-1611534

A family of 2-(9 H -carbazol-9-yl)phenyl-based phosphine ligands were synthesized and their efficacy in promoting the steric hindered Buchwald-Hartwig amination was evaluated. In the presence of Pd(OAc) ₂ (0.03-1.0 molpercent) associated with t

Full text of DOI:10.1055/s-0037-1611534

SYNTHESIS
0
0
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9
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7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
special topic
A
en
W. I. Lai et al.
Special Topic
Synthesis
Sterically Hindered Amination of Aryl Chlorides Catalyzed by a New
Carbazolyl-Derived P,N-Ligand-Composed Palladium Complex
Wing In Lai‡
Man Pan Leung‡
R"
R'
R"
R'
Pd(OAc)2 (0.03–1 mol%)
L4
H
N
Pui Ying Choy
H2N
Cl
+
NaOt-Bu
toluene/hexane
110 °C, 24 h
R"'
R"'
R
R
Fuk Yee Kwong*
R"
R'
R"
R'
Department of Chemistry, The Chinese University of Hong Kong, Shatin,
New Territories, Hong Kong
fykwong@cuhk.edu.hk
PCy2
‡ These authors contributed equally to this work.
N
OEt
Published as part of the Special Topic Amination Reactions in Organic Synthesis
L4
Received: 11.03.2019
Accepted after revision: 12.04.2019
Published online: 06.05.2019
Me
Me
O
S
O
Me
Me
OH
DOI: 10.1055/s-0037-1611534; Art ID: ss-2019-h0168-st
Me
Me
HN
Abstract A family of 2-(9H-carbazol-9-yl)phenyl-based phosphine li-
gands were synthesized and their efficacy in promoting the steric hin-
dered Buchwald–Hartwig amination was evaluated. In the presence of
Pd(OAc)2 (0.03–1.0 mol%) associated with the newly developed a car-
bazolyl-derived phosphine ligand, the synthesis of tetra-ortho-substi-
tuted diarylamines proceeded smoothly with excellent product yields
(up to 99%). A remarkable result was obtained even for the coupling of
highly sterically congested 2,6-diisopropylaniline and hindered 2-
chloro-1,3,5-triisopropylbenzene (96% isolated yield). A possible de-
composition pathway for the anthracenyl C–N coupling product is also
reported.
Me
Me
O
N
NH
O
S
HO
NH
Me
Me
Me
Me
HN
O
Me
HO
S
NH
Me
O
Me
Me
Coloring materials - ink
Chiral catalyst
Key words palladium, amination, aryl chlorides, phosphine, sterically
congested
Figure 1 Examples of useful materials with a sterically demanding aryl-
amine scaffold
Arylamines are important structural elements found in
pharmaceuticals, electronic materials, catalysts, and agri-
cultural chemicals.1 Particularly tetra-ortho-substituted di-
arylamine subunits are a unique component for the func-
tion of coloring materials and chiral ligands (Figure 1).2 Tra-
ditional nucleophilic substitution,3 addition to benzyne,4
electrophilic nitration,5 and reductive amination6 are com-
monly used in synthetic routes to achieve C(sp2)–N bonds.
Complementary, the palladium-catalyzed aromatic C–N
bond-forming reaction has emerged as a viable alternative
to traditional methods for accessing arylamines in both in-
dustrial and academic research.7 Despite recent advances,
the arylation of hindered amines with hindered aryl chlo-
rides is still a challenging topic. The reductive dehalogena-
tion of the steric bulky aryl halides seems to be a critical
side reaction.8
In the past decades, improvements to this versatile
transformation have been demonstrated. Most of the litera-
ture investigations have improved the catalyst system by
using tailor-made ligands. Several ligand families have been
shown to overcome the challenge of sterically demanding
substrate activation. For instance, N-heterocyclic carbenes
(NHCs) were found capable of tackling this difficulty in am-
ination reaction, as reported by the Nolan group.9 Other
NHCs and ferrocene-based ligands were further employed
to facilitate the synthesis of tetra-ortho-substituted diaryl-
amines.10 Yet, only a few phosphorus-containing ligands
were successfully applied in the Pd-catalyzed cross-cou-
pling of steric hindered aryl chlorides and steric congested
aniline derivatives (Figure 2).11
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

B
W. I. Lai et al.
Special Topic
Synthesis
ners). This new catalyst system allowed the synthesis of tet-
ra-ortho-substituted diarylamines in excellent yields (up to
99%), in particular for extremely hindered coupling part-
ners.
Phosphorous-Containing Catalyst System (Coupling of Hindered
Anilines and Sterically Bulky Aryl Chlorides) Yields >50%
n-Bu
i-Pr
i-Pr
i-Bu
i-Bu
P
P
N
N
N
i-Bu
N
N
N
P
We have previously reported the carbazolyl- and ben-
zo[c]carbazolyl-based monophosphine ligands, PhenCar-
Phos for the Suzuki–Miyaura coupling of steric bulky
arenes.16 It is believed that the flattened carbazole ring fa-
cilitates the reductive elimination process and a flexible
N(sp3)–Pd coordination provides catalyst longevity.16c Given
the wide possibility of fine-tuning the carbazolyl skeleton,
we are interested to further amend the substitution pattern
of the ligand in order to tackle the specific window of cur-
rent steric bulky arene amination process. Here the new li-
gands L2–L4 were accessed via the Cu-assisted C–N bond
coupling between an aryl halide and carbazole derivatives.
Subsequent nucleophilic phosphination using R2PCl afford-
ed the target ligands.
To evaluate the effectiveness of these newly prepared li-
gands, we chose 2-chloro-m-xylene (1a) and 2,6-dimeth-
ylaniline (2a) as model substrates in the prototypical at-
tempts (Scheme 1). Pd(OAc)2 (0.25 mol%) was initially ap-
plied in probing the ligand efficacy. Ph-PhenCarPhos with a
diphenylphosphino moiety did not provide any noticeable
substrate conversion, while other carbazolyl-based ligands
with dicyclohexylphosphino moiety gave good-to-excellent
Cl
i-Pr
i-Pr
Beller, 2002
0.5 mol% Pd
Verkade, 2004
0.25–1.0 mol% Pd
Ackermann, 2006
5.0 mol% Pd
Me2N
Me
N
t-Bu
t-Bu
P
N
N
P
i-Bu
i-Bu
Cl
t-Bu P Pd
t-Bu
Ph
N
N
N
i-Bu
Me
Fe
Pd
Cl
N
DCPAB
Verkade, 2008
0.2–0.5 mol% Pd
Xu/Ji, 2009
1.0 mol% Pd
Cazin/Nolan, 2011
0.15 mol% Pd
O
P
DMAPPAd2
Pt-Bu3
PCy3
PhPCy2
t-BuPCy2
t-Bu
t-Bu
P
t-Bu
MeO
OMe
t-Bu
Beller, 2002
0.5 mol% Pd
Tang/Rodriguez, 2011
5.0 mol% Pd
Shaughnessy, 2013
2.0 mol% Pd
P
Other catalyst system
PS
OH
F
PS
N
t-Bu
PS
Me
Me
Me Me
Pd(OAc)2
Ligand
F
t-Bu
H
N
Cai/ Tao, 2012
Pd (2.0 mol%)
Pd(PPh3)2Cl2
Cl
H2N
Sawamura, 2013
1.5 mol% Pd
+
KOt-Bu
toluene/hexane (1:1)
110 °C, 24 h
t-Bu
Me
Me
Me Me
Figure 2 Examples of phosphorus-containing ligands and other cata-
1a
2a
3aa
lyst system used in Pd-catalyzed cross-coupling of hindered anilines and
sterically bulky aryl chlorides
PCy2
PPh2
PCy2
N
N
N
Recently, a kinetic study towards rational ligand design
for the arylation of hindered primary amines was report-
ed.12 Interestingly, upon altering the Ar–PPh2 group to the
Ar–PPh(t-Bu) moiety, the C–N coupling proceeded even
more effectively. In 2017, Shaughnessy and co-workers re-
ported a mechanistic study of the Pd/PNp3 (Np = neopentyl)
catalyzed coupling of steric bulky aryl halides and aniline
derivatives.13 The oxidative addition step was found not to
be the rate-limiting step when hindered aryl bromides
were coupled with hindered aniline derivatives. Unlike the
usual cross-coupling of privileged substrates, the ligand ge-
ometry appears to be more influential when the coupling
partners become more sterically congested. Thus, it is de-
sirable to develop a general catalyst system capable of han-
dling sterically demanding C–N bond-forming process. In
continuing our research interest of ligand development for
tackling challenging coupling reactions14 and amination,15
we herein report the application of an air-stable 2-(9H-car-
bazol-9-yl)phenyl-phosphine ligand to the sterically con-
gested C–N coupling reaction (both hindered coupling part-
t-Bu
t-Bu
Ph-PhenCarPhos
trace (0.25 mol% Pd)
PhenCarPhos
98% (0.25 mol% Pd)
87% (0.20 mol% Pd)
L1
99% (0.25 mol% Pd)
84% (0.20 mol% Pd)
PCy2
N
PCy2
N
PCy2
N
OMe
OEt
MeO
OMe
L4
98% (0.25 mol% Pd)
98% (0.20 mol% Pd)
16% (0.10 mol% Pd)
L2
L3
47% (0.25 mol% Pd)
77% (0.25 mol% Pd)
Scheme 1 An evaluation of ligand efficacy in Pd-catalyzed sterically
hindered amination of aryl chlorides. Reagents and conditions: 2-chloro-
m-xylene (0.5 mmol), 2,6-dimethylaniline (0.75 mmol), KOt-Bu (1.25
mmol), Pd(OAc)2/ligand = 1:4, toluene/hexane (1:1, 1 mL), 110 °C, stir-
ring, N2, 24 h. GC yields are reported using dodecane as the internal
standard.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

C
W. I. Lai et al.
Special Topic
Synthesis
yields. Further lower the catalyst loading revealed that L4 is
the best ligand for the sterically congested amination reac-
tions among (Scheme 1). Single crystals of L4 were grown
by a liquid-liquid diffusion of hexane into a dichlorometh-
ane solution of L4 at room temperature and an X-ray crystal
structure was obtained (Figure 3).
Table 1 Initial Optimization of Reaction Conditions for Pd-Catalyzed
Sterically Hindered Amination of Bulky Aryl Chloridesa
Me
Me
Me Me
Pd source/L4
H
N
+
Cl
H2N
base, solvent
110 °C, 24 h
Me
Me
Me Me
1a
2a
3aa
Entry Pd source (mol%)
Base
KOt-Bu
Solvent
Yieldb (%)
1
2
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.20)
Pd(dba)2 (0.20)
Pd2(dba)3 (0.20)
Pd(tfa)2 (0.20)
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.20)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.04)
Pd(OAc)2 (0.03)
1,4-dioxane
16
73
97
41
99
74
49
trace
99
15
33
23
99
15
98
63
98
52
64
88
97
53
73
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
NaOt-Bu
Cs2CO3
K3PO4
toluene
3
hexane
4
THF
5
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
toluene/hexane (1:1)
6
7
8
9
10
11
12
13
14
15
16
17
18
K2CO3
NaOH
Figure 3 ORTEP diagram of L4 (CCDC 1896461); all hydrogen atoms
have been omitted for clarity
KOt-Bu
NaOt-Bu
NaOH
Having the lead ligand in hand, we next revisited the re-
action conditions for this sterically congested amination
(Table 1). Among the commonly used solvents, hexane
showed a superior result in this coupling process (Table 1,
entries 1–4). Further investigation revealed that a mixed
solvent system of toluene and hexane in 1:1 ratio is the
most suitable reaction medium (Table 1, entry 5). Palladium
sources were also surveyed and Pd(OAc)2 was found to be
the best palladium precursor in promoting this reaction
(Table 1, entries 5–8). Strongly basic alkoxides and hydrox-
ide were found to be superior to other inorganic bases
screened (Table 1, entries 5, 9–13). An evaluation of the
base effect under lower catalyst loading conditions revealed
that NaOt-Bu is more desirable even at 0.04 mol% of Pd (Ta-
ble 1, entries 15–18). Further reducing the Pd/ligand ratio
(e.g., 1:1, 1:2) resulted in lower product yields (Table 1, en-
tries 19–21).
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
19c Pd(OAc)2 (0.05)
20d Pd(OAc)2 (0.05)
21e Pd(OAc)2 (0.05)
22f Pd(OAc)2 (0.05)
23g Pd(OAc)2 (0.05)
a Reaction conditions: 2-Chloro-m-xylene (0.5 mmol), 2,6-dimethylaniline
(0.75 mmol), base (1.25 mmol), Pd source/L4 = 1:4, solvent (1 mL), 110 °C,
stirring, N2, 24 h.
b GC yields are reported using dodecane as the internal standard.
c Pd/L4 = 1:1.
d Pd/L4 = 1:2.
e Pd/L4 = 1:3.
f 90 °C was used.
g SPhos was used instead of L4.
To further investigate on the efficiency of the newly de-
veloped carbazolyl-based ligands, even more demanding
sterically congested 2,6-diisopropylaniline (2d) was chosen
for the coupling reaction (Scheme 2). Only the new ligand
L4 allowed the efficient coupling of these substrates in gen-
eral (Scheme 2, amination 1 and amination 2). Under 0.05
mol% palladium loading, the synthesis of tetra-ortho-sub-
stituted diarylamine 3ad was found possible.
With the optimized reaction conditions in hand, we
then explored the substrate scope with respect to the steri-
cally demanding aryl chlorides 1 and 2,6-dimethylanilines
2a (Scheme 3). In general, 0.05–0.1 mol% of Pd(OAc)2 was
sufficient to catalyze these coupling reactions. The Pd cata-
lyst loading was even down to 0.03 mol% for the coupling of
inert 2-chloro-1,3,5-trimethylbenzene and 2,6-dimethyl-
aniline to give 3ba (Scheme 3). It should be noted that this
is the lowest catalyst loading achieved so far for such an
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

D
W. I. Lai et al.
Special Topic
Synthesis
85% yield under 0.5 mol% Pd conditions (Scheme 3). To the
best of our knowledge, this is the first example of the cou-
pling of sterically hindered heteroaryl chlorides with hin-
dered anilines using a Pd-catalyzed coupling strategy.
R"
Me
R"
Me
Pd(OAc)2/L4
H
+
Cl
H2N
N
NaOt-Bu
toluene/hexane (1:1)
110 °C, 24 h
R
R
R'
Me
R'
Me
Me
1
2a
3
Me
Me
Me
Me
Me
Me
H
Me
N
H
H
N
O
N
Me
Me
3ba 90%
Me
Amination 1:
Me
Me
Me
Me
Me
Me
Me
H2N
Me
Me Me
Pd(OAc)2 (0.035 mol%)
Ligand (0.14 mol%)
Me
Cl
3aa 98%
(0.05 mol%)
3ca 96%
(0.1 mol%)
(0.03 mol%)
H
N
+
NaOt-Bu
toluene/hexane
110 °C, 18 h
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
4a
2d
5ad
H
O
N
MeO
N
Amination 2:
Me
Me
Me
Pd(OAc)2 (0.05 mol%)
Ligand (0.2 mol%)
3da 98%
(0.1 mol%)
3ea 84%
(0.1 mol%)
Me
Me
H2N
Me
Me Me
H
N
Me
+
Cl
Me Me
Me Me
NaOt-Bu
toluene/hexane
110 °C, 18 h
Me
Me
Me
1a
Me Me
H
N
H
N
Me
Me
2d
3ad
Me
Me Me
Me Me
Scheme 2 Investigation of the new carbazolyl-based ligand efficacy in
sterically hindered aminations of aryl chlorides. Reagents and conditions:
ArCl (0.5 mmol), aniline 2d (0.75 mmol), base (1.25 mmol),
Pd(OAc)2/ligand = 1:4, toluene/hexane (1:1, 1 mL), 110 °C, stirring, N2,
18 h. GC yields used dodecane as the internal standard. Reaction times
were not optimized for each substrate.
Me
3fa 80%
(0.05 mol%)
3ga 94%
(0.5 mol%)
OMe Me
Me
Me
Me
H
H
N
H
N
N
MeO
N
OMe Me
Me Me
amination using a phosphine ligand. The amination reac-
tions proceeded well with the aniline containing di-ortho-
methyl, -ethyl, or even -isopropyl substituents (Scheme 3,
products 3aa, 3ba, 3ca, 3da, 3ea, 3fa, and 3ga). 2-Chloro-
1,3,5-trimethoxybenzene is a challenging electrophilic sub-
strates (deactivated coupling partner), and fortunately it
was still found applicable and gave 3ha with only 1 mol% Pd
loading (Scheme 3). Surprisingly, no desired product 3ia
was obtained when 9-chloroanthracene was used as the
coupling partner (Scheme 3); a brick red solid of 10-[(2,6-
dimethylphenyl)imino]anthracen-9(10H)-one (6) was af-
forded as the sole product in this reaction as confirmed by
X-ray crystal structure analysis (Scheme 4). It is believed
that the N-(2,6-dimethylphenyl)anthracen-9-amine (3ia)
was initially formed during the course of coupling reaction
and it subsequently underwent oxidation upon exposure to
air during the chromatographic purification procedures and
3ha 55%
(1.0 mol%)
3ia 0%
(0.2 mol%)
3ja 85%
(0.5 mol%)
Scheme 3 Pd-catalyzed amination of sterically hindered aryl chlorides.
Reagents and conditions: ArCl (0.5 mmol), 2,6-dimethylaniline (0.75
mmol), NaOt-Bu (1.25 mmol), Pd(OAc)2 (mol% as indicated)/L4 = 1:4,
toluene/hexane (1:1, 1 mL), 110 °C, stirring, N2, 24 h. Isolated yields
were reported. Reaction times were not optimized for each substrate.
To further evaluate the Pd/L4 catalyst system, we next
turned our attention to investigate the scope of sterically
hindered anilines and amines (Scheme 5). Sterically even
more congested amines, such as 2,6-diethylaniline (2c), 2,6-
diisopropylaniline (2d) were able to couple with aryl chlo-
ride in excellent yields (>90%) (Scheme 5, 3ac, 3ad, 3fd, and
3gd). 2,6-Dimethoxyaniline (2e) was a feasible coupling
partner and gave 3ae in 97% yield under a slightly higher
catalyst loading conditions (Scheme 5). The attempt to cou-
ple extremely hindered 2-chloro-1,3,5-triisopropylbenzene
with highly steric bulky 2,6-diisopropylaniline used 1 mol%
of Pd and gave 3gd in 96% yield (Scheme 5). It is noteworthy
that this product is one of the most sterically congested sec-
yielded the unexpected monoimine anthraquinone
6
(Scheme 4).11i Sterically hindered heteroaryl chlorides are
seldom applied in amination reactions. The coupling of 4-
chloro-3-methylquinoline with 2,6-dimethylanilines was
examined and gave the sterically encumbered amine 3ja in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

E
W. I. Lai et al.
Special Topic
Synthesis
R"
R'
R"
R"
R'
R"
R"
Me
Me
Me
Pd(OAc)2 (0.2 mol%)
L4 (0.8 mol%)
Pd(OAc)2/L4
H
+
Cl
H2N
N
H
Cl
H2N
N
NaOt-Bu
toluene/hexane (1:1)
110 °C, 24 h
R
R
NaOt-Bu
toluene/hexane
110 °C, 24 h
R"'
R"'
R"
Me
1
2
3
Me
1i
2a
3ia
intermediate
Me
Me
Me
Me Me
Me Me
H
H
N
H
N
air
N
Me
Me
Me
3ab 98%
Me Me
Me Me
Me
O
N
3ac 93%
3ad 99%
(0.05 mol%)
(0.1 mol%)
(0.05 mol%)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
6: side product
Me
Me
79%
H
N
H
N
Me
Scheme 4 Pd-catalyzed amination of 9-chloroanthracene (1i) and 2,6-
dimethylaniline (2a) and further oxidation reaction. Reagents and con-
ditions were the same as those stated in Scheme 3. ORTEP diagram of 6
(CCDC 1903721). All hydrogen atoms have been omitted for clarity.
Me
Me
Me
Me
Me
3fd 93%
(1.0 mol%)
3gd 96%
(1.0 mol%)
Me MeO
Me
Me
Me
H
N
Me
Me
Me
ondary amines reported via Pd-catalyzed amination of aryl
chlorides with all four branched ortho-substituents.17 Bulky
primary alkylamines were also tested under the optimized
reaction conditions. sec-Butylamine and tert-butylamine
reacted smoothly with 2-chloro-m-xylene to give the target
products 3af and 3ag, respectively, in good-to-excellent
yields (Scheme 5).
In conclusion, we have reported new 2-(9H-carbazol-9-
yl)phenylphosphine ligands L2–L4 for the sterically hin-
dered amination. The new Pd(OAc)2/L4 catalyst system suc-
ceeded in promoting the synthesis of tetra-ortho-substitut-
ed diarylamines from sterically hindered aryl chlorides and
bulky anilines/amines. The catalyst loading could reach the
level of 0.03 mol% Pd and achieve good-to-excellent product
yields. It is worthy to note that the carbazolyl-based ligand
L4 can be synthesized on a larger scale by using a simple li-
gand-free copper-catalyzed amination and phosphination
method from readily available starting materials. We be-
lieve this newly developed catalyst system would be useful
in generating pharmaceutical- and agricultural-relevant in-
termediates having unique, yet difficult to be accessed, ste-
ric encumbered skeletons.
N
N
H
H
Me
Me
Me
Me MeO
3ae 97%
(1.0 mol%)
3af 95%
(0.5 mol%)
3ag 68%
(0.5 mol%)
Scheme 5 Pd-catalyzed amination of sterically hindered aryl chlorides
with sterically hindered amines. Reagents and conditions: ArCl (0.5
mmol), amines (0.75 mmol), NaOt-Bu (1.25 mmol), Pd(OAc)2 (mol% as
indicated)/L4 = 1:4, toluene/hexane (1:1, 1 mL), 110 °C, stirring, N2, 24
h. Isolated yields are reported. Reaction times were not optimized for
each substrate.
use. Commercial aryl chlorides and amines (liquid form only) were
purified by passing through a short plug (0.5 cm wide × 4 cm high) of
neutral alumina or distillation. All bases were used without grinding
and were used as received. New bottle of n-BuLi was used (Note:
since the concentration of n-BuLi from an old bottle may vary, titra-
tion is highly recommended prior to use). TLC was performed on pre-
coated silica gel 60 F254 plates. Silica gel (70–230 and 230–400 mesh)
was used for column chromatography. Melting points were recorded
on an uncorrected instrument. 1H NMR spectra were recorded on a
400 or 500 MHz spectrometer. Spectra were referenced internally to
the residual proton resonance in CDCl3 ( = 7.26) or with TMS ( =
0.00) as the internal standard. 13C NMR spectra were recorded on a
100 or 125 MHz spectrometer and the spectra were referenced to
CDCl3 ( = 77.0, the middle peak). 31P NMR spectra were referenced to
85% H3PO4 externally. Mass spectra (EI-MS and ES-MS) were recorded
on a mass spectrometer. HRMS were obtained by Q Exactive Focus
Orbitrap with APCI source. GC-MS analysis was conducted on a GCD
system using a column with 30 m × 0.25 mm. GC yields were accord-
ed to the authentic samples/dodecane calibration standard from GC-
FID system. Compounds described in the literature were character-
ized by comparison of their 1H, and/or 13C NMR spectra to the previ-
ously reported data.
Unless otherwise noted, all reagents were purchased from commer-
cial suppliers and used without purification. All amination reactions
were performed in a resealable screw cap Schlenk tube (approx. 20
mL volume) in the presence of a Teflon-coated magnetic stirrer bar (3
mm × 10 mm). PhenCarPhos, Ph-PhenCarPhos and L1 were prepared
according to the reported procedures.16 For full details and character-
ization of ligands L2–L4, see the Supporting Information. THF, tolu-
ene, and 1,4-dioxane were distilled from Na/benzophenone ketyl un-
der N2.18 DMF was distilled with CaH2 under reduced pressure and N2.
DCM and hexane were freshly distilled from CaH2 under N2 before
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

F
W. I. Lai et al.
Special Topic
Synthesis
9-[2-(Dicyclohexylphosphino)phenyl]-2-ethoxy-9H-carbazole (L4)
To solution of 2-hydroxy-9H-carbazole (3.66 g, 20 mmol),
vent was then removed under high vacuum. Base (1.25 mmol) was
loaded to Schlenk tube, and the system was further evacuated and
flushed with N2 (3 cycles). 2-Chloro-m-xylene (0.5 mmol), 2,6-di-
methylaniline (0.75 mmol), and solvent (1 mL) were added with stir-
ring at rt for several minutes. The tube was then placed into a pre-
heated oil bath (indicated in Table 1) and stirred for the duration as
indicated. The reaction tube was allowed to cool to rt. EtOAc (~3 mL),
dodecane (114 L, internal standard), and water (~2 mL) were added.
The organic layer was subjected to GC analysis. The GC yield was pre-
viously calibrated by authentic sample/dodecane calibration curve.
a
Bu4N(HSO4) (0.068 g, 0.02 mmol) and K2CO3 (3.32 g, 24 mmol) in
EtOAc (80 mL), EtI (2.41 mL, 30 mmol) was added; the mixture was
refluxed for 12 h. After completion of the reaction, it was quenched
with water and the organic layer was extracted with EtOAc and
washed with sat. aq NH4Cl solution. The crude product was purified
by flash column chromatography (hexane/EtOAc 2:1, Rf = 0.5, see Sup-
porting Information for details) to give 2-ethoxy-9H-carbazole (2.38
g, 56%) as a brown solid. 2-Ethoxy-9H-carbazole (0.84 g, 4 mmol), CuI
(0.76 g, 4 mmol), K2CO3 (1.1 g, 8 mmol), and a Teflon-coated magnetic
stirrer bar were charged to a two-necked round-bottomed flask
equipped with a condenser and fitted with a septum. The system was
carefully evacuated and backfilled with N2 (3 cycles). 1,2-Dibromo-
benzene (0.97 mL, 8 mmol) and distilled dry xylene (15 mL) were
added by syringe via a septum. The mixture was refluxed in a heating
mantle/preheated oil bath (185 °C) for 7 d. After completion of reac-
tion, the solution was filtered through Celite to remove the copper
powder and the xylene was removed by distillation under high vacu-
um. The crude product was purified by flash column chromatography
(hexane/EtOAc 5:1, Rf = 0.5, see Supporting Information for details) to
afford 9-(2-bromophenyl)-2-ethoxy-9H-carbazole (0.91 g, 62%) as a
pale yellow solid. The purified ligand precursor (0.73 g, 2 mmol) was
then dissolved in freshly distilled THF (15 mL) at rt under N2. The
solution was cooled to –78 °C in a dry ice/acetone bath. Titrated n-
BuLi (2.2 mmol) was added dropwise with a syringe, and the mixture
was stirred for 30 min at –78 °C. Cy2PCl (0.49 mL, 2.2 mmol) was then
added dropwise to the mixture by syringe. The mixture was warmed
to rt and stirred for 12 h. The solvent was then removed under re-
duced pressure. MeOH (5 mL) was added to the residue, and the mix-
ture was stirred at 1250 rpm for 10 min. The white solid product was
successively filtered and washed with cold MeOH. The white solid
was collected and dried under vacuum to afford L4 (0.52 g, 54%); Rf =
0.6 (hexane/EtOAc 5:1); mp 159.5–163.3 °C
Screening of Ligands and Reaction Conditions with Pd Catalyst
Loading Lower than 0.1 mol%; General Procedure
Pd source (0.01 mmol) and ligand with corresponding ratio in freshly
distilled DCM (10 mL) was initially prepared under N2 with continu-
ous stirring at rt until all solids were dissolved. A dilution tube was
equipped with a Teflon-coated magnetic stir bar (4 mm × 10 mm) and
evacuated and flushed with N2 (3 cycles). Stock solution of Pd com-
plex (1 mL) was added to the dilution tube by syringe. Additional
freshly distilled DCM (9 mL) was added to the dilution tube for a 2nd
stock solution. The corresponding volume of 2nd stock solution of Pd
complex was then immediately added to the Schlenk tube by syringe
according to the Pd loading indicated in Schemes 1 and 2 and Table 1
(0.02 mol% Pd per 1 mL 2nd stock solution). The solvent was then re-
moved under high vacuum. Base (1.25 mmol) was loaded to Schlenk
tube, and the system was further evacuated and flushed with N2 (3
cycles). 2-Chloro-m-xylene (0.5 mmol), 2,6-dimethylaniline (0.75
mmol), and solvent (1 mL) were added with stirring at rt for several
minutes. The tube was then placed into a pre-heated oil bath (indicat-
ed in Table 1) and stirred for the duration as indicated. The reaction
tube was allowed to cool to rt. EtOAc (~3 mL), dodecane (114 L, in-
ternal standard), and water (~2 mL) were added. The organic layer
was subjected to GC analysis. The GC yield was previously calibrated
by authentic sample/dodecane calibration curve.
1H NMR (500 MHz, CDCl3):  = 7.96–8.02 (dd, J = 8.5, 8.0 Hz, 2 H),
7.76–7.77 (m, 1 H), 7.51–7.55 (m, 2 H), 7.30–7.33 (m, 1 H), 7.24–7.27
(t, J = 7.2 Hz, 1 H), 7.18–7.21 (t, J = 7.5 Hz, 1 H), 6.93–6.95 (d, J = 8.0 Hz,
1 H), 6.84–6.86 (dd, J = 7.5 Hz, 1 H), 6.47–6.47 (d, J = 2.0 Hz, 1 H),
3.95–4.00 (m, 2 H), 1.74–1.78 (m, 2 H), 1.56–1.67 (m, 8 H), 1.76 (s, 2
H), 1.47–1.53 (m, 2 H), 1.36–1.39 (t, J = 14 Hz, 3 H), 1.04–1.19 (m, 8
H), 0.91–0.98 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 158.1, 144.0, 143.8, 143.6, 142.4,
137.6, 137.4, 134.3, 134.3, 130.4, 130.0, 130.0, 128.1, 124.0, 123.2,
120.9, 119.5, 119.3, 116.8, 110.5, 108.9, 95.5, 63.7, 34.0, 33.9, 33.9,
30.4, 30.3, 30.3, 30.2, 29.5, 29.5, 29.4, 29.4, 27.3, 27.3, 27.2, 27.2, 27.2,
26.4, 26.4, 15.0.
Sterically Hindered Amination of Aryl Chlorides; General Proce-
dure
Pd(OAc)2 (0.0022 g, 0.01 mmol) and L4 (0.0193 g, 0.04 mmol) in
freshly distilled DCM (10 mL) was initially prepared under N2 with
continuous stirring at rt until all solids were dissolved. A dilution
tube was equipped with a Teflon-coated magnetic stir bar (4 mm × 10
mm) and evacuated and flushed with N2 (3 cycles). Stock solution of
Pd complex (1 mL) was added to the dilution tube by syringe. Addi-
tional freshly distilled DCM (9 mL) was added to the dilution tube for
a 2nd stock solution. The corresponding volume of 2nd stock solution
of palladium complex was then immediately added to the Schlenk
tube by syringe according to the Pd loading indicated in Schemes 3–5
(0.02 mol% Pd per 1 mL 2nd stock solution). The solvent was then re-
moved under high vacuum. NaOt-Bu (0.12 g, 1.25 mmol) was loaded
into a Schlenk tube, and the system was further evacuated and
flushed with N2 (3 cycles). Sterically hindered aryl chlorides (0.5
mmol), sterically hindered amines (0.75 mmol), toluene (0.5 mL), and
hexane (0.5 mL) were added with stirring at rt for several minutes.
The tube was then placed into a pre-heated oil bath (110 °C) and
stirred for 24 h. After the completion of reaction as judged by GC or
TLC analysis, the reaction tube was allowed to cool to rt. The reaction
was quenched with water (~2 mL) and diluted with EtOAc (~3 mL).
The filtrate was concentrated under reduced pressure. The crude
products were purified by flash column chromatography on silica gel
(230–400 mesh) to afford the desired product.
31P NMR (202 MHz, CDCl3):  = –14.49.
HRMS (ESI+): m/z [M + H]+ calcd for C32H39NOP: 484.2764; found:
484.2771.
Screening of Ligands and Reaction Conditions with Pd Catalyst
Loading Ranging from 0.1–1.0 mol%; General Procedure
Pd source (0.01 mmol) and ligand with corresponding ratio in freshly
distilled DCM (10 mL) was initially prepared under N2 with continu-
ous stirring at rt until all solids were dissolved. A Schlenk tube was
equipped with a Teflon-coated magnetic stir bar (4 mm × 10 mm) and
evacuated and flushed with N2 (3 cycles). The corresponding volume
of stock solution of Pd complex was then immediately added to the
Schlenk tube by syringe according to the Pd loading indicated in
Scheme 1, and Table 1 (0.2 mol% Pd per 1 mL stock solution). The sol-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

G
W. I. Lai et al.
Special Topic
Synthesis
Bis(2,6-dimethylphenyl)amine (3aa)10o
N-(2,6-Dimethylphenyl)-4-methoxy-2,6-dimethylaniline (3ea)10w
Pink solid; yield: 107 mg (84%); Rf = 0.5 (hexane/EtOAc 10:1).
Colorless liquid; yield: 110 mg (98%); Rf = 0.7 (hexane/EtOAc 10:1).
1H NMR (500 MHz, CDCl3):  = 6.98 (d, J = 7.5 Hz, 4 H), 6.86–6.83 (t, J =
1H NMR (500 MHz, CDCl3):  = 6.94 (d, J = 7.5 Hz, 2 H), 6.75–6.72 (t, J =
7.0 Hz, 2 H), 2.01 (s, 12 H).
7.5 Hz, 1 H), 6.57 (s, 2 H), 3.77 (s, 3 H), 2.05 (s, 6 H), 1.98 (s, 6 H).
13C NMR (125 MHz, CDCl3):  = 141.8, 129.6, 128.7, 121.7, 19.1.
13C NMR (125 MHz, CDCl3):  = 155.4, 142.8, 134.8, 133.9, 129.1,
126.7, 119.9, 113.5, 55.4, 19.4, 19.1.
2,6-Diisopropyl-N-(o-tolyl)aniline (5ad)19
N-(2,6-Dimethylphenyl)-2,4,6-triethylaniline (3fa)
Yellow liquid; yield: 124 mg (93%); Rf = 0.7 (hexane/EtOAc 10:1).
Yellow oil; yield: 112 mg (80%); Rf = 0.5 (hexane/EtOAc 10:1).
1H NMR (500 MHz, CDCl3):  = 7.29–7.32 (t, J = 8.0 Hz, 1 H), 7.24 (d, J =
7.5 Hz, 2 H), 7.13 (d, J = 7.5 Hz, 1 H), 6.94–6.97 (t, J = 7.5 Hz, 1 H),
6.66–6.69 (t, J = 7.5 Hz, 1 H), 6.13 (d, J = 8.0 Hz, 1 H), 3.08–3.16 (m, 2
H), 2.35 (s, 3 H), 1.12–1.19 (dd, J = 6.5 Hz, 12 H).
13C NMR (125 MHz, CDCl3):  = 147.27, 146.02, 135.71, 130.11,
127.07, 126.98, 123.81, 121.27, 117.48, 111.41, 28.23, 24.73, 23.00,
17.65.
1H NMR (500 MHz, CDCl3):  = 7.04 (d, J = 7.5 Hz, 2 H), 7.00 (s, 2 H),
6.86–6.83 (t, J = 7.5 Hz, 1 H), 4.92 (s, 1 H), 2.75–2.70 (q, J = 8.0 Hz, 2 H),
2.58–2.53 (q, J = 7.5 Hz, 4 H), 2.09 (s, 6 H), 1.37–1.34 (t, J = 7.5 Hz, 3 H),
1.25–1.22 (t, J = 7.5 Hz, 6 H).
13C NMR (125 MHz, CDCl3):  = 142.7, 139.5, 138.0, 137.9, 129.3,
129.3, 129.3, 126.7, 125.7, 125.7, 120.1, 120.0, 28.8, 28.6, 28.5, 25.1,
25.0, 24.9, 19.4, 16.1, 15.9, 14.3.
N-(2,6-Diisopropylphenyl)-2,6-dimethylaniline (3ad)10p
Orange oil; yield: 139 mg (99%); Rf = 0.8 (hexane/EtOAc 10:1).
HRMS (ESI+): m/z [M + H]+ calcd for C20H28N: 282.2216; found:
282.2217.
1H NMR (500 MHz, CDCl3):  = 7.15–7.10 (m, 3 H), 6.94 (d, J = 7.5 Hz, 2
H), 6.71–6.74 (t, J = 7.5 Hz, 1 H), 3.18–3.12 (m, 2 H), 1.98 (s, 6 H), 1.12
(d, J = 7.0 Hz, 12 H).
N-(2,6-Dimethylphenyl)-2,4,6-triisopropylaniline (3ga)
Orange solid; yield: 152 mg (94%); Rf = 0.8 (hexane/EtOAc 10:1); mp
81.2–83.0 °C.
13C NMR (125 MHz, CDCl3):  = 144.2, 143.1, 138.8, 129.6, 129.5,
125.6, 124.8, 123.3, 123.3, 119.7, 119.5, 28.1, 28.0, 23.5, 23.4, 23.3,
19.4, 19.3.
1H NMR (500 MHz, CDCl3):  = 6.95 (s, 2 H), 6.92 (d, J = 7.5 Hz, 2 H),
6.70–6.67 (t, J = 7.5 Hz, 1 H), 3.21–3.13 (m, 2 H), 2.94–2.85 (m, 1 H),
1.96 (s, 6 H), 1.27 (d, J = 7.0 Hz, 6 H), 1.12 (d, J = 7.0 Hz, 12 H).
N-(2,6-Dimethylphenyl)-2,4,6-trimethylaniline (3ba = 3ab)11e
13C NMR (125 MHz, CDCl3):  = 145.6, 144.6, 143.6, 136.3, 129.5,
124.8, 121.1, 118.9, 34.1, 28.2, 24.2, 23.6, 19.3.
HRMS (ESI+): m/z [M + H]+ calcd for C23H34N: 324.2686; found:
Orange solid; yield of Scheme 3, 3ba: 108 mg (90%); yield of Scheme
5, 3ab: 117 mg (98%); Rf = 0.6 (hexane/EtOAc 10:1).
1H NMR (500 MHz, CDCl3):  = 6.97 (d, J = 7.5 Hz, 2 H), 6.80–6.78 (m,
J = 7.5 Hz, 3 H), 2.25 (s, 3 H), 1.99 (s, 12 H).
324.2688.
N-(2,6-Dimethylphenyl)-2,4,6-trimethoxyaniline (3ha)9j
Red solid; yield: 79 mg (55%); Rf = 0.5 (hexane/EtOAc 5:1).
13C NMR (125 MHz, CDCl3):  = 142.2, 139.0, 131.5, 130.5, 129.2,
128.8, 128.4, 120.9, 20.6, 19.1, 19.0.
1H NMR (500 MHz, CDCl3):  = 6.94 (d, J = 7.0 Hz, 2 H), 6.84–6.82 (t, J =
7.0 Hz, 1 H), 6.16 (s, 2 H), 3.78 (s, 3 H), 3.65 (s, 6 H), 2.12 (s, 6 H).
N-(2,6-Dimethylphenyl)-4-isopropoxy-2,6-dimethylaniline (3ca)
13C NMR (125 MHz, CDCl3):  = 152.4, 131.4, 128.0, 122.1, 92.1, 56.2,
55.6, 18.8.
Purple solid; yield: 136 mg (96%); Rf = 0.7 (hexane/EtOAc 10:1); mp
81.1–82.0 °C.
1H NMR (500 MHz, CDCl3):  = 6.95 (d, J = 7.5 Hz, 2 H), 6.76–6.73 (t, J =
7.5 Hz, 1 H), 6.57 (s, 2 H), 4.51–4.46 (m, 1 H), 2.03 (s, 6 H), 1.98 (s, 6
H), 1.32 (d, J = 6.0 Hz, 6 H).
13C NMR (125 MHz, CDCl3):  = 153.6, 142.8, 134.8, 133.8, 129.1,
129.0, 126.7, 120.0, 119.9, 116.0, 115.8, 70.1, 22.4, 22.3, 22.1, 22.0,
19.4, 19.3, 19.2, 19.1, 19.0.
N-(2,6-Dimethylphenyl)-3-methylquinolin-4-amine (3ja)
Yellow solid; yield: 111 mg (85%); Rf = 0.1 (hexane/EtOAc 1:2); mp
179.9–181.1 °C.
1H NMR (500 MHz, CDCl3):  = 8.48 (s, 1 H), 8.01 (d, J = 8.5 Hz, 1 H),
7.64 (d, J = 8.5 Hz, 1 H), 7.58–7.55 (t, J = 7.5 Hz, 1 H), 7.31–7.28 (t, J =
7.5 Hz, 1 H), 7.10 (s, 3 H), 5.96 (s, 1 H), 2.11 (s, 6 H), 2.00 (s, 3 H).
HRMS (ESI+): m/z [M + H]+ calcd for C19H26NO: 284.2009; found:
284.2011.
13C NMR (125 MHz, CDCl3):  = 153.4, 148.3, 146.0, 139.4, 134.4,
129.7, 128.5, 128.2, 125.8, 124.9, 121.2, 120.4, 113.9, 53.6, 18.9, 16.0.
HRMS (ESI+): m/z [M + H]+ calcd for C18H19N2: 263.1543; found:
263.1546.
N-(2,6-Dimethylphenyl)-2,6-dimethyl-4-phenoxyaniline (3da)
Orange liquid; yield: 155 mg (98%); Rf = 0.3 (hexane/EtOAc 20:1).
1H NMR (500 MHz, CDCl3):  = 7.34–7.31 (t, J = 7.5 Hz, 2 H), 7.09–7.06
(t, J = 7.0 Hz, 1 H), 6.99 (d, J = 8.0 Hz, 4 H), 6.83–6.80 (t, J = 7.0 Hz, 1 H),
6.72 (s, 2 H), 4.74 (s, 1 H), 2.04 (d, J = 4.5 Hz, 12 H).
13C NMR (125 MHz, CDCl3):  = 158.3, 151.6, 142.2, 137.6, 132.8,
129.7, 129.1, 129.0, 128.1, 122.5, 121.1, 120.9, 119.5, 119.3, 118.0,
117.9, 19.3, 19.3, 19.2, 19.2.
10-[(2,6-Dimethylphenyl)imino]anthracen-9(10H)-one (6)11i
Brick red solid; yield: 156 mg (79%); Rf = 0.6 (hexane/EtOAc 1:5).
1H NMR (500 MHz, CDCl3):  = 8.59 (br, 1 H), 8.35 (d, J = 7.5 Hz, 2 H),
7.62 (br, 3 H), 7.32 (br, 2 H), 7.09 (d, J = 7.5 Hz, 2 H), 6.98 (t, J = 7.5 Hz,
1 H), 1.98 (s, 6 H).
HRMS (ESI+): m/z [M + H]+ calcd for C22H24NO: 318.1852; found:
318.1855.
13C NMR (125 MHz, CDCl3):  = 183.8, 152.8, 148.9, 133.3, 132.1,
131.0, 128.4, 127.7, 126.6, 123.1, 123.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

H
W. I. Lai et al.
Special Topic
Synthesis
N-(2,6-Diethylphenyl)-2,6-dimethylaniline (3ac)10m
Funding Information
Orange oil; yield: 118 mg (93%); Rf = 0.7 (hexane/EtOAc 10:1).
We thank the Research Grants Council of Hong Kong, General Re-
search Fund (GRF 15303415/15P) and The Chinese University of Hong
1H NMR (500 MHz, CDCl3):  = 7.07 (d, J = 7.0 Hz, 2 H), 7.04–7.01 (m, 1
H), 6.97 (d, J = 7.5 Hz, 2 H), 6.81–6.78 (t, J = 7.5 Hz, 1 H), 2.47–2.43 (q,
J = 7.5 Hz, 4 H), 2.00 (s, 6 H), 1.16–1.13 (t, J = 7.5 Hz, 6 H).
Kong (CUHK) Direct Grant (4442122) for financial support.
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13C NMR (125 MHz, CDCl3):  = 142.1, 140.4, 137.0, 129.2, 129.1,
129.1, 127.6, 126.2, 126.2, 123.1, 123.1, 123.1, 123.0, 120.7, 120.6,
25.0, 24.8, 19.3, 19.2, 13.9, 13.8.
Acknowledgment
We are grateful to Ms. Bella Chan Hoi Shan for X-ray crystal structure
analysis and Ms. Sarah Ng Hau Yan for HRMS analysis.
N-(2,6-Diisopropylphenyl)-2,4,6-triethylaniline (3fd)
Colorless oil; yield: 157 mg (93%); Rf = 0.8 (hexane/EtOAc 10:1).
1H NMR (500 MHz, CDCl3):  = 7.10 (d, J = 8.0 Hz, 2 H), 7.07–7.04 (m, 1
H), 6.86 (s, 2 H), 3.12–3.07 (m, 2 H), 2.62–2.57 (q, J = 8.0 Hz, 2 H),
2.42–2.37 (q, J = 7.5 Hz, 4 H), 1.26–1.23 (t, J = 7.5 Hz, 3 H), 1.13–1.11
(m, 18 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611534.
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13C NMR (125 MHz, CDCl3):  = 141.6, 139.7, 139.5, 137.2, 134.0,
126.3, 123.6, 123.0, 28.4, 27.8, 24.9, 23.6, 16.0, 14.2.
HRMS (ESI+): m/z [M + H]+ calcd for C24H36N: 338.2842; found:
Reference
(1) (a) Lawrence, S. A. Amines: Synthesis, Properties and Applica-
tions; Cambridge University Press: Cambridge, 2004. (b) Travis,
A. S. Manufacture and Uses of the Anilines: A Vast Array of Pro-
cesses and Products, In The Chemistry of Anilines; Rappoport, Z.,
Ed.; John Wiley & Sons: New York, 2007, 715.
(2) (a) Tani, Y.; Seki, M.; Kinoshita, Y.; Gouda, K. Patent
US2017247557A, 2017. (b) Mu, Y.; Zhang, Y.; Yao, W. Patent
CN102391294B, 2015.
338.2845.
N-(2,6-Diisopropylphenyl)-2,4,6-triisopropylaniline (3gd)11g
White solid; yield: 182 mg (96%); Rf = 0.5 (hexane/EtOAc 10:1).
1H NMR (500 MHz, CDCl3):  = 7.07 (d, J = 8.0 Hz, 2 H), 6.98–6.93 (m, 3
H), 3.16–3.01 (m, 4 H), 2.89–2.83 (m, 1 H), 1.24 (d, J = 7.0 Hz, 6 H),
1.09–1.06 (t, J = 7.0 Hz, 24 H).
13C NMR (125 MHz, CDCl3):  = 143.6, 141.7, 141.0, 139.8, 138.0,
123.8, 121.9, 121.6, 34.0, 27.9, 27.7, 24.3, 23.7, 23.6.
(3) Burnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 237.
(4) Heaney, H. Chem. Rev. 1962, 62, 81.
(5) Smith, M. B.; March, J. Advanced Organic Chemistry: Reaction,
Mechanism, and Structure, 5th ed; Wiley-Interscience: New
York, 2001.
(6) For a recent review described the reductive amination, see:
(a) Alinezhad, H.; Yavari, H.; Salehian, F. Curr. Org. Chem. 2015,
19, 1021. (b) Raoufmoghaddam, S. Org. Biomol. Chem. 2014, 12,
7179. For a selected example, see: (c) Abdel-Magid, A. F.;
Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org.
Chem. 1996, 61, 3849.
N-(2,6-Dimethoxyphenyl)-2,6-dimethylaniline (3ae)10w
White solid; yield: 125 mg (97%); Rf = 0.6 (hexane/EtOAc 10:1).
1H NMR (500 MHz, CDCl3):  = 6.98 (d, J = 7.5 Hz, 2 H), 6.93–6.90 (t, J =
7.0 Hz, 1 H), 6.76–6.73 (t, J = 8.0 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 2 H), 3.63
(s, 6 H), 2.15 (s, 6 H).
13C NMR (125 MHz, CDCl3):  = 149.6, 141.6, 134.0, 127.6, 125.9,
123.6, 118.3, 105.8, 56.4, 18.8.
(7) (a) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599.
(b) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
(c) Scholz, U. Amino Group Chemistry: From Synthesis to the Life
Sciences; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2008, 333–375.
(d) Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027.
(e) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177.
(f) Wong, S. M.; So, C. M.; Kwong, F. Y. Synlett 2012, 23, 1132.
(g) Wong, S. M.; Yuen, O. Y.; Choy, P. Y.; Kwong, F. Y. Coord.
Chem. Rev. 2015, 293–294, 158. (h) Ruiz-Castillo, P.; Buchwald,
S. L. Chem. Rev. 2016, 116, 12564. (i) So, C. M.; Kwong, F. Y. Chem.
Soc. Rev. 2011, 40, 4963.
N-sec-Butyl-2,6-dimethylaniline (3af)20
Colorless oil; yield: 84 mg (95%); Rf = 0.6 (hexane/EtOAc 10:1).
1H NMR (500 MHz, CDCl3):  = 6.99 (d, J = 7.5 Hz, 2 H), 6.81–6.78 (t, J =
7.5 Hz, 1 H), 3.24–3.17 (m, 1 H), 2.27 (s, 6 H), 1.65–1.56 (m, 1 H),
1.44–1.36 (m, 1 H), 1.07 (d, J = 6.5 Hz, 3 H), 0.99–0.96 (t, J = 7.5 Hz, 3
H).
13C NMR (125 MHz, CDCl3):  = 145.1, 129.0, 128.9, 121.1, 53.9, 30.9,
20.8, 19.1, 10.8.
N-tert-Butyl-2,6-dimethylaniline (3ag)21
(8) Hartwig, J. F.; Richards, S.; Barañano, D.; Paul, F. J. Am. Chem.
Soc. 1996, 118, 3626.
Yellow oil; yield: 60 mg (68%); Rf = 0.6 (hexane/EtOAc 10:1).
(9) (a) Marion, N.; Ecarnot, E. C.; Navarro, O.; Amoroso, D.; Bell, A.;
Nolan, S. P. J. Org. Chem. 2006, 71, 3816. (b) Marion, N.; Navarro,
O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am. Chem.
Soc. 2006, 128, 4101. (c) Marion, N.; de Frémont, P.; Puijk, I. M.;
Ecarnot, E. C.; Amoroso, D.; Bell, A.; Nolan, S. P. Adv. Synth. Catal.
2007, 349, 2380. (d) Chartoire, A.; Frogneux, X.; Nolan, S. P. Adv.
Synth. Catal. 2012, 354, 1897. (e) Meiries, S.; Chartoire, A.;
Slawin, A. M. Z.; Nolan, S. P. Organometallics 2012, 31, 3402.
(f) Chartoire, A.; Frogneux, X.; Boreux, A.; Slawin, A. M. Z.;
Nolan, S. P. Organometallics 2012, 31, 6947. (g) Chartorie, A.;
Boreux, A.; Martin, A. R.; Nolan, S. P. RSC Adv. 2013, 3, 3840.
1H NMR (500 MHz, CDCl3):  = 7.03 (d, J = 7.5 Hz, 2 H), 6.92–6.89 (t, J =
7.5 Hz, 1 H), 2.35 (s, 6 H), 1.22 (s, 9 H).
13C NMR (125 MHz, CDCl3):  = 143.9, 134.7, 128.6, 128.5, 128.5,
123.2, 123.2, 123.1, 55.3, 31.1, 31.0, 20.3, 20.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

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W. I. Lai et al.
Special Topic
Synthesis
(h) Meiries, S.; Le Duc, G.; Chartoire, A.; Collado, A.; Speck, K.;
Arachchige, K. S. A.; Slawin, A. M. Z.; Nolan, S. P. Chem. Eur. J.
2013, 19, 17358. (i) Meiries, S.; Speck, K.; Cordes, D. B.; Slawin,
A. M. Z.; Nolan, S. P. Organometallics 2013, 32, 330. (j) Le Duc,
G.; Meiries, S.; Nolan, S. P. Organometallics 2013, 32, 7547.
(k) Bastug, G.; Nolan, S. P. Organometallics 2014, 33, 1253.
(l) Marelli, E.; Chartoire, A.; Le Duc, G.; Nolan, S. P. Chem-
CatChem 2015, 7, 4021.
S.; Qu, B.; Haddad, N.; Reeves, D. C.; Tang, W.; Lee, H.;
Krishnamurthy, D.; Senanayake, C. H. Adv. Synth. Catal. 2011,
353, 533. (h) Chartoire, A.; Lesieur, M.; Slawin, A. M. Z.; Nolan, S.
P.; Cazin, C. S. J. Organometallics 2011, 30, 4432. (i) Raders, S. M.;
Moore, J. N.; Parks, J. K.; Miller, A. D.; Leißing, T. M.; Kelley, S. P.;
Rogers, R. D.; Shaughnessy, K. H. J. Org. Chem. 2013, 78, 4649.
(j) Iwai, T.; Harada, T.; Hara, K.; Sawamura, M. Angew. Chem. Int.
Ed. 2013, 52, 12322. (k) Liu, T.-P.; Cheng, Q.; Song, W.-J.; Cai, L.-
Z.; Tao, X.-C. Synlett 2012, 23, 2333. (l) Reddy, C. V.; Kingston, J.
V.; Verkade, J. G. J. Org. Chem. 2008, 73, 3047.
(10) For related references, see: (a) Sadighi, J. P.; Harris, M. C.;
Buchwald, S. L. Tetrahedron Lett. 1998, 39, 5327. (b) Gooßen, L.
J.; Paetzold, J.; Briel, O.; Rivas-Nass, A.; Karch, R.; Kayser, B.
Synlett 2005, 275. (c) Li, J.; Cui, M.; Yu, A.; Wu, Y. J. Organomet.
Chem. 2007, 692, 3732. (d) Organ, M. G.; Abdel-Hade, M.; Avola,
S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Sayah,
M.; Valente, C. Chem. Eur. J. 2008, 14, 2443. (e) Xu, C.; Wang, Z.-
Q.; Fu, W.-J.; Lou, X.-H.; Li, Y.-F.; Cen, F.-F.; Ma, H.-J.; Ji, B.-M.
Organometallics 2009, 28, 1909. (f) Schoeps, D.; Sashuk, V.;
Ebert, K.; Plenio, H. Organometallics 2009, 28, 3922.
(g) Winkelmann, O. H.; Riekstins, A.; Nolan, S. P.; Navarro, O.
Organometallics 2009, 28, 5809. (h) Tu, T.; Fang, W.; Jiang, J.
Chem. Commun. 2011, 47, 12358. (i) Lee, D.-H.; Taher, A.;
Hossain, S.; Jin, M.-J. Org. Lett. 2011, 13, 5540. (j) Chen, M.-T.;
Vicic, D. A.; Turner, M. L.; Navarro, O. Organometallics 2011, 30,
5052. (k) Zhu, L.; Ye, Y.-M.; Shao, L.-X. Tetrahedron 2012, 68,
2414. (l) Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson, A. C.;
Organ, M. G. Chem. Eur. J. 2012, 18, 145. (m) Li, Y.-J.; Zhang, J.-L.;
Li, X.-J.; Geng, Y.; Xu, X.-H.; Jin, Z. J. Organomet. Chem. 2013, 737,
12. (n) Fang, W.; Jiang, J.; Xu, Y.; Zhou, J.; Tu, T. Tetrahedron
2013, 69, 673. (o) Zhang, Y.; César, V.; Storch, G.; Lugan, N.;
Lavigne, G. Angew. Chem. Int. Ed. 2014, 53, 6482. (p) Krinsky, J.
L.; Martínez, A.; Godard, C.; Castillón, S.; Claver, C. Adv. Synth.
Catal. 2014, 356, 460. (q) Liu, F.; Zhu, Y.-R.; Song, L.-G.; Lu, J.-M.
Org. Biomol. Chem. 2016, 14, 2563. (r) Zhao, X.-Y.; Zhou, Q.; Lu,
J.-M. RSC Adv. 2016, 6, 24484. (s) Zhang, Y.; Lavigne, G.; Lugan,
N.; César, V. Chem.–Eur. J. 2017, 23, 13792. (t) Rühling, A.;
Rakers, L.; Glorius, F. ChemCatChem 2017, 9, 547. (u) Lan, X.-B.;
Li, Y.; Li, Y.-F.; Shen, D.-S.; Ke, Z.; Liu, F.-S. J. Org. Chem. 2017, 82,
2914. (v) Khadra, A.; Mayer, S.; Mitchell, D.; Rodriguez, M. J.;
Organ, M. G. Organometallics 2017, 36, 3573. (w) Huang, F.-D.;
Xu, C.; Lu, D.-D.; Shen, D.-S.; Li, T.; Liu, F.-S. J. Org. Chem. 2018,
83, 9144. (x) Liu, F.; Hu, Y.-Y.; Li, D.; Zhou, Q.; Lu, J.-M. Tetrahe-
dron 2018, 74, 5683. (y) Tian, X.; Lin, J.; Zou, S.; Lv, J.; Huang, Q.;
Zhu, J.; Huang, S.; Wang, Q. J. Organomet. Chem. 2018, 861, 125.
(11) (a) Ehrentraut, A.; Zapf, A.; Beller, M. J. Mol. Catal. A: Chem.
2002, 182–183, 515. (b) Urgaonkar, S.; Nagarajan, M.; Verkade, J.
G. J. Org. Chem. 2003, 68, 452. (c) Urgaonkar, S.; Xu, J.-H.;
Verkade, J. G. J. Org. Chem. 2003, 68, 8416. (d) Urgaonkar, S.;
Verkade, J. G. J. Org. Chem. 2004, 69, 9135. (e) Ackermann, L.;
Spatz, J. H.; Gschrei, C. J.; Born, R.; Althammer, A. Angew. Chem.
Int. Ed. 2006, 45, 7627. (f) Hill, L.; Moore, L. R.; Huang, R.;
Craciun, R.; Vincent, A. J.; Dixon, D. A.; Chou, J.; Woltermann, C.
J.; Shaughnessy, K. H. J. Org. Chem. 2006, 71, 5117. (g) Rodriguez,
(12) Ruiz-Castillo, P.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2015, 137, 3085.
(13) Hu, H.; Qu, F.; Gerlach, D. L.; Shaughnessy, K. H. ACS Catal. 2017,
7, 2516.
(14) For selected references, see: (a) So, C. M.; Lau, C. P.; Kwong, F. Y.
Org. Lett. 2007, 9, 2795. (b) So, C. M.; Lee, H. W.; Lau, C. P.;
Kwong, F. Y. Org. Lett. 2009, 11, 317. (c) Choy, P. Y.; Chow, W. K.;
So, C. M.; Lau, C. P.; Kwong, F. Y. Chem. Eur. J. 2010, 16, 9982.
(d) Chow, W. K.; So, C. M.; Lau, C. P.; Kwong, F. Y. Chem. Eur. J.
2011, 17, 6913. (e) Choy, P. Y.; Luk, K. C.; Wu, Y.; So, C. M.;
Wang, L.-L.; Kwong, F. Y. J. Org. Chem. 2015, 80, 1457. (f) Lee, H.
W.; Lam, F. L.; So, C. M.; Lau, C. P.; Chan, A. S. C.; Kwong, F. Y.
Angew. Chem. Int. Ed. 2009, 48, 7436. (g) Kwong, F. Y.; Lai, C. W.;
Chan, K. S. J. Am. Chem. Soc. 2001, 123, 8864. (h) Lee, H. W.;
Chan, A. S. C.; Kwong, F. Y. Chem. Commun. 2007, 2633.
(15) (a) Chen, G.; Lam, W. H.; Fok, W. S.; Lee, H. W.; Kwong, F. Y.
Chem. Asian J. 2007, 2, 306. (b) So, C. M.; Zhou, Z.; Lau, C. P.;
Kwong, F. Y. Angew. Chem. Int. Ed. 2008, 47, 6402. (c) Chung, K.
H.; So, C. M.; Wong, S. M.; Luk, C. H.; Zhou, Z.; Lau, C. P.; Kwong,
F. Y. Synlett 2012, 23, 1181. (d) Yang, Q.; Choy, P. Y.; Fu, W. C.;
Fan, B.; Kwong, F. Y. J. Org. Chem. 2015, 80, 11193. (e) Choy, P. Y.;
Chung, K. H.; Yang, Q.; So, C. M.; Sun, R. W. Y.; Kwong, F. Y. Chem.
Asian J. 2018, 13, 2465. (f) Yeung, P. Y.; Tsang, C. P.; Kwong, F. Y.
Tetrahedron Lett. 2011, 52, 7038. (g) Yeung, P. Y.; Chung, K. H.;
Kwong, F. Y. Org. Lett. 2011, 13, 2912.
(16) (a) To, S. C.; Kwong, F. Y. Chem. Commun. 2011, 47, 5079. (b) For
an
example
of
commercial
availability,
see:
http://www.strem.com/catalog/family/PhenCar-Phos/.
(accessed Apr 21, 2019). (c) Fu, W. C.; Zhou, Z.; Kwong, F. Y.
Organometallics 2016, 35, 1553. (d) Fu, W. C.; Zhou, Z.; Kwong,
F. Y. Org. Chem. Front. 2016, 3, 273.
(17) The Pd-catalyzed coupling of 2,6-diisopropylaniline and 1-
chloro-2,6-diisopropylbenzene to afford tetra-ortho-substi-
tuted diarylamine was previously reported by Shao (1.0 mol%
Pd-NHC, 84%);10k Sawamura (1.5 mol% Pd, 80%);11j Jin and Xu (2
mol% Pd-NHC, 54%).10m
(18) Armarego, W. L. F. Purification of Laboratory Chemicals, 8th ed;
Butterworth-Heinemann: Oxford, 2017.
(19) Johansson Seechurn, C. C. C.; Sperger, T.; Scrase, T. G.;
Schoenebeck, F.; Colacot, T. J. J. Am. Chem. Soc. 2017, 139, 5194.
(20) Xin, H. Y.; Biehl, E. R. J. Org. Chem. 1983, 48, 4397.
(21) Cran, J. W.; Vdhani, D. V.; Krafft, M. E. Synlett 2014, 25, 1550.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I