A General Palladium–Phosphine Complex To Explore Aryl Tosylates in the N-Arylation of Amines: Scope and Limitations

Article abstract of DOI:10.1002/asia.201800575

The scope and limitations of the monoselective N-arylation of various amines by using aryl and hetaryl tosylates are presented. The air-stable and easily accessible Pd(OAc)₂/CM-phos {CM-phos=2-[2-(dicyclohexylphosphino)phenyl]-1-methyl-1H-indole}catalyst system was able to deal with a wide range of aryl tosylate substrates as well as amine nucleophiles, including primary and secondary cyclic/acyclic aliphatic amines and anilines. NH-Bearing heterocycles such as indole, carbazole, pyrrole, 10-phenothiazine, and 10-phenoxazine were shown to be feasible coupling partners under this catalytic system. The described reaction conditions tolerate a wide range of functional groups and allow an array of aromatic amines as well as unsymmetrical amine products to be easily accessed from the various phenolic derivatives. Interestingly, this catalyst system even offers the opportunity to perform the reaction in water medium. We also report the intermolecular coupling of optically active α-central chiral amines with aryl tosylates without erosion of the enantiomeric purity.

Full text of DOI:10.1002/asia.201800575

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: A General Palladium-Phosphine Complex for Exploring Aryl
Tosylates in N-arylation of Amines: Scope and Limitation
Authors: Pui Ying Choy, Kin Ho Chung, Qingjing Yang, Chau Ming So,
Raymond Wai-Yin Sun, and Fuk Yee Kwong
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To be cited as: Chem. Asian J. 10.1002/asia.201800575
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10.1002/asia.201800575
Chemistry - An Asian Journal
FULL PAPER
A General Palladium-Phosphine Complex for Exploring Aryl
Tosylates in N-arylation of Amines: Scope and Limitation
Pui Ying Choy,† Kin Ho Chung,† Qingjing Yang, Chau Ming So,* Raymond Wai-Yin Sun and Fuk Yee
Kwong*
8
]
Abstract: The scope and limitation of mono-selective N-arylation of
various amines using aryl or heteroaryl tosylates are presented. Air-
stable and easily accessible Pd(OAc)2/CM-phos catalyst system
was found capable to deal with a wide range of aryl tosylate
substrates as well as amine nucleophiles, including primary and
secondary cyclic/acyclic aliphatic amines, and anilines. NH-bearing
heterocycles such as indole, carbazole, pyrrole, 10-phenothiazine
and 10-phenoxazine were shown to be feasible coupling partners
under this catalytic system. The described reaction conditions
tolerate a wide range of functional groups and allow an array of
aromatic amines as well as unsymmetrical amine products to be
easily accessed from the various pattern of phenolic derivatives.
Interestingly, this catalyst system even offers opportunity for reaction
to be performed under water medium. We also reported the
intermolecular coupling of optically active α-central chiral amines
with aryl tosylates without the erosion of enantiomeric purity.
protocol,[
and significantly expanded and extraordinary
improved by Buchwald and Hartwig (a tin-free protocol, and later
named as Buchwald-Hartwig amination),[9,10] is one of the most
well-adopted synthetic tools in frontier organic syntheses. Key
to success of this transformation has been illustrated regarding
the use of appropriately-tuned ancillary ligands, which allow
more challenging substrates to be applicable in this aromatic C–
N bond-construction process.[11]
In addition to aryl(alkenyl) halides, tremendous effort has
been made to expand the choice of electrophiles as the
complementary coupling partners. Arene electrophiles coming
from phenolic raw materials are indeed sustainable.[12] In fact,
aryl sulfonates are alternative electrophiles which receive
increasing popularity in the C(sp2)–N bond-forming reactions.[13]
Among them, aryl tosylates are of particularly attractive due to
their ease of preparation (easily accessible from the
corresponding phenol), ease of purification (simply by
crystallization in most cases), more stable towards hydrolysis
and lower cost (as compared to triflate). Nevertheless, their
inherently low activity toward oxidative addition limited their
genuine application in cross-coupling reactions. In fact, this
difficulty can be addressed by modifying the ligand structure.
The first Pd-catalyzed amination of aryl tosylates was reported
by Hartwig in 1998 using Pd-DBtPF as the catalyst.[14] After this
discovery, some other supporting ligands were reported to
facilitate this reaction, for instance, XPhos,[ 15 ] JosiPhos-type
ligands,[16] DPPF,[17] Mor-DalPhos,[18] MOP-type phosphine,[19]
Pd/NHC precatalyst[ 20 ] and graphene-oxide supported PdCl2
catalyst.[21]
Introduction
It has been well-documented that arylamine-containing
compounds are important basic building blocks of many natural
products and biologically active molecules.[1] The development
of efficient catalytic methods for diversely accessing these
valuable products is thus significantly desirable. Traditional
nucleophilic substitution,[2] addition to benzyne,[3] electrophilic
nitration[ 4 ] and reductive amination[ 5 ] are commonly used
synthetic routes to achieve C(sp2)–N bonds. Metal-assisted (-
catalyzed) C(sp2)–N bond-forming reaction was first reported by
Ullmann over a century using copper as the promotor.[6] In the
last two decades, many transition metals have been shown to
efficiently promote the coupling between aryl halides and
amines.[7] Among them, palladium-catalyzed amination of aryl
halides, in which it was reported by Migita using tin-mediated
Me
Me
PtBu2
P(1-Ad)2
Pt-Bu2
Pt-Bu2
N
Fe
PR2
Fe
N
O
Cy2P
DBtPF
JosiPhos-type ligand
Mor-DalPhos
CM-phos
Me2N
NMe2
iPr
iPr
Dr. P. Y. Choy, Mr. Q. Yang, Prof. Dr. C. M. So, Prof. Dr. F. Y. Kwong
The Hong Kong Polytechnic University Shenzhen Research Institute
(SZRI), Shenzhen, P. R. of China
N
N
PCy2
Cl
Pt-Bu2
OiPr
i-Pr
i-Pr
iPr
iPr
Pd
Dr. P. Y. Choy, Prof. Dr. F. Y. Kwong
Cl
Department of Chemistry, The Chinese University of Hong Kong, Shatin,
New Territories, Hong Kong
Email: fykwong@cuhk.edu.hk
Mr. K. H. Chung, Prof. Dr. C. M. So, Prof. Dr. F. Y. Kwong
Department of Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University, Hung Hom, Kowloon, Hong Kong
Email: chau.ming.so@polyu.edu.hk
i-Pr
Cl
Pd/NHC precatalyst
MOP-type
ligand
XPhos
Figure 1. Selected ligand examples used in Pd-catalyzed amination of aryl
tosylates (present work, CM-phos)
Dr. R. W.-Y. Sun
Guangzhou Lee & Man Technology Company Limited, 8 Huanshi Avenue
South, Nansha, Guangzhou, Guangdong Province, China
†Dr. P.Y. Choy and Mr. K. H. Chung contributed equally
Although progress has been made, it is still highly
desirable to develop a general catalyst system for this C–N
bond-forming process, in particular it can handle across various
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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10.1002/asia.201800575
Chemistry - An Asian Journal
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nature of nitrogen nucleophiles (e.g. primary/secondary aliphatic
amine, cyclic/acyclic amine, aryl(heteroaryl) amine, NH-
heterocycle and etc.) without significant change of reaction
conditions. In continuing our research program on developing
ligand system for tackling challenging coupling reactions,[22] we
herein report the full scope of using Pd/CM-phos complex for
coupling of aryl(heteroaryl) tosylates across a wide range of
aromatic amines, aliphatic amines, heterocyclic amines, and α-
chiral amines. Particularly noteworthy is that this catalyst
system allowed the C–N bond-forming reaction to be proceeded
even in aqueous medium without diminishing the product yields.
[a] Reaction conditions: ArOTs (1.0 mmol), amine (1.5 mmol), base (2.5
mmol), Pd(OAc)2 (0.5 mol%), CM-phos (2.0 mol%), Pd/L = 1:4, PhB(OH)2
(0.04 mmol), solvent (3.0 mL) were stirred for 24 h at 110 °C under nitrogen.
[b] Calibrated GC yields were reported using dodecane as the internal
standard. [c] In the absence of CM-phos ligand.
Exploration of Substrate Scopes
With the optimized reaction conditions in hand, we first explored
the substrate scope with respect to arylamines and
functionalized aryl tosylates (Table 2).
The coupling of
unactivated aryl tosylate with N-methylaniline proceeded
smoothly and the catalyst loading of even 0.2 mol% Pd was
reached (Table 2, entry 1).
Arene electrophiles bearing
Results and Discussion
functional group substituents (e.g. ester-, keto-, cyano-group)
were feasible coupling partners (Table 2, entries 2, 3, 7-9).
Deactivated electron-rich aryl tosylate was successfully coupled
with aniline (Table 2, entry 9). Examples of heteroaryl tosylates,
for instance 2-methylbenzo[d]thiazol-5-yl tosylate and quinolin-6-
yl tosylate gave the corresponding products in 80% and 94%
yields, respectively (Table 2, entries 4, 5). The coupling of
sterically hindered 2,6-dimethylanilines with aryl tosylates also
proceeded well to afford the target products in good yields
(Table 2, entries 10-12).
To probe the best reaction conditions, we carried out an array of
experiments with different reaction parameters using
electronically neutral 4-(tert-butyl)phenyl tosylate and N-
methylaniline as model substrates (Table 1). Initial base
screening revealed that K3PO4 was the best base of choice
(Table 1, entries 1-5). Strong base NaOt-Bu is often employed
in amination reaction, however, in this reaction, majority of
phenolic side product was detected due to the competitive
alkaline hydrolysis of aryl tosylate (Table 1, entry 2). Previous
reports showed that alcoholic solvent gave superior effect in
amination of aryl sulfonates probably due to the better solubility
of the substrates and faster oxidative addition in polar solvent.[23]
Therefore, we aimed to evaluate the efficacy of several common
alcoholic solvents including tert-butanol, iso-propanol, and tert-
amyl alcohol. Surprisingly, only tert-butanol afforded the desired
product while other alcoholic solvents were found inferior (Table
1, entries 1, 8, and 9). Other polar solvents were tested and
DMF was proven to be an ideal alternative solvent for achieving
the desired coupling product (Table 1, entry 6).
Table 2. Palladium-catalyzed N-arylation of arylamines with aryl/heteroaryl
tosylates[a]
Table 1. Initial screening of Pd-catalyzed N-arylation of amine with aryl
tosylate[a]
t-Bu
/ CM-phos
t-Bu
Pd(OAc)2
+
Me
N
N
base, solvent
110 °C, 24 h
OTs
H
Me
entry
base
solvent
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
DMF
%yield[b]
1
K2CO3
84
0
2
NaOt-Bu
K3PO4
Cs2CO3
Na2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
3
96
14
39
95
41
0
4
5
6
7
dioxane
i-PrOH
t-AmOH
t-BuOH
8
9
0
10[c]
0
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10.1002/asia.201800575
Chemistry - An Asian Journal
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yield was obtained even the catalyst loading down to 0.05 mol%
Pd was employed (Table 3, entry 2).
/ CM-phos R
Pd(OAc)2
R"
R"
+
R
entry
1[c]
H
N
N
K2CO
3, t-BuOH
110 °C, 24 h
OTs
R'
R'
%yield[b]
ArOTs
product
t-Bu
Amine
Table 3. Palladium-catalyzed N-arylation of secondary aliphatic amines with
aryl/alkenyl tosylates[a]
[Pd]
0.2
t-Bu
90
90
Ph
Me
Me
R'
N
R
N
/ CM-phos
Pd(OAc)2
N
H
+
R
R"
OTs
N
Me
K3PO
4, t-BuOH
110 °C, 24 h
O
H
R"
OTs
O
R'
MeO
%yield[b]
entry
ArOTs
Amine
product
2
3
0.5
0.5
[Pd]
MeO
NC
Ph
N
H
N
OTs
1
2[c]
0.25
0.05
96
90
Me
t-Bu
OTs
HN
O
t-Bu
N
N
O
O
NC
87
Ph
Me
O
O
N
N
H
3[d]
0.5
0.5
83
95
OTs
HN
HN
HN
O
O
O
OTs
Me
MeO
O
MeO
S
N
S
N
Me
O
4
5
Me
Ph
2.0
1.0
80
94
Me
Me
4[d]
N
N
N
O
O
O
OTs
N
N
H
OTs
Ph
O
Ph
Me
N
N
OTs
OTs
O
Ph
1.0
1.0
84
75
5
6
N
N
H
OTs
OTs
O
O
Me
HN
HN
HN
O
O
O
6[c,d]
Ph
1.0
0.5
75
92
Me
TsO
O
N
N
H
Cl
Me
Me
Me
O
7[e,f]
2.0
1.0
66
66
Ph
N
N
O
O
OTs
7
Ph
Ph
H2N
H2N
N
H
Me
Me
OTs
OTs
OTs
O
O
Ph
Ph
8[d]
1.0
75
8
Me
N
O
N
H
N
O
Me
Me
MeO
Me
MeO
HN
9
0.5
1.0
88
91
t-Bu
OTs
t-Bu
N
1.0
2.0
77
89
9
N
H
H2N
Me
OTs
OTs
HN
Me
t-Bu
t-Bu
10
N
N
10[c]
OTs
N
H
H2N
Me
Me
Me
Me
Me
Me
11
1.0
2.0
80
79
HN
Me
N Me
OTs
N
Me
Me
Me
H2N
Me
11
0.5
83
Me
t-Bu
Me
N
H
Me
Me
OTs
OTs
Me
Me
Me
Me
12[e]
OTs
N
H
t-Bu
N
Me
Me
12
0.5
2.0
77
67
H2N
n-C
n-C
N
H
6H13
6H13
6H13
13[e]
N
2.0
62
t-Bu
t-Bu
HN
t-Bu
OTs
Me
n-C
n-C
6H13
Me
13[d]
n-C
n-C
4H9
4H9
N
H
N
14[e]
15[e]
N
2.0
2.0
74
87
Me
HN
t-Bu
t-Bu
OTs
OTs
Me
OTs
n-C
n-C
Ph
4H9
Ph
4H9
Ph
HN
Me
t-Bu
N
Me
[a] Reaction conditions: ArOTs (1.0 mmol), amine (1.5 mmol), K2CO3 (2.5
mmol), Pd(OAc)2 (as indicated), Pd/CM-phos = 1:4, PhB(OH)2 (0.04 mmol),
t-BuOH (3.0 mL) were stirred for 24 h at 110 °C under nitrogen. Reaction
times were not optimized for each substrate. [b] Isolated yields. [c] K3PO4
was used as base. [d] ArOTs (1.5 mmol), amine (1.0 mmol) were used.
Me
Me
Me
Ph
HN
Me
Ph
16[e]
2.0
1.0
91
84
N
OTs
OTs
Me
Me
Ph
HN
Ph
Ph
17[e
t-Bu
N
]
t-Bu
To further evaluate the Pd/CM-phos catalytic system, we next
turned our attention to investigate the scope of primary aliphatic
amines, secondary cyclic, and acyclic aliphatic amines (Table 3).
Morpholine was used as the secondary amine model for
coupling with various electrophilic partners. Notably, excellent
Ph
[a] Reaction conditions: ArOTs (1.0 mmol), secondary amine (1.5 mmol),
K3PO4 (2.5 mmol), Pd(OAc)2 (as indicated), Pd/CM-phos = 1:4, PhB(OH)2
(0.04 mmol), t-BuOH (3.0 mL) were stirred for 24 h at 110 °C under nitrogen.
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10.1002/asia.201800575
Chemistry - An Asian Journal
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Reaction times were not optimized for each substrate. [b] Isolated yields. [c]
The reaction was run for 40 hours. [d] K2CO3 was used as base. [e] DMF
was used as solvent. [f] Reaction temperature was 120 °C.
hindered α-branched primary amine provided the desired
coupling products in good-to-excellent yields (Table 4, entries 3
and 5). Heterocyclic-moiety containing primary aliphatic amine,
e.g. furfurylamine, reacted smoothly to afford the coupling
product (Table 4, entry 7).
Ester-, keto-substituted aryl tosylates provided the desired
product in good yields (83-95%) (Table 3, entries 3 and 4).
Alkenyl tosylate 1-methyl-2-oxo-1,2-dihydroquinolin-4-yl tosylate
also served as an applicable coupling partner (Table 3, entry 8).
With the excellent results obtained, we next investigated the
amination of aryl tosylates with other alkyl amines. Secondary
cyclic amines including pyrrolidine, and 1-methylpiperazine also
provided the corresponding products in good-to-excellent yields
(Table 3, entries 9-11). Acyclic secondary amines were also
found to be suitable coupling partners (Table 3, entries 13-17).
Table 5. Palladium-catalyzed N-arylation of various NH-heterocycles with aryl
tosylates[a]
R
/ CM-phos
Pd(OAc)2
+
R
R'
HN
R'
N
K2CO
3, t-BuOH
OTs
110 °C, 24 h
%yield[b]
entry
1
product
ArOTs
Amine
[Pd]
t-Bu
0.5
97
N
N
t-Bu
H
OTs
Me
Me
Table 4. Palladium-catalyzed monoarylation of primary aliphatic amines with
aryl tosylates[a]
2
0.25
99
N
N
H
Me
OTs
OTs
Me
R'
N
R
/ CM-phos
Pd(OAc)2
K3PO
+
R
H
N
4, t-BuOH
110 °C, 24 h
3
4
5
0.5
0.5
0.5
90
93
72
H
H
OTs
N
H
R'
N
%yield[b]
73
entry
1
ArOTs
Amine
N
product
[Pd]
O
O
Ph
O
Ph
H
N
N
H
N
1.0
t-Bu
OTs H2N
O
O
t-Bu
N
N
O
O
OTs
OTs
OTs
O
Me
Me
Me
Me
MeO
H
N
N
H
N
2
1.0
2.0
75
91
H2N
Me
N
OTs
OTs
MeO
OMe
OMe
t-Bu
Me
Me
6
0.5
91
Me
3[c]
N
t-Bu
N
t-Bu
H
t-Bu
NH
NH2
Me
Me
Me
Me
Me
Me
Me
7
8
0.5
0.5
90
88
4
H2N
Me
2.0
79
OTs
NH
Me
N
N
H
Me
OTs
Me
Me
Me
Me
F
Me
Me
F
N
N
5[c]
2.0
2.0
70
91
H2N
NH
OTs
OTs
H
Me
OTs
OTs
Me
Me
Me
Me
t-Bu
Me
9
N
0.5
1.0
78
77
H2N
t-Bu
N
H
6[c]
NH
NH
Me
Me
Me
Me
Me
Me
10
N
N
H
O
Me
OTs
OTs
Me
7[c]
2.0
82
OTs
t-Bu
O
H2N
t-Bu
N
Me
Me
11[c]
1.0
1.0
96
87
N
H
Me
Me
[a] Reaction conditions: ArOTs (1.0 mmol), primary amine (1.5 mmol),
K3PO4 (2.5 mmol), Pd(OAc)2 (as indicated), Pd/CM-phos = 1:4, PhB(OH)2
(0.04 mmol), t-BuOH (3.0 mL) were stirred for 24 h at 110 °C under nitrogen.
Reaction times were not optimized for each substrate. [b] Isolated yields.
[c] DMF was used as solvent.
Me
Me
S
12[d]
Me
Me
N
HN
S
Me
OTs
OTs
Primary aliphatic amines underwent the N-arylation
transformation smoothly and essentially only mono-N-arylated
products were afforded (Table 4). N-Aminomorpholine reacted
with aryl tosylates in the presence of 1.0 mol% Pd catalyst to
give secondary amines without noticeable formation of
diarylated tertiary amines (Table 4, entries 1-2). Sterically
O
13
1.0
84
N
HN
O
Me
[a] Reaction conditions: ArOTs (1.0 mmol), NH-heterocycle (1.5 mmol),
K2CO3 (2.5 mmol), Pd(OAc)2 (as indicated), Pd/CM-phos = 1:4, PhB(OH)2
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10.1002/asia.201800575
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(0.04 mmol), t-BuOH (3.0 mL) were stirred for 24 h at 110 °C under nitrogen.
Reaction times were not optimized for each substrate. [b] Isolated yields.
[c] ArOTs (1.5 mmol), amine (1.0 mmol) were used. [d] Cs2CO3 was used
as base.
yields (Table 6, entries 1-5). Particularly noteworthy is that the
Pd/CM-phos system retained to be effective even in solvent-free
environment. No detrimental effects were found when the
catalyst loading was down to 0.5 mol% of Pd (Table 6, entries 2
and 5). A comparison between the aqueous system and
solvent-free conditions revealed that the solventless system
required slightly lower catalyst loading (Table 6, entries 1 vs 2,
and 4 vs 5).
Nitrogen-containing heterocycles are important constituents of
pharmaceutically active compounds and hence versatile method
for diversely modifying these skeletons are of high interest.[24]
We came across the coupling reaction between NH-heterocyclic
compounds and aryl tosylates (Table 5). Indole core with
different substituents were investigated. Excellent product yields
were obtained even the catalyst loading was down to 0.25-0.5
mol% of Pd (Table 5, entries 1-8). Other NH-heterocylces such
as pyrrole, 1,2,3,4-tetrahydrocyclopenta[b]indole, carbazole, 10-
phenothiazine and 10-phenoxazine were also found to be
applicable (Table 5, entries 9-13). Weakly nucleophilic and/or
more steric bulky NH-heterocycles required slightly higher
catalyst loading in this coupling reaction (from 0.5 mol% Pd to
1.0 mol% Pd).
Table 7. Palladium-catalyzed N-arylation of α-chiral amines with aryl
tosylates[a]
R'
N
R
/ CM-phos
Pd(OAc)2
K3PO
+
R
H
N
4, DMF
110 °C, 24 h
H
H
OTs
ArOTs
R'
% yield[b]
78
% ee[c]
entry
1
product
Me
Amine
Me
Me
Me
Me
NH
NH2
OTs
Me
Me
Table 6. Palladium-catalyzed N-arylation of amines with aryl tosylates under
Me
NH
aqueous medium or solvent-free conditions[a]
Me
Me
Me
Me
Me
Me
2[d]
72
91
85
97 (S)
Me
/ CM-phos R
R"
R"
Pd(OAc)2
+
R
NH2
H
OTs
OTs
OTs
Me
Me
N
N
water, K
2CO3
,
OTs
R'
110 °C, 24 h
R'
Me
NH
% yield[b]
entry
product
Amine
ArOTs
[Pd]
Me
3
t-Bu
NH2
t-Bu
t-Bu
Me
Me
1
2[c]
1.0
0.5
95
95
Me
N
N
H
Me
NH
OTs
OTs
Me
Me
4
99 (S)
Me
Me
t-Bu
NH2
3
1.0
82
Me
H2N
N
H
Me
Me
Me
Me
H
N
Me
Me
5
6
71
70
Me
OTs
OTs
4
1.0
0.5
94
97
NH2
H2N
5[c]
N
H
Me
Me
Me
OTs
OTs
H
N
97 (R)
NH2
6
7
1.0
1.0
90
87
Me
N
N
H
Me
[a] Reaction conditions: ArOTs (1.0 mmol), chiral amine (1.5 mmol), K3PO4
(2.5 mmol), Pd(OAc)2 (2.0 mol%), Pd/CM-phos = 1:4, PhB(OH)2 (0.04
mmol), DMF (3.0 mL) were stirred for 24 h at 110 °C under nitrogen.
Reaction times were not optimized for each substrate. [b] Isolated yields.
[c] Determined by HPLC analysis using Daicel Chiralcel OD-H column. [d]
5.0 mmol of amine was used.
OTs
HN
O
N
O
[a] Reaction conditions: ArOTs (1.0 mmol), amine (2.0 mmol), K2CO3 (2.5
mmol), Pd(OAc)2 (as indicated), Pd/CM-phos = 1:4, PhB(OH)2 (0.04 mmol),
water (3.0 mL) were stirred for 24 h at 110 °C under nitrogen. Reaction
times were not optimized for each substrate. [b] Isolated yields. [c] Amine
(5.0 mmol) was used and no solvent was added.
Amine having proximal central chiral carbon(s) are often
found sub-skeleton in various bioactive compounds, such as
25
]
topoisomerase II inhibitor GL331,[
and 4β-N-amino-4-
desoxypodophylotoxin congeners (antitumor antibiotics).[ 26] In
fact, the challenge of C–N coupling between α-central chiral
Organic solvents are often employed in various cross-
coupling reactions. Yet, it would be of great interest if more
environmentally benign solvents can be used to replace
common organic solvents. In view of the attractiveness of using
water as solvent, we embarked to perform this reaction in
aqueous medium. To our delight, by using the weak base
K2CO3, no alkaline hydrolysis of aryl tosylates was observed
under these aqueous conditions (Table 6). Sterically hindered
amines were able to afford the desired product in excellent
amine
and
electrophile
is
to
keep
the
product
enantioselectivity.[ 27] The possible β-elimination of the Pd-N-
CHR2 intermediate, and subsequent re-insertion of flipped
C(sp2)-imine moiety would ruin the enantiomeric purity of the final
product. To our delight, under our monophosphine/Pd system,
no racemization of the products was observed (Table 7). (S)-1-
Phenylethanamine (98% ee) (Table 7, entry 2), (S)-1-
(naphthalen-1-yl)ethanamine (99% ee) (Table 7, entry 4) and
(R)-1,2,3,4-tetrahydronaphthalen-1-amine (98% ee) (Table 7,
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Pd(OAc)2 (2.0 mol%, 0.02 mmol) and CM-phos (8.0 mol%, 0.08 mmol) in
freshly distilled dichloromethane (2 ml, 1.0 mol% Pd per 1 ml stock
solution) were initially prepared with continuously stirring at room
temperature for 5 min. A Schlenk tube was charged with a Teflon-coated
magnetic stir bar (4 mm x 10 mm) and was evacuated and backfilled with
nitrogen (3 cycles). The corresponding volume of stock solution was
added by syringe to the tube (indicated in Tables 2-6). Et3N (0.4 equiv.)
was introduced to the tube for precomplexation. The palladium complex
solution was then stirred and warmed using a hair drier for 1 to 2 minutes
until the solvent started boiling. The solvent was removed under reduced
pressure. Aryl tosylates (1.0 mmol), phenylboronic acid (0.04 mmol, 0.04
equiv.) and K2CO3 or K3PO4 (2.5 mmol, 2.5 equiv.) were loaded into the
tube, which was again evacuated and flushed with nitrogen for three
times. Amines (1.5 mmol, 1.5 equiv.) and t-BuOH or DMF (3.0 mL if
solvent is used) were then added with continuous stirring at room
temperature for 3-4 minutes. The tube was resealed and then placed
into a preheated oil bath (110 °C) and stirred for 24 hours. After
completion of reaction, the reaction tube was allowed to reach room
temperature and quenched with water and diluted with ethyl acetate.
The organic layer was separated and the aqueous layer was washed
with ethyl acetate. The organic layers were combined and concentrated
under reduced pressure. The crude products were purified by flash
column chromatography on silica gel (230-400 mesh) to afford the
desired product.
entry 6) were examined and the product enantioselectivities
were retained under this catalyst system.
Conclusions
In conclusion, we reported a Pd/CM-phos catalyst system
that promote the cross-coupling between N-nucleophiles and
aryl tosylates for the first time. This system broadly allowed the
C–N bond coupling to be proceeded across different nature of
amines, e.g. arylamines, primary and secondary aliphatic
amines, cyclic and acyclic amines, N-heterocycles and α-central
chiral amines. It is of note that particular catalyst loading can be
as low as 0.05 mol% Pd. Interestingly, no erosion of product
enantiopurity was observed when α-chiral amine was subjected
to this coupling reaction under the Pd/CM-phos catalytic system.
While most reported aryl sulfonate coupling procedures required
organic solvents (to minimize undesirable alkaline hydrolysis),
we here also showed the feasibility of using water as the solvent
medium without detrimental effects. We believe this general
catalyst system would be of interest to organic and
pharmaceutical chemists working on phenol-related (sulfonate-
protected phenol) areas, as the inherently inert feature of the
tosyloxy group could serve as the protecting group in the early
stage of synthetic route and ultimately allow post-
functionalization via cross-coupling strategy.
4-(tert-Butyl)-N-methyl-N-phenylaniline (Table 2, Entry 1; Table 6,
Entry 1 and 2)[22b]
Hexane: DCM = 20:1, Rf = 0.4; 1H NMR (400 MHz, CDCl3): δ 1.55 (s,
9H), 3.49 (s, 3H), 7.10 (t, J=7.3 Hz, 1H), 7.18-7.25 (m, 4H), 7.43-7.47 (m,
2H), 7.52-7.54 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 31.4, 34.1, 40.1,
118.9, 120.2, 121.2, 126.0, 129.0, 144.6, 146.3, 149.1.
Experimental Section
Methyl 4-(N-methyl(N-phenyl)amino)benzoate (Table 2, Entry 2)[30]
General considerations
Hexane: DCM = 20:1, Rf = 0.4; 1H NMR (400 MHz, CDCl3): δ 1.55 (s,
9H), 3.49 (s, 3H), 7.10 (t, J=7.3 Hz, 1H), 7.18-7.25 (m, 4H), 7.43-7.47 (m,
2H), 7.52-7.54 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 31.4, 34.1, 40.1,
118.9, 120.2, 121.2, 126.0, 129.0, 144.6, 146.3, 149.1.
Unless otherwise noted, all reagents were purchased from commercial
suppliers and used without purification. All the reactions were performed
in Rotaflo®(England) resealable screw-cap tube (approx. 20 mL volume)
in the presence of Teflon coated magnetic stirrer bar (4 mm × 10 mm).
Dioxane was freshly distilled over sodium under nitrogen.
Dimethylformamide (DMF) was distilled from calcium hydride under
N,N-
4-(N-Methyl(N-phenyl)amino)benzonitrile (Table 2, Entry 3)[22b]
reduced pressure. t-Butanol was first distilled over sodium and stored
with calcium hydride under nitrogen.[28] CM-phos ligand was developed
1
Hexane: EA = 4:1, Rf = 0.6; H NMR (400 MHz, CDCl3): δ 3.32 (s, 3H),
29]
by Kwong group and prepared according to literature.[
Thin layer
6.70 (d, J=9.0 Hz, 2H), 7.17-7.19 (m, 2H), 7.22-7.26 (m, 1H), 7.34-7.43
(m, 4H); 13C NMR (100 MHz, CDCl3) δ 39.7, 98.7, 113.4, 119.9, 125.8,
126.0, 129.7, 132.7, 146.3, 151.5.
chromatography was performed on precoated silica gel 60 F254 plates.
Silica gel (230-400 mesh) was used for column chromatography. 1H
NMR spectra were recorded on a 400 MHz or 500 MHz spectrometer.
Spectra were referenced internally to the residual proton resonance in
CDCl3 (δ 7.26 ppm), or with TMS (δ 0.00 ppm) as the internal standard.
Chemical shifts (δ) were reported as part per million (ppm) in δ scale
downfield from TMS. 13C NMR spectra were recorded on a 100 MHz or
125 MHz spectrometer and the spectra were referenced to CDCl3 (δ 77.0
ppm, the middle peak). Coupling constants (J) were reported in Hertz
(Hz). Mass spectra (EI-MS and ES-MS) were recorded on a Mass
Spectrometer. High-resolution mass spectra (HRMS) were obtained on
an ESI-QToF mass spectrometer which the ionization method is
electrospray ionization (ESI) and the mass analyzer is a quadrupole time-
of-flight mass analyzer. HPLC analyses were performed on a HP 1100
instrument using Chiralcel® OD-H columns (0.46 cm diameter x 25 cm
long).
N,2-Dimethyl-N-phenylbenzo[d]thiazol-5-amine (Table 2, Entry 4)[31]
Hexane: EA = 20:1, Rf = 0.16; 1H NMR (400 MHz, CDCl3): δ 2.28 (s, 3H),
3.35 (s, 3H), 6.96-7.07 (m, 4H), 7.26-7.30 (m, 2H), 7.57-7.65 (m, 2H); 13
NMR (100 MHz, CDCl3) δ 19.7, 40.2, 112.7, 118.7, 120.3, 121.0, 121.3,
C
127.7, 128.9, 147.5, 148.7, 154.4, 167.2.
N-Methyl-N-phenylquinolin-6-amine (Table 2, Entry 5)[32]
Hexane: EA = 9:1, Rf = 0.16; 1H NMR (400 MHz, CDCl3): δ 3.32 (s, 3H),
7.05-7.06 (m, 2H), 7.10-7.12 (m, 2H), 7.18-7.20 (m, 1H), 7.27-7.35 (m,
3H), 7.85-7.90 (m, 2H), 8.65-8.66 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
40.2, 110.6, 121.0, 123.0, 123.2, 123.4, 129.2, 129.4, 134.0, 143.6,
146.5, 147.1, 148.1.
General procedures for palladium-catalyzed N-arylation of amines
with aryl tosylates:
3-(Methyl(phenyl)amino)phenyl 4-methylbenzenesulfonate (Table 2,
Entry 6)[33]
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1
1
Hexane: EA = 3:7, Rf = 0.3; H NMR (400 MHz, CDCl3): δ 2.44 (s, 3H),
Hexane: EA = 9:1, Rf = 0.3; H NMR (400 MHz, CDCl3): δ 1.41 (s, 9H),
3.21 (t, J=4.8 Hz, 4H), 3.93 (t, J=4.7 Hz, 4H), 6.96 (d, J=8.8 Hz, 2H), 7.41
(d, J=8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 31.3, 33.8, 49.4, 66.8,
115.2, 125.8, 142.5, 148.8.
3.26 (s, 3H), 6.80-6.87 (m, 4H), 7.03-7.07 (m, 3H), 7.29-7.32 (m, 4H),
7.75 (d, J=8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.4, 40.0, 118.3,
122.2, 122.6, 128.2, 129.2, 129.5, 132.2, 142.3, 145.0, 147.5, 148.1.
Phenyl(4-(phenylamino)phenyl)methanone (Table 2, Entry 7)[34]
4-Morpholinobenzoic acid methyl ester (Table 3, Entry 3)[37]
Hexane: EA = 4:1, Rf = 0.33; 1H NMR (400 MHz, CDCl3): δ 6.55 (bs, 1H),
7.02-7.10 (m, 3H), 7.21 (d, J=7.7 Hz, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.47 (t,
J=7.5 Hz, 1H), 7.54-7.56 (m, 1H), 7.78 (t, J=7.6 Hz, 4H); 13C NMR (100
MHz, CDCl3) δ 114.2, 120.6, 123.1, 128.0, 128.2, 129.4, 129.5, 131.5,
132.6, 138.6, 140.6, 148.3, 195.2.
Hexane: EA = 9:1, Rf = 0.13; 1H NMR (400 MHz, CDCl3): δ 3.23 (t, J=4.8
Hz, 4H), 3.80 (t, J=4.8 Hz, 4H) 3.83 (s, 3H), 6.81 (d, J=8.9 Hz, 2H), 7.90
(d, J=8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 47.4, 51.5, 66.4, 113.2,
120.0, 131.0, 154.0, 166.8.
(4-Morpholinophenyl)(phenyl)methanone (Table 3, Entry 4)[34]
1-(3-(Phenylamino)phenyl)ethanone (Table 2, Entry 8)[35]
Hexane: EA = 9:1, Rf = 0.1; 1H NMR (400 MHz, CDCl3): δ 3.25 (t, J=4.8
Hz, 4H), 3.79 (t, J=4.8 Hz, 4H), 6.84 (d, J=8.9 Hz, 2H), 7.41 (t, J=7.4 Hz,
2H), 7.48-7.50 (m, 1H), 7.69-7.71 (m, 2H), 7.76 (d, J=8.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 47.1, 66.2, 112.8, 127.3, 127.8, 129.3, 131.3,
132.1, 138.4, 153.7, 194.8.
Hexane: EA = 9:1, assist with high vacuum, Rf = 0.2; 1H NMR (400 MHz,
CDCl3): δ 2.58 (s, 3H), 6.24 (bs, 1H), 7.00 (t, J=7.3 Hz, 1H), 7.13 (d,
J=7.6 Hz, 2H), 7.30-7.35 (m, 4H) 7.48 (d, J=7.2 Hz, 1H), 7.68 (s, 1H); 13
C
NMR (100 MHz, CDCl3) δ 26.5, 116.2, 118.1, 120.3, 121.3, 121.4, 129.2,
138.0, 142.2, 143.7, 198.4.
4-(Benzo[d][1,3]dioxol-5-yl)morpholine (Table 3, Entry 5)[38]
4-Methoxy-N-phenylaniline (Table 2, Entry 9)[36]
Hexane: EA = 4:1, Rf = 0.4; 1H NMR (400 MHz, CDCl3): δ 3.03 (t, J=4.8
Hz, 4H), 3.84 (t, J=4.8 Hz, 4H), 5.90 (s, 2H), 6.34-6.37 (dd, J=2.4, 8.4 Hz,
1H), 6.55 (d, J=2.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 51.0, 66.9, 99.5, 100.9, 108.2, 108.6, 141.7, 147.3, 148.3.
1
Hexane: EA = 9:1, Rf = 0.4; H NMR (400 MHz, CDCl3): δ 3.87 (s, 3H),
5.56 (bs, 1H), 6.91-7.00 (m, 5H), 7.15 (d, J=8.8 Hz, 2H), 7.29-7.33 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 55.4, 114.5, 115.5, 119.4, 122.0,
129.2, 135.6, 145.0, 155.1.
4-(Naphthalen-1-yl)morpholine (Table 3, Entry 6)[38]
N-(4-(tert-Butyl)phenyl)-2,6-dimethylaniline (Table 2, Entry 10; Table
6, Entry 3)[22b]
Hexane: EA = 20:1, Rf = 4.5; 1H NMR (400 MHz, CDCl3): δ 3.15 (t, J=4.4
Hz, 4H), 4.02 (t, J=4.4 Hz, 4H), 7.12 (d, J=7.6 Hz, 1H), 7.45 (t, J=8.0 Hz,
1H), 7.50-7.55 (m, 2H), 7.61 (d, J=8.0 Hz, 1H); 7.86-7.89 (m, 1H), 8.25 (d,
J=9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 53.5, 67.5, 114.7, 123.4,
123.8, 125.5, 125.9, 128.5, 128.8, 134.8, 149.4.
Hexane: EA = 20:1, Rf = 0.5; 1H NMR (400 MHz, CDCl3): δ 1.53 (s, 9H),
2.44 (s, 6H), 5.27 (bs,1H), 6.69 (d, J=8.5 Hz, 2H), 7.29-7.35 (m, 3H),
7.41 (d, J=8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 18.4, 31.5, 33.8,
113.3, 125.3, 125.8, 128.4, 135.4, 138.7, 140.8, 143.6.
4-(2,5-Dimethylphenyl)morpholine (Table 3, Entry 7)[39]
N-(3,5-Dimethylphenyl)-2,6-dimethylaniline (Table 2, Entry 11; Table
6, Entry 4 and 5)[22b ]
Hexane: EA = 20:1, Rf = 0.5; 1H NMR (400 MHz, CDCl3): δ 2.36 (t, J=7.6
Hz, 6H), 3.2.95 (t, J=4.4Hz, 4H), 3.90 (t, J=4.4 Hz, 4H), 6.87 (s, 1H),
6.89 (s, 1H), 7.14 (d, J=7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 17.4,
21.2, 52.3, 67.5, 119.7, 124.0, 129.3, 131.0, 136.2, 151.1.
Hexane: EA = 20:1, Rf = 0.5; 1H NMR (400 MHz, CDCl3): δ 2.53 (s, 12H),
5.3 (bs, 1H), 6.46 (s, 2H), 6.74 (s, 1H), 7.39-7.45 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 18.2, 21.3, 111.2, 120.1, 125.4, 128.3, 135.7, 138.3,
138.6, 146.1.
1-Methyl-4-morpholinoquinolin-2(1H)-one (Table 3, Entry 8)
N-(2,6-Dimethylphenyl)naphthalen-2-amine (Table 2, Entry 12)[34]
Hexane: EA = 1:2, Rf = 0.3; 1H NMR (400 MHz, CDCl3): δ 3.13 (t, J=4.4
Hz, 4H), 3.69 (s, 3H), 3.95 (t, J=4.4 Hz, 4H), 6.22 (s, 1H), 7.23 (t, J=8.0
Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.54-7.58 (m, 1H), 7.81 (d, J=8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 29.1, 52.2, 66.7, 106.6, 114.8, 117.4,
121.4, 124.9, 130.5, 140.5, 157.9, 163.2; HRMS: calcd. for C14H16N2O2:
245.1285, found 245.128.
Hexane: EA = 20:1, Rf = 0.16; 1H NMR (400 MHz, CDCl3): δ 2.43 (s, 6H),
5.42 (bs, 1H), 6.76 (d, J=1.8 Hz, 1H), 7.10 (q, J=6.6 Hz, 1H), 7.33-7.41
(m, 4H), 7.50 (m, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.86 (t, J=9.3 Hz, 2H); 13
C
NMR (100 MHz, CDCl3) δ 18.3, 106.0, 117.4, 122.2, 125.9, 125.9, 126.2,
127.6, 127.8, 128.6, 129.1, 134.9, 136.0, 137.9, 143.9.
1-(4-(tert-Butyl)phenyl)pyrrolidine (Table 3, Entry 9)[22b ]
3,5-Dimethyl-N,N-diphenylaniline (Table 2, Entry 13)[36]
1
Hexane: EA = 1:4, Rf = 0.6; H NMR (400 MHz, CDCl3): δ 1.58 (s, 9H),
Hexane, Rf = 0.4; 1H NMR (500 MHz, CDCl3): δ 2.27 (s, 6H), 6.73 (s,
1H), 6.78 (s, 2H), 7.04 (t, J=7.5 Hz, 2H), 7.14 (d, J=1.0 Hz, 4H), 7.29 (t,
J=2.0 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 21.3, 122.3, 122.4, 124.0,
124.8, 129.1, 138.8, 147.7, 148.0.
2.19-2.23 (m, 4H), 3.50- 3.53 (m, 4H), 6.79 (d, J=8.7 Hz, 2H), 7.52-7.54
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 25.4, 31.5, 33.6, 47.5, 111.2,
125.7, 137.7, 145.8.
1-(Naphthalen-2-yl)pyrrolidine (Table 3, Entry 10)[22b]
4-(4-tert-Butylphenyl)morpholine (Table 3, Entry 1 and 2)[22b]
Hexane: DCM = 1:4, Rf = 0.6; 1H NMR (400 MHz, CDCl3): δ 2.08-2.11
(m, 4H), 3.44-3.47 (m, 4H), 6.83 (m, 1H), 7.04-7.07 (m, 1H), 7.22-7.26 (m,
1H), 7.41-7.45 (m, 1H), 7.71-7.78 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
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25.4, 47.7, 104.6, 115.6, 120.1, 125.7, 126.1, 126.2, 127.5, 128.7, 135.2,
145.8.
N-(3,5-Dimethylphenyl)morpholin-4-amine (Table 4, Entry 2)[41]
1
Hexane: EA = 1:7, Rf = 0.5; H NMR (400 MHz, CDCl3): δ 2.31 (s, 6H),
2.78 (s, 4H), 3.86 (t, J=4.8 Hz, 4H), 3.52 (s, 1H), 6.60 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.5, 56.5, 67.0, 111.6, 121.7, 138.9, 147.1.
1-(3,5-Dimethylphenyl)-4-methylpiperazine (Table 3, Entry 11)[36]
Acetone: EA = 1:4, Rf = 0.4; 1H NMR (400 MHz, CDCl3): δ 2.32 (s, 6H),
2.38 (s, 3H), 2.60 (t, J=4.8 Hz, 4H), 3.23 (t, J=4.8 Hz, 4H), 6.56 (s, 1H),
6.61 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 21.6, 46.1, 49.2, 55.2, 114.0,
121.7, 138.6, 151.4.
N-(sec-Butyl)-4-(tert-butyl)aniline (Table 4, Entry 3)[42]
Hexane: EA = 9:1, Rf = 0.6; 1H NMR (400 MHz, CDCl3): δ 1.04 (t, J=7.6
Hz, 3H), 1.24 (d, J=6.4 Hz, 3H), 1.37 (s, 9H), 1.51-1.58 (m, 1H), 1.65-
1.72 (m, 1H), 3.43-3.48 (m, 1H), 6.63 (t, J=6.8 Hz, 2H), 7.27 (t, J=6.4 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 10.4, 20.4, 29.8, 31.6, 33.8, 50.0,
112.8, 126.0, 139.5, 145.4.
4-(tert-Butyl)-N-cyclohexyl-N-methylaniline (Table 3, Entry 12)
Hexane: EA = 20:1, Rf = 0.7;1H NMR (400 MHz, CDCl3): δ 1.20-1.23 (m,
1H), 1.39 (s, 9H), 1.42-1.57 (m, 4H), 1.79 (d, J=13.0 Hz, 1H), 1.90 (t,
J=16.4 Hz, 4H), 2.85 (s, 3H), 3.59-3.66 (m, 1H), 6.82 (d, J=8.8 Hz, 2H),
7.34-7.36 (dd, J=1.9, 6.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 25.9,
26.1, 30.0, 31.1, 31.4, 33.6, 58.1, 112.8, 125.7, 138.7, 147.8; HRMS:
calcd. for C17H28N+: 246.2222, found 246.2223.
N-Hexyl-3,5-dimethylaniline (Table 4, Entry 4)[42]
Hexane: EA = 9:1, Rf = 0.6; 1H NMR (400 MHz, CDCl3): δ 1.01 (t, J=6.8
Hz, 3H), 1.41-1.51 (m, 6H), 1.66-1.72 (m, 2H), 2.32-2.37 (m, 6H), 3.16 (d,
J=6.8 Hz, 2H), 3.19 (bs, 1H), 6.34 (s, 2H), 6.46 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 14.1, 21.5, 22.7, 26.9, 29.7, 31.7, 44.1, 110.7, 118.8,
119.1, 138.8, 148.7.
4-(tert-Butyl)-N,N-dihexylaniline (Table 3, Entry 13)
Hexane: EA = 20:1, Rf = 0.7; 1H NMR (400 MHz, CDCl3): δ 1.11 (t, J=5.8
Hz, 6H), 1.50 (d, J=9.9 Hz, 21H), 1.78 (s, 4H), 3.43 (t, J=7.6 Hz, 4H),
6.79 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 14.0, 22.7, 26.9, 27.3, 31.5, 31.7, 33.5, 51.1, 111.3, 125.8,
137.5, 145.9; HRMS: calcd. for C22H40N+: 318.3161, found 318.3154.
N-Cyclopentyl-3,5-dimethylaniline (Table 4, Entry 5)[43]
Hexane: EA = 20:1, Rf = 0.5; 1H NMR (400 MHz, CDCl3): δ 1.48-1.56 (m,
2H), 1.64-1.83 (m, 4H), 2.04-2.12 (m, 2H), 2.31 (s, 6H), 3.81-3.88 (m,
1H), 6.32 (s, 2H), 6.42 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.5, 24.1,
33.7, 54.7, 111.2, 119.0, 138.8, 148.1.
4-(tert-Butyl)-N,N-dihexylaniline (Table 3, Entry 14)[40]
Hexane: EA = 20:1, Rf = 0.7; 1H NMR (400 MHz, CDCl3): δ 1.09 (t, J=7.2
Hz, 6H), 1.43 (s, 9H), 1.46-1.54 (m, 4H), 1.67-1.74 (m, 4H), 3.38 (t, J=7.6
Hz, 4H), 6.74 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 14.1, 20.5, 29.6, 31.7, 33.7, 51.0, 111.5, 126.0, 137.8,
146.1.
3,5-Dimethyl-N-(naphthalen-1-ylmethyl)aniline (Table 4, Entry 6)[44]
Hexane: EA = 20:1, Rf = 0.5; 1H NMR (400 MHz, CDCl3): δ 2.39 (s, 6H),
4.80 (s, 2H), 6.44 (s, 2H), 6.57 (s, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.62-7.65
(m, 3H), 7.91 (d, J=8.0 Hz, 1H), 8.00-8.02 (m, 1H), 8.17-8.20 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 21.6, 46.5, 110.8, 119.7, 123.8, 125.7,
125.9, 126.1, 126.4, 128.2, 128.8, 131.7, 134.0, 134.7, 139.1, 148.5.
N-Benzyl-4-(tert-butyl)-N-methylaniline (Table 3, Entry 15)[40]
Hexane: EA = 1:20, Rf = 0.7; 1H NMR (400 MHz, CDCl3): δ 1.67 (s, 9H),
N-(Furan-2-ylmethyl)-3,5-dimethylaniline (Table 4, Entry 7)[45]
3.29 (s, 3H), 4.80 (s, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.58-7.62 (m, 7H); 13
C
Hexane: EA = 20:1, Rf = 0.4; 1H NMR (400 MHz, CDCl3): δ 2.28 (s, 6H),
4.33 (s, 2H), 6.26 (d, J=3.2 Hz, 1H), 6.36 (s, 3H), 6.45 (s, 1H), 7.40 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 21.5, 41.6, 106.9, 110.3, 111.2, 120.1,
138.9, 141.8, 147.6, 152.9.
NMR (100 MHz, CDCl3) δ 31.5, 33.6, 38.3, 56.8, 112.1, 125.8, 126.7,
128.4, 139.0, 139.2, 147.5.
N-Benzyl-N-ethyl-3,5-dimethylaniline (Table 3, Entry 16)
Hexane: EA = 1:20, Rf = 0.7, colorless oil; 1H NMR (400 MHz, CDCl3): δ
1.35 (t, J=7.2 Hz, 3H), 2.41 (s, 6H), 3.57-3.62 (q, J=6.8, 7.2 Hz, 2H), 4.66
(s, 2H), 6.54 (s, 3H), 7.37-7.49 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
12.2, 21.9, 44.9, 53.9, 110.2, 118.4, 126.8, 128.6, 138.9, 139.6, 148.9;
HRMS: calcd. for C17H21N: 240.1747, found 240.1751.
1-(4-(tert-Butyl)phenyl)-1H-indole (Table 5, Entry 1)[22b]
Hexane: EA = 20:1, Rf = 0.6; 1H NMR (400 MHz, CDCl3): δ 1.57 (s, 9H),
6.86 (d, J=3.1 Hz, 1H), 7.36-7.42 (m, 2H), 7.48 (d, J=3.2 Hz, 1H), 7.59 (d,
J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.0 Hz, 1H), 7.89 (d,
J=7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 31.4, 34.5, 103.2, 110.6,
120.2, 121.0, 122.2, 123.9, 126.4, 128.0, 129.2, 135.9, 137.2, 149.3.
N,N-Dibenzyl-4-(tert-butyl)aniline (Table 3, Entry 17)[22b]
Hexane: EA = 4:1, Rf = 0.6; 1H NMR (400 MHz, CDCl3): δ1.57 (s, 9H),
4.89 (s, 4H), 6.99 (d, J=8.9 Hz, 2H), 7.46-7.59 (m, 12H); 13C NMR (100
MHz, CDCl3) δ 31.5, 33.6, 54.2, 112.1, 125.9, 126.6, 126.7, 128.5, 138.8,
139.1, 146.9.
1-(3,5-Dimethylphenyl)-1H-indole (Table 5, Entry 2)[46]
Hexane: EA = 20:1, Rf = 0.6; 1H NMR (400 MHz, CDCl3): δ 2.65 (s, 6H),
6.95-6.96 (m, 1H), 7.24 (s, 1H), 7.39 (s, 2H), 7.46-7.56 (m, 3H), 7.90 (d,
J=8.0 Hz, 1H), 8.00 (d, J=7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
21.2, 103.1, 110.6, 120.1, 121.0, 121.9, 122.1, 127.9, 128.0, 129.2,
135.8, 139.2, 139.6.
N-(4-(tert-Butyl)phenyl)morpholin-4-amine (Table 4, Entry 1)[41]
1
Hexane: EA = 9:1, Rf = 0.2; H NMR (400 MHz, CDCl3): δ 1.34 (s, 9H),
2.78 (s, 4H), 3.84 (t, J=4.8 Hz, 4H), 4.35 (bs, 1H), 6.90 (d, J=8.4 Hz, 2H),
7.27 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 31.5, 34.0, 56.5,
67.0, 113.5, 125.9, 142.6, 144.6.
1-(Naphthalen-2-yl)-1H-indole (Table 5, Entry 3)[22b]
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Hexane: EA = 9:1, Rf = 0.3; 1H NMR (400 MHz, CDCl3): δ 7.05 (d, J=3.1
Hz, 1H), 7.56-7.58 (m, 2H), 7.67-7.65 (m, 1H), 7.75-7.77 (m, 2H), 7.86
(m, 1H), 8.04 (m, 1H), 8.09-8.13 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
103.8, 110.5, 120.4, 121.1, 121.6, 122.4, 122.9, 125.8, 126.7, 127.5,
127.7, 128.0, 129.4, 131.6, 133.6, 135.9, 137.0.
9-(4-(tert-Butyl)phenyl)-9H-carbazole (Table 5, Entry 11)[22b]
Hexane: DCM = 9:1, Rf = 0.4; 1H NMR (400 MHz, CDCl3): δ 1.60 (s, 9H),
7.45 (t, J=7.3 Hz, 2H), 7.54-7.64 (m, 6H), 7.74 (d, J=8.4 Hz, 2H), 8.33 (d,
J=7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 31.4, 34.7, 109.8, 119.7,
120.2, 123.2, 125.8, 126.5, 126.6, 134.9, 140.9, 150.3.
(4-(1H-Indol-1-yl)phenyl)(phenyl)methanone (Table 5, Entry 4)[22b]
10-(3,5-Dimethylphenyl)-10H-phenothiazine (Table 5, Entry 12)
Hexane: DCM = 7:3, Rf = 0.15; 1H NMR (400 MHz, CDCl3): δ 6.80 (d,
J=3.2 Hz, 1H), 7.29-7.34 (m, 2H), 7.42 (d, J=3.2 Hz, 1H), 7.54-7.66 (m,
5H), 7.74-7.79 (m, 2H), 7.92 (d, J=7.2 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 104.8, 110.4, 120.8, 121.2, 122.7, 127.2,
128.1, 129.6, 129.7, 131.6, 132.2, 134.5, 135.1, 137.3, 143.0, 195.0.
1
Hexane: EA = 9:1, Rf = 0.8; H NMR (400 MHz, CDCl3): δ 2.47 (s, 6H),
6.32-6.34 (dd, J=1.2, 6.8 Hz, 2H), 6.84-6.93 (m, 4H), 7.06-7.08 (dd,
J=1.6, 5.6 Hz, 2H), 7.09 (s, 2H), 7.18 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 21.4, 116.0, 119.9, 122.3, 126.6, 126.8, 128.3, 129.9, 140.6, 140.7,
144.3; HRMS: calcd. for C20H17NS+: 303.1076, found 303.1067.
Methyl 4-(1H-indol-1-yl)benzoate (Table 5, Entry 5)[22b]
10-(3,5-Dimethylphenyl)-10H-phenothiazine (Table 5, Entry 13)
1
Hexane: EA = 9:1, Rf = 0.3; H NMR (400 MHz, CDCl3): δ 4.01 (s, 3H),
Hexane, Rf = 0.7; 1H NMR (400 MHz, CDCl3): δ 2.42 (s, 6H), 5.99 (s,
2H), 6.63-6.72 (m, 6H), 6.99 (s, 2H), 7.14 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 21.29, 113.3, 115.3, 121.0, 123.2, 128.0, 130.1, 134.5, 138.8,
140.8, 143.9; HRMS: calcd. for C20H17NO: 287.1305, found 287.1309.
6.78 (d, J=3.0 Hz, 1H), 7.27-7.37 (m, 3H), 7.57 (d, J=8.5 Hz, 2H), 7.69 (d,
J=7.8 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 8.22 (d, J=8.5 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 51.9, 104.7, 110.3, 120.7, 121.1, 122.6, 122.8,
127.1, 127.2, 129.6, 130.9, 135.1, 143.3, 166.0
N-Methyl-N-phenylnaphthalen-2-amine (Table 6, Entry 6)[22b]
1-(4-(tert-Butyl)phenyl)-5-methoxy-1H-indole (Table 5, Entry 6)
1
1
Hexane: EA = 9:1, Rf = 0.6; H NMR (400 MHz, CDCl3): δ 1.57 (s, 9H),
Hexane: DCM = 20:1, Rf = 0.26; H NMR (400 MHz, CDCl3): δ 3.61 (s,
4.03 (s, 3H), 6.79 (d, J=3.1 Hz, 1H), 7.10 (q, J=6.5 Hz, 1H), 7.36 (d,
J=2.4 Hz, 1H), 7.45 (d, J=3.2 Hz, 1H), 7.54-7.56 (m, 2H), 7.64-7.68 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 31.3, 34.4, 55.6, 102.5, 102.9, 111.3,
112.3, 123.4, 126.3, 128.2, 129.7, 131.0, 137.2, 149.0, 154.4; HRMS:
calcd. for C19H22NO+: 280.1701, found 280.1698.
3H), 7.26 (m, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.48-7.58 (m, 5H), 7.65 (m,
1H), 7.88-7.95 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 40.4, 114.5, 121.3,
121.7, 121.8, 123.6, 126.2, 126.6, 127.4, 128.5, 129.0, 129.2, 134.6,
146.5, 148.9.
4-(Naphthalen-2-yl)morpholine (Table 6, Entry 7)[38]
1-(3,5-Dimethylphenyl)-5-methyl-1H-indole (Table 5, Entry 7)[22b]
Hexane: EA = 9:1, Rf = 0.23; 1H NMR (400 MHz, CDCl3): δ 3.24 (t, J=4.8
Hz, 4H), 3.94 (t, J=4.7 Hz, 4H), 7.18 (d, J=2.0 Hz, 1H), 7.28 (q, J=6.7 Hz,
1H), 7.46-7.48 (m, 1H), 7.55-7.59 (m, 1H), 7.82-7.88 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 49.2, 66.5, 109.6, 118.5, 123.2, 126.0, 126.5, 127.2,
128.3, 128.4, 134.3, 148.8.
Hexane: DCM = 20:1, Rf = 0.3; 1H NMR (400 MHz, CDCl3): δ 2.70 (s,
6H), 2.85 (s, 3H), 6.93 (d, J=3.1 Hz, 1H), 7.27 (s, 1H), 7.39-7.44 (m, 3H),
7.58 (d, J=3.2 Hz, 1H), 7.38-7.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
21.2, 21.3, 102.7, 110.3, 120.7, 121.7, 123.7, 127.7, 127.8, 129.2, 129.6,
134.1, 139.1, 139.8.
3,5-Dimethyl-N-(1-phenylethyl)aniline (Table 7, Entry 1 and 2)[46,47]
1-(3,5-Dimethylphenyl)-5-fluoro-1H-indole (Table 5, Entry 8)
Hexane: EA = 20:1, Rf = 0.5; 1H NMR (400 MHz, CDCl3): δ 1.60 (d,
J=6.4 Hz, 3H), 2.29 (d, J= 10.8 Hz, 6H), 4.57-4.62 (q, J=6.8 Hz, 1H), 6.29
(s, 2H), 6.44 (s, 1H), 7.33 (t, J=7.2 Hz, 1H), 7.41-7.49 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 21.5, 24.9, 53.4, 111.3, 119.4, 125.9, 126.8, 128.6,
138.8, 145.5, 147.4. Enantiomeric excess was determined by HPLC
analysis (UV) on Chiralcel OD-H column using hexane/i-PrOH (98/2) as
eluent (0.5 mL/min). Retention time of the enantiomers: 10.6 min, 12.3
min, 97% ee.
Hexane: DCM = 9:1, Rf = 0.4; 1H NMR (400 MHz, CDCl3): δ 2.54 (s, 6H),
6.75 (d, J=3.0 Hz, 1H), 7.12-7.14 (m, 2H), 7.22 (s, 2H), 7.44 (d, J=3.2 Hz,
1H), 7.48-7.51 (m, 1H), 7.61-7.62 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 21.2, 102.9, 103.0, 105.5, 105.7, 110.2, 110.4, 111.3, 111.3, 121.8,
128.2, 129.4, 129.5, 129.6, 132.4, 139.3, 156.8, 159.2; HRMS: calcd. for
C
16H15NF+: 240.1189, found 240.1192.
1-(4-(tert-Butyl)phenyl)-1H-pyrrole (Table 5, Entry 9)[22b]
3,5-Dimethyl-N-(1-phenylethyl)aniline (Table 7, Entry 3 and 4)
Hexane: EA = 20:1, Rf = 0.6; 1H NMR (400 MHz, CDCl3): δ 1.55 (s, 9H),
6.56 (s, 2H), 7.27 (s, 2H), 7.50 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 31.3, 34.3, 110.1, 119.2, 120.0, 126.2,
138.2, 148.4.
Hexane: EA = 20:1, Rf = 0.6; 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H),
2.36 (s, 6H), 4.18 (bs, 1H), 5.48 (d, J=6.4 Hz, 1H), 6.37 (s, 2H), 6.55 (s,
1H), 7.58 (d, J=7.2 Hz, 1H), 7.61-7.77 (m, 2H), 7.84 (d, J=6.8 Hz, 1H),
7.92 (d, J=7.2 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H), 8.36 (d, J=7.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 21.4, 23.2, 49.1, 110.9, 119.2, 122.2,
122.7, 125.2, 125.7, 125.9, 127.3, 128.9, 130.7, 134.0, 138.6, 140.0,
147.1; HRMS: calcd. for C20H22N+: 276.1752, found 276.1758.
Enantiomeric excess was determined by HPLC analysis (UV) on
Chiralcel OD-H column using hexane/i-PrOH (98/2) as eluent (0.7
mL/min). Retention time of the enantiomers: 10.0 min, 11.5 min, 99% ee.
4-(3,5-Dimethylphenyl)-1,2,3,4-tetrahydrocyclopenta[b]indole (Table
5, Entry 10)[22b]
Hexane: DCM = 9:1, Rf = 0.5; 1H NMR (400 MHz, CDCl3): δ 2.58 (s, 6H),
2.72-2.77 (m, 2H), 3.07-3.14 (m, 4H), 7.16 (s, 1H), 7.27 (s, 2H), 7.32-
7.34 (m, 2H), 7.66-7.72 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.3,
24.5, 26.2, 28.3, 110.9, 118.5, 119.9, 120.0, 120.6, 122.4, 124.9, 127.8,
138.8, 139.0, 140.9, 145.6.
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N-(1,2,3,4-Tetrahydronaphthalen-1-yl)naphthalen-2-amine (Table 7,
Entry 5 and 6)
[7]
For recent book chapter of transition metal-catalyzed amination, see: a)
M. Taillefer, D. Ma, Top Organomet. Chem. 2013, 46, 1-204; b) J.
Paradies in Metal-Catalyzed Cross-Coupling Reactions and More, Vol.
3 (Eds.: A. De Meijere, S. Brase, M. Oestreich), Wiley-VCH, Weinheim,
2014, pp. 995-1066; for review, see: c) J. L. Klinkenberg, J. F. Hartwig,
Angew. Chem., Int. Ed. 2011, 50, 86.
Hexane: EA = 20:1, Rf = 0.5; 1H NMR (400 MHz, CDCl3): δ 1.92-2.07 (m,
2H), 2.12-2.20 (m, 2H), 2.87-3.01 (m, 2H), 4.15 (s, 1H), 4.89 (t, J=4.8 Hz,
1H), 6.95-6.98 (dd, J=2.4, 8.8 Hz, 1H), 7.05 (s, 1H), 7.26-7.36 (m, 4H),
7.49 (t, J=8.0 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H),
7.80 (d, J=8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.4, 28.5, 29.2,
51.0, 104.2, 117.9, 121.7, 125.7, 126.1, 126.3, 127.1, 127.3, 127.5,
129.0, 129.2, 135.2, 137.5, 138.0, 145.0; HRMS: calcd. for C20H19N:
274.1590, found 274.1593. Enantiomeric excess was determined by
HPLC analysis (UV) on Chiralcel OD-H column using hexane/i-PrOH
(90/10) as eluent (0.9 mL/min). Retention time of the enantiomers: 7.9
min, 9.7 min, 97% ee.
[8]
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Acknowledgements
We thank the Shenzhen Strategic New Industry Development
Research Fund of Shenzhen Science, Technology and
Innovation Commission (SZSTI) (JCYJ20150618110015259)
and the Research Grants Council of Hong Kong (CRF: C5023-
14G) for financial support. We are grateful to Guangzhou Lee &
Man Technology Company Limited for providing some
hydroxyarenes and Guangdong Province Zhu Jiang Talents
Plan (Project code: 2016ZT06C090) for financial support.
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Conflict of interest
[13] For recent reviews, see: a) B.-J. Li, D.-G. Yu, C.-L. Sun, Z.-J. Shi,
Chem. Eur. J. 2011, 17, 1728; b) C. M. So, F. Y. Kwong, Chem. Soc.
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Ober, J. P. O’Brien, T. S. Staton, ACS Catal. 2016, 6, 3515.
The authors declare no conflict of interest.
Keywords: cross-coupling • aryl tosylate • amination • palladium
• phosphine • C-N bond formation
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Entry for the Table of Contents
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Pui Ying Choy, Kin Ho Chung, Qingjing
Yang, Chau Ming So,* Raymond Wai-
Yin Sun and Fuk Yee Kwong*
Page No. – Page No.
A General Palladium-Phosphine
Complex for Exploring Aryl Tosylates
in N-arylation of Amines: Scope and
Limitation
A general Pd/CM-phos catalyst system is presented for broad scope of amination of
aryl tosylates. Various nature of N-nucleophiles are applicable substrates and the
reactions can even be performed under water medium or at a particular catalyst
loading as low as 0.05 mol% Pd.
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