An Effective Heterogeneous Copper Catalyst System for C-N Coupling and Its Application in the Preparation of 2-Methyl-4-methoxydiphenylamine (MMDPA)

Article abstract of DOI:10.1055/s-0037-1609578

A ligand-recyclable, environmentally benign heterogeneous catalyst system composed of CuI and polystyrene-supported N (-(4-(aminomethyl)naphthalen-1-yl)- N (-phenyl-1 H -pyrrole-2-carbohydrazide (PSAP) has been established for Ullmann type C-N coupling based on the homogeneous catalyst system N ′, N ′-diphenyl-1 H -pyrrole-2-carbohydrazide/CuI. This heterogeneous catalyst system maintained the catalytic effectiveness of the homogeneous catalyst. A variety of functionalized aryl bromides can be efficiently aminated with aryl amines and aliphatic amines with high selectivity for amines over alcohols. Moreover, a practical application of this catalyst system to promote the reaction of commercially available 4-methoxy-2-methylaniline and bromobenzene in 10 mmol scale, provided 2-methyl-4-methoxydiphenylamine (MMDPA) with 93% yield with the merit of the approach being simple operation for work-up and purification.

Full text of DOI:10.1055/s-0037-1609578

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–J
paper
A
en
Z. Yi et al.
Paper
Synthesis
An Effective Heterogeneous Copper Catalyst System for C–N
Coupling and Its Application in the Preparation of
2-Methyl-4-methoxydiphenylamine (MMDPA)
Zhou Yia
CuI (5 mol%)
K3PO4 (200 mol%)
DEG (2 mL)
70 °C, 14 h
H
Manna Huang*a
Yiqian Wana
Xinhai Zhub
0
0
0
0
0-
0
0
2
2-
8
0
5
1-
5
9
3
N
R1
R2
R1
R2
HN
Ar
N
Ar-Br
+
O
MMDPA
10 mmol scale
1.98 g, 93%
Ar = phenyl
aryl amines
pyridyl aliphatic amines
thienyl
O
H
36 examples
up to 98% yield
a School of Chemical Engineering and Technology,
Guangdong Engineering Technology Research Center
for Platform Chemicals from Marine Biomass and
Their Functionalization, Sun Yat-sen University,
Guangzhou 510275, P. R. of China
N
N
N
H
H
N
PSAP (5 mol%)
huangmn25@mail.sysu.edu.cn
b Instrument Analysis & Research Center, Sun Yat-sen
University, Guangzhou 510275, P. R. of China
Received: 07.05.2018
Accepted after revision: 13.06.2018
Published online: 25.07.2018
nonactivated aryl chlorides.5 These advances have led to
numerous practical approaches to synthesizing anilines in
both academic and industrial settings.
DOI: 10.1055/s-0037-1609578; Art ID: ss-2018-f0318-op
However, further endeavors are still required to make
this class of reactions more attractive and practical because
of its limitations in comparison to the Buchwald–Hartwig
reaction, which include: (1) less expensive aryl chlorides
remain poor substrates for Cu/ligand-catalyzed aryl amina-
tion reactions;5a and (2) turnover numbers and turnover
frequencies are low at low temperatures in the general cat-
alytic version of the Ullmann reaction (25–80 °C).3b,6
Homogeneous catalytic reactions usually have well-de-
fined active sites, and intimate knowledge of these can fa-
cilitate the design of catalysts with relatively high activity
and selectivity,7 which can aid in our understanding of the
mechanism of catalysis in more detail. On the other hand,
heterogeneous catalysis has intrinsic advantages including
(1) simple work-up for products separation, and (2) often
easy recycling of the catalyst ultimately leading to greener
and more environmentally sustainable chemical transfor-
mation processes.8 However, the essential scientific basis
underlying both homogeneous and heterogeneous catalysis
has led to numerous efforts to combine the intrinsic merits
of both homogeneous and heterogeneous catalytic systems.
These efforts have led to great progress in the development
of heterogeneous catalysts by applying a strategy of immo-
bilization of molecular catalysts on solid supports that take
the advantages of both homogeneous and heterogeneous
catalysis.9
Abstract A ligand-recyclable, environmentally benign heterogeneous
catalyst system composed of CuI and polystyrene-supported N(-(4-
(aminomethyl)naphthalen-1-yl)-N(-phenyl-1H-pyrrole-2-carbohydra-
zide (PSAP) has been established for Ullmann type C–N coupling based
on the homogeneous catalyst system N′,N′-diphenyl-1H-pyrrole-2-car-
bohydrazide/CuI. This heterogeneous catalyst system maintained the
catalytic effectiveness of the homogeneous catalyst. A variety of func-
tionalized aryl bromides can be efficiently aminated with aryl amines
and aliphatic amines with high selectivity for amines over alcohols.
Moreover, a practical application of this catalyst system to promote the
reaction of commercially available 4-methoxy-2-methylaniline and bro-
mobenzene in 10 mmol scale, provided 2-methyl-4-methoxydiphenyl-
amine (MMDPA) with 93% yield with the merit of the approach being
simple operation for work-up and purification.
Key words heterogeneous catalysis, copper catalysis, C–N coupling,
recyclability, 2-methyl-4-methoxydiphenylamine (MMDPA)
The N-arylation of amines has attracted significant at-
tention for over a century because of the ubiquitous pres-
ence of anilines as highly valuable moieties in numerous
natural and synthetic functional products.1 One of the most
attractive and direct approaches for the preparation of ani-
lines is the Ullmann type C–N coupling,2 because of the
lower cost of copper in comparison with other precious
metals and because no toxic phosphane-containing ligands
are needed. It should be noted that the main drawbacks of
the requirement for harsh reaction conditions (e.g., strong
bases, stoichiometric copper, high reaction temperatures)
for Ullmann type C–N coupling have always baffled re-
searchers until the 2000s.3 Since then, several break-
throughs have overcome most of these drawbacks4 and
have greatly extended the reaction scope, in particular to
Notably, several effective heterogeneous copper-cata-
lyzed Ullmann type C–N coupling systems have recently
been established,10 including (1) constructing polymer-
supported copper complexes,11 (2) using suitable reaction
media, such as CuI in ionic liquid,12 Cu2O in PEG with micro-
wave irradiation at 150 °C,13 and (3) using nanocatalysts.14
However, heterogenization of an effective and general
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

B
Z. Yi et al.
Paper
Synthesis
homogeneous catalyst for C–N coupling to make a more
easily operational and recyclable catalyst system is very at-
tractive but still challenging.15 One successful example was
reported by Alper and co-workers,15 in which magnetic
nanoparticle-supported proline was constructed as a recy-
clable and recoverable ligand for the CuI-catalyzed arylation
of nitrogen nucleophiles and used to perform the arylation
of many kinds of N-heterocycles such as imidazole, pyra-
zole, indole and benzimidazole with aryl bromides in N,N-
dimethylformamide (DMF). This work inspired us to con-
struct a heterogeneous catalyst system with almost the
same catalytic competence as that of our previously report-
ed homogeneous system.16 However, the need for relatively
high catalyst loading (10 mol% of CuI and 50 mol% of ligand)
and the prerequisite for a large excess of amine was clearly
detrimental and prompted us to continue our research. Re-
cently, we established a general and effective homogeneous
catalyst system for the CuI-catalyzed amination of aryl io-
dides and bromides using N′,N′-diphenyl-1H-pyrrole-2-car-
bohydrazide as a ligand, which exhibited the following
main advantages: (1) need for a relatively low catalyst/li-
gand loading (only 5 mol% CuI and ligand); (2) need for only
a slight excess of amine (1.3 equiv); (3) very good chemose-
lectivity between OH groups (alcohols and phenol) and NH2
groups (aliphatic and aryl amines). Hence, we explored the
construction of a heterogeneous catalyst system from our
recently reported homogeneous catalyst system and as-
sessed its practical application for the preparation of 2-
methyl-4-methoxydiphenylamine (MMDPA), which was
prepared through Pd/C-catalyzed aromatization17 and Pd-
catalyzed C–N coupling reaction,18 and is a common inter-
mediate for production of the aminofluoran dye for ther-
mographic and pressure-sensitive recording.
aryl halides. We have previously revealed that the corre-
sponding derivatives with substituents on the phenyl rings
exhibited differing activity for CuI-catalyzed amination. As
shown in Scheme 1, the 4-bromobenzyl moiety would be a
good spacer for linking to solid support because of the di-
verse range of reactions offered by the bromine atom. How-
ever, the designed compound C had little activity (< 5%
yield) for the model reaction, which implied that the spacer
should be on the phenyl rings rather than on the pyrrole ring.
By means of our previously reported protocol for the
synthesis of polystyrene-supported pyrrole-2-carbohydra-
zide (PSP),16 amino polystyrene (PS-NH2) was prepared
from polystyrene through nitration and reduction sequen-
tially. N′-(4-Formylphenyl)-N′-phenyl-1H-pyrrole-2-carbo-
hydrazide (L-CHO) was designed and readily synthesized
from 4-iodobenzaldehyde. As expected, the polystyrene-
supported N′-(4-(aminomethyl)naphthalen-1-yl)-N′-phe-
nyl-1H-pyrrole-2-carbohydrazide (PSAP) was obtained by
reductive amination (Scheme 2) and confirmed to be ther-
mally stable below 309 °C by thermal gravitational analysis
(Figure S9 in the Supporting Information, SI).
We then started to examine PSAP as a ligand for pro-
moting the Cu-catalyzed amination of 4-bromoanisole with
aniline. After exploring the reaction parameters such as sol-
vents, copper sources, bases, and the corresponding pro-
portions (Table S2, SI) we established the optimized reac-
tion conditions as consisting of 5 mol% of PSAP (30 mg, size
> 100 mesh) and 5 mol% of CuI, aryl bromides (100 mol%),
amines (150 mol%) and K3PO4 (200 mol%) in diethylene gly-
col (DEG) at 70 °C (Table S2, SI, entry 31). As expected, this
heterogeneous catalyst system was almost the same as our
previously reported homogeneous counterpart19 except for
the need for higher reaction temperature.
To assess the possible linking site as a prerequisite for
obtaining the heterogeneous catalyst with the intrinsic
merits inherited from a homogeneous catalyst system, we
initially explored whether the derivatives of N′,N′-diphenyl-
1H-pyrrole-2-carbohydrazide substituted on the pyrrole
ring were effective ligands for CuI-catalyzed amination of
This result inspired us to continue our examination of
the scope and generality of the C–N coupling reaction, al-
though the catalytic performance of the heterogeneous cat-
alyst system decreased in comparison with its original ho-
mogeneous counterpart with respect to reaction tempera-
ture and reaction time.19
NHNH2
Br
Br
1) K2CO3, MeCN, [Bmim]+[BF4]–
80 oC, 5 h
O
+
N
Et3N, MeCN, r.t.
N
H
H
2) CCl3COCl , Et2O, 0 °C to r.t.
CCl3
Br
A (39%)
I
O
Br
O
Br
N
H
HN
N
N
H
HN NH
CuI, Cs2CO3
55 °C, 4 h
C (52%)
B (90%)
18% (total yield)
Scheme 1 The synthesis of compound C
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

C
Z. Yi et al.
Paper
Synthesis
As shown in Scheme 3 and Scheme 4, this heteroge-
neous catalyst system retained the catalytic competence of
our previously reported homogeneous system. In detail,
most aryl bromides regardless of being electron-rich (1a–d,
1f, 1m–o, 1q, 2a, 2e, 2f, 2i, 2m, 2o), electron-neutral (1e,
1p, 2d, 2g, 2j, 2n) or electron-poor (1g–h, 1j–l, 2c, 2k, 2p),
or even heteroaryl bromides (1r, 1s, 2b, 2h, 2l, 2q), were ef-
ficiently aminated with various aryl amines (Scheme 3) and
O
O
H
N
CuI, Cs2CO3
DEG, 55 °C
N
I
CHO
+
N
H
N
H
NH
NH
CHO
L0
L-CHO (83%)
HNO3/H2SO4
DCM
L-CHO
Sn/HCl
MeOH, reflux
NO2
NH2
PS-NO2
(nitrification rate 48%)
Atactic PS
PS-NH2 (70%)
NaBH4
HN
HN
N
H
N
H
N
H
N
N
N
O
O
PSAP
PS-N=CH-L (52%)
(94%,ML = 0.51g/g)
Scheme 2 Preparation of PSAP
CuI (5 mol%)
PSAP (5 mol%)
K3PO4 (200 mol%)
Ar1 Br
+
Ar2-NH2
Ar1 Ar2
N
H
DEG (2 mL), 70 °C, 14 h
O
(1 mmol)
(1.5 mmol)
H
N
H
N
H
N
H
N
O
O
1b
93%
1a
1c
93%
1d
92%
92%, 90%a, traceb
17%c, 20%d
H
N
H
H
N
H
N
N
Cl
F
1f
91%
1e
89%
1g
89%
1h
85%
H
H
H
N
H
N
N
N
O
O2N
F3C
HO
1i
68%
1j
84%
1l
60%
1k
34%
H
N
H
N
H
N
H
N
O
O
O
O
Cl
Cl
1n
96%
1m
97%
1o
87%
1p
65%
H
N
H
N
H
N
N
S
O
NO2
1q
17%
1r
77%
1s
66%
Scheme 3 Copper-catalyzed amination of aryl bromides with aryl amines. a 4-Iodoanisole. b 4-Chloroanisole. c 4-Chloroanisole, 120 °C, 16 h. d 4-
Chloroanisole 150 °C, 16 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

D
Z. Yi et al.
Paper
Synthesis
CuI (5 mol%)
PSAP (5 mol%)
K3PO4 (200 mol%)
Ar1
N
H
N
Ar1 Br
R1
R2
+
R1
R2
DEG (2 mL), 70 °C, 14 h
(1 mmol)
(1.5 mmol)
H
H
N
O
NH
O2N
NH
N
S
2a
93%
2b
83%
2c
44%
2d
94%
NH
O
H
N
H
N
O
NH
H
OH
OH
O
S
OH
H
2f
90%
2h
63%
2g
98%
H
2e
82%
O
O
N
O
N
O
N
O
N
O
S
2j
88%
2i
96%
2l
73%
2k
90%
O
O
N
N
N
N
2n
53%
2o
75%
2p
64%
2m
79%
N
S
2q
34%
Scheme 4 Copper-catalyzed amination of aryl bromides with aliphatic amines
CuI (5 mol%)
PSAP (5 mol%)
K3PO4 (2 equiv)
aliphatic amines (Scheme 4). Notably, the high selectivity of
N-arylation of amines over alcohols (1i, 2f–h), together
with high efficiency of amination of aryl bromides with
bulky adamantyl (2e) and acyclic secondary amines (2n–q)
was also maintained.
Br
H
NH2
N
+
DEG (20 mL)
70 °C, 14 h
O
O
(10 mmol)
(1.5 equiv)
MMDPA
MMDPA is a common intermediate that is useful for
thermographic and pressure-sensitive recording in the fine
chemical industry and has been cited frequently in the con-
text of the aminofluoran dye family. Hence, MMDPA should
be a good model molecule for further exploration of the
practical application of our catalyst system.18
After the initial run of the reaction (Scheme 5) accord-
ing to our general protocol, we directly scaled up to 10
mmol of 4-methoxy-2-methylaniline of substrate. Notably,
simple filtration easily separated the crude MMDPA from
the reaction mixture; pure MMDPA was then obtained by
dissolving and precipitating in MeOH and H2O three times
sequentially with a yield of 93% (1.98 g, off-white solids).
Considering the practicality of our protocol to prepare
MMDPA and to advance the heterogeneous catalyst system,
we further explored its recyclability. After reaction, PSAP
was obtained by filtration following washing with water
and MeOH (Figure 1). After drying in vacuo, the PSAP was
used again to run the model reaction directly. The reaction
Scheme 5 The synthesis of MMDPA
was run five additional times to afford the desired product
with good yields without significant loss of PSAP (yields
more than 80%) albeit necessitating addition of 5 mol% of
CuI to effectively complete the reaction under the experi-
mental conditions.
The requirement for addition of CuI when applying our
supported catalyst system to re-utilization was explored in
detail. Infrared (IR) spectroscopy (Figure S10, SI) demon-
strated that no clear decomposition of PSAP occurred, and
scanning electron microscopy (SEM) analysis (Figure S11,
SI) showed no clear changes of the surface characteristics
(size and shape) of the PSAP developed before and after re-
cycling. However, X-ray photoelectron spectroscopy (XPS)
analysis (Table 1) indicated that leaking of copper took
place. As can be seen, after four recycling runs, the catalytic
efficiency decreased markedly and half the quantity of cop-
per on PSAP was determined. In addition, XPS analysis indi-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

E
Z. Yi et al.
Paper
Synthesis
DECA XP instrument. GC/MS was run with a Finnigan Voyager with an
electron impact (70 eV) mass-selective detector and an innowax 30
m×0.25 mm×0.25 μm capillary apolar column. GC-MS method: Initial
temperature: 50 °C, initial time: 3 min; Ramp: 20 °C/min; Final tem-
perature: 250 °C, Final time: 2 min. Elemental analyses were recorded
with an Elementar Vario EL Elemental Analyser. IR spectra were re-
corded with a Perkin–Elmer Frontier Fourier Transformation infrared
spectrophotometer coupled with an infrared microscope. SEM spec-
tra were recorded with a JSM-6330F (120 KV). XPS analysis was run
with a Thermo Fisher Scientific-ESCALAB 250. Thermogravimetric
analyses (TGA) were performed with a NETZSCH TG 209 F1 Libra un-
der nitrogen at a heating rate of 10 °C/min.
Synthesis of 1-(5-(4-Bromobenzyl)-1H-pyrrol-2-yl)-2,2,2-trichloro-
ethanone (A)20
A three-neck flask was charged with pyrrole (6.7 g, 100 mmol), potas-
sium carbonate (2.2 g, 16 mmol), 1-butyl-3-methylimidazoliumtetra-
fluoroborate (20 mL), and acetonitrile (12 mL) under nitrogen atmo-
sphere. A solution of 4-bromobenzylbromide (5.0 g, 20 mmol) in ace-
tonitrile (25 mL) was then added dropwise with stirring at 80 °C for
about 1 h. The reaction mixture was then stirred at that temperature
for 5 h. After cooling to r.t., the reaction mixture was filtered and the
filtrate was concentrated in vacuo. The residue was extracted with di-
ethyl ether (3 × 20 mL). The combined organic phase was dried over
Na2SO4. After Na2SO4 was removed, a solution of trichloroacetyl chlo-
ride (4.4 g, 24 mmol) in diethyl ether (20 mL) was added dropwise
with stirring at 0 °C about 0.5 h. The reaction mixture was then
stirred at r.t. for 2 h. The reaction mixture was washed with sodium
carbonate solution (1 M, 3 × 20 mL) and water (2 × 20 mL), dried over
Na2SO4, and concentrated in vacuo. The residue was washed with
hexane to give A.
Figure 1 The recyclability of PSAP for the synthesis of MMDPA
cated that some active catalytic sites originally containing
Cu(I) were occupied by inactive insoluble Cu(II) species,
with both Cu(I) and Cu(II) species being observed (Figure
S12, SI).
Table 1 XPS Analysis
Recycle run
0
1
2
3
4
Isolated yield (%)
Cu (atom%)
90
–
79
6.76
62
4.48
43
3.08
trace
2.84
Yield: 3.0 g (39%); white solid; mp 147–148 °C.
1H NMR (400 MHz, CDCl3): δ = 9.33 (s, NH 1 H), 7.49 (d, J = 8.3 Hz,
2 H), 7.35 (dd, J = 3.8, 2.5 Hz, 1 H, ArH), 7.13 (d, J = 8.2 Hz, 2 H, ArH),
6.14 (t, J = 3.1 Hz, 2 H, ArH), 4.03 (s, CH2, 2 H).
13C NMR (100 MHz, CDCl3): δ = 174.3, 142.9, 137.5, 133.4, 133.2,
131.8, 131.3, 124.0, 122.5, 112.5, 35.0.
In summary, we have established a ligand-recyclable,
environmentally benign heterogeneous CuI/PSAP catalyst
system for general Ullmann type C–N coupling reaction and
an alternative practical protocol to prepare MMDPA, which
is a common intermediate useful for thermographic and
pressure-sensitive recording in the fine chemical industry.
This heterogeneous catalyst system maintained the catalyt-
ic competence of our previously reported homogeneous
N′,N′-diphenyl-1H-pyrrole-2-carbohydrazide/CuI system. In
detail, a variety of functionalized aryl bromides can be ami-
nated efficiently with aryl amines and aliphatic amines
with high selectivity for amines over alcohols. It should be
noted that this heterogeneous CuI/PSAP catalyst system has
clear advantages when applied to the synthesis of MMDPA,
including (1) low loading of catalyst and ligand (5 mol%);
(2) less excess of bromobenzene (1.5 equivalent); (3) simple
operation for work-up and purification (4) recyclability of
ligand.
MS (ESI–): m/z = 380 [M – H]–.
Synthesis of 5-(4-Bromobenzyl)-N′-phenyl-1H-pyrrole-2-carbohy-
drazide (B)
Compound A (2.0 g, 5.2 mmol) was dissolved in acetonitrile (30 mL),
then phenylhydrazine (1.1 g, 10.4 mmol) and triethylamine (1.6 g,
15.6 mmol) were added. The mixture was stirred at r.t. until com-
pound B was completely consumed as indicated by TLC. The mixture
was concentrated in vacuo. The residues was filtrated, washed with
CH2Cl2 and dried in vacuo to give B.
Yield: 1.8 g (90%); white solid; mp 236–237 °C.
IR (KBr): 3362.6, 332.4, 3179.0, 3126.1, 1635.1, 1601.0, 1536.8,
1487.8, 1402.4, 1326.6, 1223.5, 1181.7, 1010.2, 798.9, 752.2,
694.3 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.50 (s, NH, 1 H), 9.78 (s, NH, 1 H),
7.77 (s, NH, 1 H), 7.48 (d, J = 8.3 Hz, 2 H, ArH), 7.22 (d, J = 8.3 Hz, 2 H,
ArH), 7.13 (t, J = 7.8 Hz, 2 H, ArH), 6.85 (s, 1 H, ArH), 6.75–6.66 (m, 3 H,
ArH), 5.86 (t, J = 2.7 Hz, 2 H, ArH), 3.88 (s, CH2, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 161.3, 150.3, 140.1, 135.6, 131.6,
131.2, 129.1, 123.9, 119.5, 118.7, 112.5, 111.4, 107.8, 32.8.
All starting materials and reagents are commercially available and
were used as received. Flash column chromatography was performed
with silica gel (200–300 mesh). Thin-layer chromatography was per-
formed with Merck silica gel GF254 plates. 1H and 13C NMR spectra
were recorded at r.t. with a Bruker AVANCE 400 instrument with TMS
as an internal reference. LC/MS was run with a LCMS-2010A or a LCQ
Anal. Calcd for C18H16BrN3O: C, 58.39; H, 4.36; N, 11.35; Found: C,
58.08, H, 4.35; N, 11.32.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

F
Z. Yi et al.
Paper
Synthesis
MS (ESI–): m/z = 368 [M – H]–, 370 [M – H]–.
Synthesis of 1a–s and 2a–q; General Procedure
A 10 mL vial was charged with CuI (9.5 mg, 0.05 mmol), PSAP (30 mg,
0.05 mmol, > 100 mesh), K3PO4 (424 mg, 2 mmol), aryl bromides (1
mmol), amines (1.5 mmol), DEG (2 mL), and a magnetic stir bar. The
vessel was sealed with a septum and placed into a preheated oil batch
at 70 °C. The reaction mixture was held at this temperature for 14
hours. After cooling to r.t., the reaction mixture was filtered, and the
precipitates were thoroughly washed with water and EtOAc (3 × 20
mL). The combined organic phases were washed with water and
brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified using flash column chromatography on silica gel
(eluting with petroleum ether/EtOAc) to afford the desired products.
Synthesis of 5-(4-Bromobenzyl)-N′,N′-diphenyl-1H-pyrrole-2-car-
bohydrazide (C)
A three-neck flask was charged with compound B (1 g, 2.7 mmol),
aryl iodides (0.71 g, 3.5 mmol), CuI (102 mg, 0.54 mmol), and Cs2CO3
(1.8 g, 5.4 mmol) under nitrogen atmosphere. After diethylene glycol
(DEG) (30 mL) was injected, the reaction mixture was stirred at 55 °C
until compound C was completely consumed as indicated by TLC. Af-
ter cooling to r.t., the reaction mixture was added dropwise to water
(300 mL) with stirring. The suspension was filtered and the precipi-
tates was washed with water to pH 7 and dried in vacuo to give
brown solids. The brown solids were recrystallized from EtOAc/hex-
ane to give C.
4-Methoxy-N-phenylaniline (1a)19
Yield: 183 mg (92%); white solid; mp 105–106 °C.
Yield: 0.62 g (52%); white solid; mp 218–219 °C.
1H NMR (400 MHz, CDCl3): δ = 7.22 (t, J = 7.1 Hz, 2 H, ArH), 7.16–7.03
(m, 2 H, ArH), 7.00–6.90 (m, 2 H, ArH), 6.86 (d, J = 8.8 Hz, 3 H, ArH),
3.80 (s, 3 H, CH3O).
13C NMR (100 MHz, CDCl3): δ = 155.3, 145.2, 135.8, 129.3, 122.2,
119.6, 115.7, 114.7, 55.6.
IR (KBr): 3273.3, 1608.8, 1582.5, 1560.0, 1475.8, 1401.8, 1368.0,
1326.9, 1308.2, 1234.8, 1180.1, 1053.8, 889.0, 803.0, 748.0, 691.4 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.56 (s, 1 H, NH), 9.08 (s, 1 H, NH),
7.56 (d, J = 7.8 Hz, 2 H, ArH), 7.46 (d, J = 8.3 Hz, 2 H, ArH), 7.34 (t,
J = 7.9 Hz, 2 H, ArH), 7.20 (d, J = 8.3 Hz, 2 H, ArH), 7.13 (dd, J = 14.6,
7.2 Hz, 3 H, ArH), 6.73 (d, J = 7.8 Hz, 2 H, ArH), 6.69 (t, J = 10.4, 7.3 Hz,
1 H, ArH), 6.59 (t, J = 5.3, 0.1 Hz, 1 H, ArH), 5.79 (t, J = 3.4, 2.9 Hz, 1 H,
ArH), 3.88 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): δ = 162.6, 147.0, 142.7, 139.9, 136.4,
131.6, 131.2, 129.7, 128.8, 125.8, 124.4, 123.4, 119.6, 119.4, 116.7,
112.4, 108.6, 32.7.
MS (ESI+): m/z = 200 [M + H]+.
3-Methoxy-N-phenylaniline (1b)21
Yield: 185 mg (93%); white solid; mp 72–73 °C.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.26 (m, 2 H, ArH), 7.17 (t,
J = 8.2 Hz, 1 H, ArH), 7.10 (d, J = 7.6 Hz, 2 H, ArH), 6.95 (t, J = 7.3 Hz,
1 H, ArH), 6.69–6.63 (m, 2 H, ArH), 6.52–6.46 (m, 1 H, ArH), 3.78 (s,
3 H, CH3).
Anal. Calcd for C24H20BrN3O·0.3H2O: C, 63.81; H, 4.60; N, 9.30; Found:
C, 63.45, H, 4.66; N, 9.25.
MS (ESI–): m/z = 444 [M – H]–, 446 [M – H]–.
13C NMR (100 MHz, CDCl3): δ = 160.7, 144.6, 142.8, 130.1, 129.4,
121.3, 118.4, 110.2, 106.2, 103.4, 55.2.
MS (ESI+): m/z = 200 [M + H]+.
Synthesis of L-CHO
A three-neck flask was charged with compound L0 (5 g, 25 mmol), 4-
iodobenzaldehyde (7.5 g, 32.5 mmol), CuI (0.94 g, 5 mmol), and Cs2-
CO3 (16 g, 50 mmol) under nitrogen atmosphere. After diethylene gly-
col (DEG) (50 mL) was injected, the reaction mixture was stirred at
55 °C until compound L0 was completely consumed as indicated by
TLC. After cooling to r.t., the reaction mixture was added dropwise to
water (500 mL) with stirring. The suspension was filtered and the
precipitates was washed with water to pH 7 and dried in vacuo to
give brown solids. The brown solids were recrystallized from EtO-
Ac/hexane to give off-white solids (5.7 g, 83%).
2-Methoxy-N-phenylaniline (1c)19
Yield: 185 mg (93%); colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.29 (m, 3 H, ArH), 7.19 (dd,
J = 8.6, 1.0 Hz, 2 H, ArH), 7.01–6.95 (m, 1 H, ArH), 6.94–6.88 (m, 3 H,
ArH), 3.93 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 148.4, 142.8, 133.1, 129.4, 121.2,
120.9, 120.0, 118.6, 114.8, 110.6, 55.7.
MS (ESI+): m/z = 200 [M + H]+.
Synthesis of PS-N=CH-L
4-Methyl-N-phenylaniline (1d)19
PS-NH2 (3.5 g) and L-CHO (6.1 g, 20 mmol) was suspended in MeOH
(200 mL), then AcOH (5 drops) was added, and the reaction mixture
was heated at reflux for 24 h. After cooling to r.t., the mixture was fil-
tered, thoroughly washed with MeOH and EtOAc, and finally dried in
vacuo to give orange solids PS-N=CH-L (5 g).
Yield: 168 mg (92%); white solid; mp 89–90 °C.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.21 (m, 2 H, ArH), 7.09 (d,
J = 8.2 Hz, 2 H, ArH), 7.05–6.98 (m, 4 H, ArH), 6.89 (t, J = 7.3 Hz, 1 H,
ArH), 2.30 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 144.0, 140.3, 131.0, 129.9, 129.4,
120.4, 119.0, 116.9, 20.8.
Synthesis of PSAP
PS-N=CH-L (5 g) was suspended in MeOH (50 mL), then NaBH4 (1.5 g,
40 mmol) was added in batches. The reaction mixture was heated at
reflux for 12 h under nitrogen. After cooling to r.t., the mixture was
filtered, washed with water, MeOH and EtOAc, and finally dried in
vacuo to give PSAP (pale-yellow solids, 4.7 g).
MS (ESI+): m/z = 184 [M + H]+.
Diphenylamine (1e)19
Yield: 150 mg (89%); white solid; mp 52–53 °C.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.23 (m, 4 H, ArH), 7.09 (d,
J = 7.6 Hz, 4 H, ArH), 6.94 (t, J = 7.3 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 143.2, 129.4, 121.0, 117.9.
MS (ESI+): m/z = 170 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

G
Z. Yi et al.
Paper
Synthesis
N-Phenyl-[1,1′-biphenyl]-4-amine (1f)22
1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.4 Hz, 2 H, ArH), 7.33 (t,
J = 7.9 Hz, 2 H, ArH), 7.15 (d, J = 7.5 Hz, 2 H, ArH), 7.05 (t, J = 8.0 Hz,
3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 146.8, 141.2, 129.6, 126.8, 126.7,
126.7, 126.67, 126.0, 123.3, 123.0, 122.1, 121.8, 121.5, 121.2, 120.1,
115.3.
Yield: 223 mg (91%); white solid; mp 112–113 °C.
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 7.2 Hz, 2 H, ArH), 7.51 (d,
J = 8.6 Hz, 2 H, ArH), 7.42 (t, J = 7.7 Hz, 2 H, ArH), 7.29 (t, J = 7.9 Hz,
3 H, ArH), 7.14 (t, J = 8.2 Hz, 4 H, ArH), 6.96 (t, J = 7.3 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 142.9, 142.6, 140.9, 133.8, 129.5,
128.8, 128.0, 126.7, 126.6, 121.3, 118.1, 117.8.
MS (ESI+): m/z = 238 [M + H]+.
MS (ESI+): m/z = 246 [M + H]+.
Bis(4-methoxyphenyl)amine (1m)21
Yield: 222 mg (97%); white solid; mp 101–102 °C.
1H NMR (400 MHz, CDCl3): δ = 6.95 (d, J = 8.2 Hz, 4 H, ArH), 6.82 (d,
J = 8.9 Hz, 4 H, ArH), 3.78 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 154.1, 137.9, 119.6, 114.7, 55.6.
MS (ESI+): m/z = 230 [M + H]+.
4-Chloro-N-phenylaniline (1g)19
Yield: 181 mg (89%); pale-yellow sold; mp 63–64 °C.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.24 (m, 3 H, ArH), 7.23–7.18 (m,
2 H, ArH), 7.07–7.02 (m, 2 H, ArH), 7.02–6.93 (m, 3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 142.7, 141.9, 129.5, 129.3, 125.5,
121.5, 118.8, 118.1.
MS (ESI+): m/z = 204 [M + H]+.
4-Methoxy-N-(p-tolyl)aniline (1n)21
Yield: 204 mg (96%); white solid; mp 84–85 °C.
4-Fluoro-N-phenylaniline (1h)23
1H NMR (400 MHz, CDCl3): δ = 7.07 (d, J = 7.6 Hz, 4 H, ArH), 6.87 (d,
J = 8.7 Hz, 4 H, ArH), 3.82 (s, 3 H, CH3O), 2.31 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 154.8, 142.4, 136.7, 129.9, 129.3,
121.1, 116.6, 114.7, 55.6, 20.6.
MS (ESI+): m/z = 214 [M + H]+.
Yield: 159 mg (85%); colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 7.24 (t, J = 7.9 Hz, 2 H, ArH), 7.07–7.02
(m, 2 H, ArH), 7.01–6.94 (m, 4 H, ArH), 6.90 (t, J = 7.3 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 159.3, 156.9, 144.0, 139.0, 139.0,
129.5, 120.6, 120.6, 116.8, 116.1, 115.9.
MS (ESI+): m/z = 188 [M + H]+.
4-Chloro-N-(4-methoxyphenyl)aniline (1o)21
Yield: 203 mg (87%); pale-yellow solid; mp 47–48 °C.
4-(Phenylamino)phenol (1i)19
1H NMR (400 MHz, CDCl3): δ = 7.14 (d, J = 8.7 Hz, 2 H, ArH), 7.04 (d,
J = 8.2 Hz, 2 H, ArH), 6.86 (d, J = 8.8 Hz, 2 H, ArH), 6.80 (d, J = 8.5 Hz,
2 H, ArH), 3.79 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 155.6, 144.0, 135.2, 129.2, 123.9,
122.6, 116.6, 114.8, 55.6.
Yield: 126 mg (68%); pale-yellow solid; mp 68–69 °C.
1H NMR (400 MHz, CDCl3): δ = 7.21 (t, J = 7.9 Hz, 2 H, ArH), 7.03 (d,
J = 8.6 Hz, 2 H, ArH), 6.91 (d, J = 7.8 Hz, 2 H, ArH), 6.84 (t, J = 7.3 Hz,
1 H, ArH), 6.79 (d, J = 8.8 Hz, 2 H, ArH).
MS (ESI+): m/z = 234 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 151.1, 145.2, 135.8, 129.4, 122.5,
119.7, 116.2, 115.8.
MS (ESI+): m/z = 186 [M + H]+.
4-Chloro-N-phenylaniline (1p)19
Yield: 181 mg (89%); pale-yellow sold; mp 63–64 °C.
1-(4-(Phenylamino)phenyl)ethanone (1j)19
1H NMR (400 MHz, CDCl3): δ = 7.30–7.24 (m, 3 H, ArH), 7.23–7.18 (m,
2 H, ArH), 7.07–7.02 (m, 2 H, ArH), 7.02–6.93 (m, 3 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 142.7, 141.9, 129.5, 129.3, 125.5,
121.5, 118.8, 118.1.
MS (ESI+): m/z = 204 [M + H]+.
Yield: 177 mg (84%); pale-yellow solid; mp 114–115 °C.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.8 Hz, 2 H, ArH), 7.35 (t,
J = 7.9 Hz, 2 H, ArH), 7.19 (d, J = 7.5 Hz, 2 H, ArH), 7.09 (t, J = 7.4 Hz,
1 H, ArH), 7.00 (d, J = 8.8 Hz, 2 H, ArH), 2.53 (s, 3 H, COCH3).
13C NMR (100 MHz, CDCl3): δ = 196.6, 148.5, 140.7, 130.7, 129.5,
128.9, 123.3, 120.7, 114.4, 26.2.
4-Methoxy-N-(4-nitrophenyl)aniline (1q)21
MS (ESI+): m/z = 212 [M + H]+.
Yield: 41 mg (17%); yellow solid; mp 156–157 °C.
1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 9.2 Hz, 2 H, ArH), 7.16 (d,
J = 8.8 Hz, 2 H, ArH), 6.94 (d, J = 8.9 Hz, 2 H, ArH), 6.76 (d, J = 9.2 Hz,
2 H, ArH), 3.84 (s, 3 H, CH3O).
13C NMR (100 MHz, CDCl3): δ = 157.4, 151.7, 139.0, 132.0, 126.3,
125.5, 115.0, 112.6, 55.6.
4-Nitro-N-phenylaniline (1k)19
Yield: 73 mg (34%); yellow solid; mp 134–135 °C.
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 9.2 Hz, 2 H, ArH), 7.39 (t,
J = 7.9 Hz, 2 H, ArH), 7.21 (d, J = 7.5 Hz, 2 H, ArH), 7.17 (t, J = 7.4 Hz,
1 H, ArH), 6.94 (d, J = 9.2 Hz, 2 H, ArH).
MS (ESI+): m/z = 245 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 150.3, 139.6, 139.5, 129.7, 126.3,
124.6, 121.9, 113.7.
N-Phenylthiophen-3-amine (1r)19
MS (ESI+): m/z = 215 [M + H]+.
Yield: 135 mg (77%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.27–7.20 (m, 3 H, ArH), 6.97 (dd,
J = 8.6, 0.9 Hz, 2 H, ArH), 6.91 (dd, J = 5.2, 2.6 Hz, 1 H, ArH), 6.89–6.83
(m, 1 H, ArH), 6.76–6.71 (m, 1 H, ArH).
N-Phenyl-4-(trifluoromethyl)aniline (1l)19
Yield: 142 mg (60%); white solid; mp 58–59 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

H
Z. Yi et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 144.7, 141.6, 129.4, 125.2, 123.0,
13C NMR (100 MHz, CDCl3): δ = 154.9, 138.0, 124.4, 113.8, 55.5, 52.7,
120.0, 115.7, 106.5.
43.7, 36.5, 29.7.
MS (ESI+): m/z = 176 [M + H]+.
MS (ESI+): m/z = 258 [M + H]+.
N-Phenylpyridin-2-amine (1s)24
2-((4-Methoxyphenyl)amino)ethanol (2f)19
Yield: 112 mg (66%); pale-yellow solid; mp 109–110 °C.
Yield: 150 mg (90%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 4.8 Hz, 1 H, ArH), 7.55–7.47
(m, 1 H, ArH), 7.36 (d, J = 4.0 Hz, 4 H, ArH), 7.13–7.03 (m, 1 H, ArH),
6.91 (d, J = 8.4 Hz, 1 H, ArH), 6.80 (s, 1 H, ArH), 6.78–6.73 (m, 1 H,
ArH).
1H NMR (400 MHz, CDCl3): δ = 6.81 (d, J = 8.9 Hz, 2 H, ArH), 6.65 (d,
J = 8.9 Hz, 2 H, ArH), 3.81 (t, J = 3.8 Hz, 2 H, CH2), 3.77 (s, 3 H, CH3O),
3.24 (t, J = 5.2 Hz, 2 H, CH2), 3.06 (br s, 2 H, NH, OH).
13C NMR (100 MHz, CDCl3): δ = 152.5, 142.2, 115.0, 114.9, 61.0, 55.8,
47.3.
13C NMR (100 MHz, CDCl3): δ = 156.3, 148.3, 140.7, 137.8, 129.3,
122.8, 120.5, 114.9, 108.2.
MS (ESI+): m/z = 171 [M + H]+.
MS (ESI+): m/z = 168 [M + H]+.
2-(Phenylamino)ethanol (2g)25
N-Benzyl-4-methoxyaniline (2a)21
Yield: 134 mg (98%); colorless liquid.
Yield: 198 mg (93%); white solid; mp 48–49 °C.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.18 (m, 2 H, ArH), 6.80–6.74 (m,
1 H, ArH), 6.71–6.67 (m, 2 H, ArH), 3.84 (t, J = 5.1 Hz, 2 H, CH2O), 3.32
(t, J = 5.2 Hz, 2 H, NCH2), 2.82 (s, 2 H, NH, OH).
13C NMR (100 MHz, CDCl3): δ = 148.1, 129.4, 118.0, 113.4, 61.1, 46.1.
MS (ESI+): m/z = 138 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.26 (m, 5 H, ArH), 6.78 (d,
J = 8.9 Hz, 2 H, ArH), 6.62 (d, J = 8.9 Hz, 2 H, ArH), 4.28 (s, 2 H, CH2),
3.74 (s, 3 H, CH3O).
13C NMR (100 MHz, CDCl3): δ = 152.2, 142.4, 139.7, 128.6, 127.6,
127.2, 114.9, 114.2, 55.8, 49.3.
MS (ESI+): m/z = 214 [M + H]+.
2-(Thiophen-3-ylamino)ethanol (2h)
[CAS Reg. No. 1520338-37-7]
N-Benzylthiophen-3-amine (2b)21
Yield: 90 mg (63%); colorless oil.
Yield: 157 mg (83%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.18 (dd, J = 5.1, 3.0 Hz, 1 H, ArH), 6.66
(dd, J = 5.1, 1.5 Hz, 1 H, ArH), 6.03 (dd, J = 3.0, 1.5 Hz, 1 H, ArH), 3.82 (t,
J = 5.1 Hz, 2 H, CH2O), 3.25 (t, J = 5.2 Hz, 2 H, NCH2).
13C NMR (100 MHz, CDCl3): δ = 148.3, 125.4, 120.3, 96.7, 60.9, 48.4.
MS (ESI+): m/z = 144 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.23 (m, 5 H, ArH), 7.14 (dd,
J = 5.1, 3.0 Hz, 1 H, ArH), 6.62 (dd, J = 5.1, 1.5 Hz, 1 H, ArH), 5.96 (dd,
J = 3.0, 1.5 Hz, 1 H, ArH), 4.24 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 148.5, 139.4, 128.7, 127.8, 127.4,
125.2, 120.0, 96.1, 50.7.
MS (ESI+): m/z = 190 [M + H]+.
4-(4-Methoxyphenyl)morpholine (2i)19
Yield: 185 mg (96%); white solid; mp 77–78 °C.
1H NMR (400 MHz, CDCl3): δ = 6.95–6.82 (m, 4 H, ArH), 3.89 (t,
J = 4.7 Hz, 4 H, CH2), 3.80 (s, 3 H, CH3O), 3.09 (t, J = 4.8 Hz, 4 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 154.0, 145.6, 117.8, 114.5, 67.0, 55.6,
50.8.
N-Benzyl-4-nitroaniline (2c)21
Yield: 100 mg (44%); yellow solid; mp 144–146 °C.
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 9.2 Hz, 2 H, ArH), 7.41–7.29
(m, 5 H, ArH), 6.58 (d, J = 9.1 Hz, 2 H, ArH), 4.43 (s, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 153.1, 138.2, 137.4, 129.0, 127.8,
127.3, 126.4, 111.4, 47.6.
MS (ESI+): m/z = 194 [M + H]+.
MS (ESI+): m/z = 229 [M + H]+.
4-Phenylmorpholine (2j)19
Yield: 143 mg (88%); white solid; mp 51–52 °C.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 2 H, ArH), 7.00–6.89 (m,
3 H, ArH), 3.90 (t, J = 4.9 Hz, 4 H, CH2O), 3.19 (t, J = 4.9 Hz, 4 H, NCH2).
13C NMR (100 MHz, CDCl3): δ = 151.3, 129.2, 120.1, 115.8, 67.0, 49.4.
MS (ESI+): m/z = 164 [M + H]+.
N-Benzylaniline (2d)19
Yield: 172 mg (94%); colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.31 (m, 4 H), 7.30–7.24 (m, 1 H),
7.20–7.14 (m, 2 H), 6.75–6.69 (m, 1 H), 6.64 (dd, J = 8.6, 0.9 Hz, 2 H),
4.32 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 148.2, 139.6, 129.4, 128.8, 127.6,
127.3, 117.7, 113.0, 48.4.
1-(4-Morpholinophenyl)ethanone (2k)19
Yield: 184 mg (90%); pale-yellow solid; mp 96–97 °C.
MS (ESI+): m/z = 184 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 9.1 Hz, 2 H, ArH), 6.90 (d,
J = 9.0 Hz, 2 H, ArH), 3.88 (t, J = 4.9 Hz, 4 H, CH2), 3.33 (t, J = 4.9 Hz,
4 H, NCH2), 2.55 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 196.6, 154.2, 130.4, 128.1, 113.3, 66.5,
47.5, 26.2.
N-(4-Methoxyphenyl)adamantan-1-amine (2e)19
Yield: 211 mg (82%); white solid; mp 61–62 °C.
1H NMR (400 MHz, CDCl3): δ = 6.84 (d, J = 8.9 Hz, 2 H, ArH), 6.76 (d,
J = 8.9 Hz, 2 H, ArH), 3.76 (s, 3 H, CH3O), 2.08 (s, 3 H, CH), 1.75 (d,
J = 2.5 Hz, 6 H, CH2), 1.63 (q, J = 12.1 Hz, 6 H, CH2).
MS (ESI+): m/z = 206 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

I
Z. Yi et al.
Paper
Synthesis
4-(Thiophen-3-yl)morpholine (2l)26
Synthesis of MMDPA and Reuse of Ligand
Yield: 123 mg (73%); white solid; mp 86–87 °C.
Run 0: A 30 mL vial was charged with CuI (95 mg, 0.5 mmol), PSAP
(300 mg, 0.5 mmol, > 100 mesh), K3PO4 (4.24 g, 20 mmol), 4-me-
thoxy-2-methylaniline (10 mmol), bromobenzene (15 mmol), DEG
(20 mL), and a magnetic stir bar. The vessel was sealed with a septum
and placed into a preheated oil bath at 70 °C. The reaction mixture
was held at this temperature for 14 hours. After reaction, the reaction
mixture was filtered, washed sequentially with water and methanol,
and the residue was dried in vacuo to afford the recovered PSAP. The
filtrate was poured into water (500 mL), the precipitates were collect-
ed and dissolved in methanol. After removal of insoluble material, the
filtrate was dropped into water to afford the crude product as precip-
itates. The crude product was dissolved in MeOH and precipitated
with water once again, filtered and washed with water, dried in vacuo
to afford 2-methyl-4-methoxydiphenylamine as off-white solids
(1.98 g, 93%). All reuse runs were performed in the same manner and
produced off-white solids.
1H NMR (400 MHz, CDCl3): δ = 7.28 (dd, J = 5.2, 3.1 Hz, 1 H, ArH), 6.89
(dd, J = 5.2, 1.5 Hz, 1 H, ArH), 6.25 (s, 1 H, ArH), 3.88 (t, J = 4.9 Hz, 4 H,
CH2O), 3.12 (t, J = 4.9 Hz, 4 H, NCH2).
13C NMR (100 MHz, CDCl3): δ = 152.4, 125.6, 119.6, 100.5, 66.7, 50.8.
MS (ESI+): m/z = 170 [M + H]+.
1-(4-Methoxyphenyl)pyrrolidine (2m)19
Yield: 140 mg (79%); white solid; mp 45–46 °C.
1H NMR (400 MHz, CDCl3): δ = 6.85 (d, J = 9.0 Hz, 2 H, ArH), 6.54 (d,
J = 7.4 Hz, 2 H, ArH), 3.76 (s, 3 H, CH3O), 3.23 (t, J = 6.8 Hz, 4 H, CH2),
1.99 (t, J = 6.3 Hz, 4 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 150.8, 143.2, 115.0, 112.7, 56.0, 48.3,
25.4.
MS (ESI+): m/z = 178 [M + H]+.
Run 1: Yield: 1.89 g (89%).
Run 2: Yield: 1.81 g (85%).
Run 3: Yield: 1.77 g (83%).
Run 4: Yield: 1.79 g (84%).
Run 5: Yield: 1.70 g (80%).
1H NMR (400 MHz, CDCl3): δ = 7.22 (t, J = 7.5 Hz, 3 H, ArH), 6.92–6.69
(m, 5 H, ArH), 3.83 (s, 3 H, OCH3), 2.25 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 156.4, 146.3, 134.1, 133.5, 129.3,
N,N-Dibutylaniline (2n)19
Yield: 109 mg (53%); colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.18 (m, 2 H, ArH), 6.78–6.62 (m,
3 H, ArH), 3.31 (t, J = 7.9, 7.2 Hz, 4 H, NCH2), 1.70–1.55 (m, 4 H,
NCH2CH2), 1.48–1.36 (m, 4 H, CH2CH3), 1.00 (t, J = 7.2 Hz, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 147.1, 128.1, 114.1, 110.7, 49.7, 28.4,
19.3, 13.0.
125.1, 118.8, 116.4, 114.8, 111.9, 55.5, 18.3.
MS (ESI+): m/z = 214 [M + H]+.
MS (ESI+): m/z = 206 [M + H]+.
N,N-Dibutyl-4-methoxyaniline (2o)19
Anal. Calcd for C14H15NO·0.05H2O: C, 78.51; H, 7.11; N, 6.54; Found: C,
78.11, H, 7.07; N, 6.51.
Yield: 176 mg (75%); colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 6.85 (d, J = 9.1 Hz, 2 H, ArH), 6.68 (d,
J = 8.7 Hz, 2 H, ArH), 3.78 (s, 3 H, CH3O), 3.20 (t, J = 7.5 Hz, 4 H, NCH2),
1.60–1.48 (m, 4 H, NCH2CH2), 1.41–1.31 (m, 4 H, CH2CH3), 0.96 (t,
J = 7.3 Hz, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 151.1, 143.3, 114.8, 114.5, 55.8, 51.8,
29.5, 20.5, 14.1.
Funding Information
This work was supported by grants from the National Natural Science
Foundation of China (21702239), Guangzhou Science and Technology
Plan Projects (201707010271), the Fundamental Research Funds for
the Central Universities (16lgpy16), and the Funds of Sun Yat-sen Uni-
MS (ESI+): m/z = 236 [M + H]+.
versity (2017sdjgpy010).
N
oaitn
a
l
N
a
utra
l
Secince
F
o
u
n
d
oaitn
of
C
h
n
i
a
2(
1
7
0
2
2
3
9
G)
u
a
n
g
z
h
o
u
S
ecin
c
e
a
n
d
Te
c
h
n
o
lg
y
Paln
Porejcst
2(
0
1
7
0
7
0
1
0
2
7
1
F)u
n
d
a
m
e
n
atl
Reseacrh
F
u
n
ds
o
f
r
hte
C
e
nrta
l
U
nv
e
itrsi
1(6glp
y
1
6F)u
n
ds
of
S
u
n
Ya-tsen
Unvieytrsi
2(
0
1
7sdgjp
y
0
1
0)
1-(4-(Dibutylamino)phenyl)ethanone (2p)27
Yield: 158 mg (64%); pale-yellow liquid.
Supporting Information
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 9.0 Hz, 2 H, ArH), 6.61 (d,
J = 8.9 Hz, 2 H, ArH), 3.35 (t, J = 7.6 Hz, 4 H, NCH2), 2.51 (s, 3 H, CH3-
CO), 1.67–1.54 (m, 4 H, NCH2CH2), 1.45–1.33 (m, 4 H, CH2CH3), 0.99 (t,
J = 7.3 Hz, 6 H, CH3).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609578.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
13C NMR (100 MHz, CDCl3): δ = 196.1, 151.5, 130.8, 124.5, 110.2, 50.7,
29.3, 25.9, 20.3, 14.0.
References
MS (ESI+): m/z = 248 [M + H]+.
(1) (a) Travis, A. S. Manufacture and Uses of the Anilines: A Vast
Array of Processes and Products, In The Chemistry of Anilines;
John Wiley & Sons Ltd: Chichester, 2007. (b) Magano, J.; Dunetz,
J. R. Chem. Rev. 2011, 111, 2177. (c) Aubin, Y.; Fischmeister, C.;
Thomas, C. M.; Renaud, J. L. Chem. Soc. Rev. 2010, 39, 4130.
(2) (a) Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64, 670.
(b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727. (c) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.;
Tao, F. J. Am. Chem. Soc. 1998, 120, 12459. (d) Kwong, F. Y.;
Buchwald, S. L. Org. Lett. 2003, 5, 793.
N,N-Dibutylthiophen-3-amine (2q)19
Yield: 72 mg (34%); colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 7.17 (dd, J = 5.1, 3.2 Hz, 1 H, ArH), 6.73
(d, J = 5.1 Hz, 1 H, ArH), 5.80 (s, 1 H, ArH), 3.15 (t, J = 7.4 Hz, 4 H,
NCH2), 1.60–1.47 (m, 4 H, NCH2CH2), 1.39–1.27 (m, 4 H, CH2CH3), 0.93
(t, J = 7.3 Hz, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 150.4, 124.7, 118.9, 94.6, 52.3, 29.5,
20.5, 14.1.
MS (ESI+): m/z = 212 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

J
Z. Yi et al.
Paper
Synthesis
(3) (a) Jiang, Y.; Ma, D. Assembly of N-Containing Heterocycles via
Pd- and Cu-Catalyzed C–N Bond Formation Reaction, In Amina-
tion and Formation of sp2 C–N Bonds; Springer-Verlag: Ber-
lin/Heidelberg, 2013. (b) Monnier, F.; Taillefer, M. Copper-Cata-
lyzed C(aryl)–N Bond Formation, In Amination and Formation of
sp2 C–N Bonds; Springer-Verlag: Berlin/Heidelberg, 2013.
(c) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42,
5400.
(4) (a) Ma, D.; Geng, Q.; Zhang, H.; Jiang, Y. Angew. Chem. Int. Ed.
2010, 49, 1291. (b) Monnier, F.; Taillefer, M. Angew. Chem. Int.
Ed. 2009, 48, 6954. (c) Klapars, A.; Antilla, J. C.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (d) Evano, G.;
Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
(e) Schranck, J.; Tlili, A. ACS Catal. 2018, 8, 405.
(12) (a) Yi, W.; Cao, R.; Wen, H.; Yan, Q.; Zhou, B.; Wan, Y.; Ma, L.;
Song, H. Bioorg. Med. Chem. Lett. 2008, 18, 6490. (b) Lv, X.;
Wang, Z.; Bao, W. Tetrahedron 2006, 62, 4756.
(13) Colacino, E.; Villebrun, L.; Martinez, J.; Lamaty, F. Tetrahedron
2010, 66, 3730.
(14) (a) Harsha, K.; Reddy, V.; Satish, G.; Ramesh, K.; Karnakar, K.;
Nageswar, Y. V. D. Tetrahedron Lett. 2012, 53, 3061. (b) Ganesh
Babu, S.; Karvembu, R. Ind. Eng. Chem. Res. 2011, 50, 9594.
(c) Rout, L.; Jammi, S.; Punniyamurthy, T. Org. Lett. 2007, 9,
3397.
(15) Chouhan, G.; Wang, D.; Alper, H. Chem. Commun. 2007, 4809.
(16) Huang, L.; Yu, R.; Zhu, X.; Wan, Y. Tetrahedron 2013, 69, 8974.
(17) Kim, B.-S.; Jung, D.-G.; Kim, K.; Lee, T.-J.; Kim, J.-C.; Kim, D.-H.
Korean J. Chem. Eng. 1998, 15, 522.
(5) (a) Zhou, W.; Fan, M.; Yin, J.; Jiang, Y.; Ma, D. J. Am. Chem. Soc.
2015, 137, 11942. (b) Huang, M.; Lin, X.; Zhu, X.; Peng, W.; Xie,
J.; Wan, Y. Eur. J. Org. Chem. 2011, 4523. (c) Fan, M.; Zhou, W.;
Jiang, Y.; Ma, D. Org. Lett. 2015, 17, 5934.
(6) Xie, R.; Fu, H.; Ling, Y. Chem. Commun. 2011, 8976.
(7) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3490.
(8) Zeng, M.; Zhang, X.; Shao, L.; Qi, C.; Zhang, X.-M. J. Organomet.
Chem. 2012, 704, 29.
(9) Munnik, P.; de Jongh, P. E.; de Jong, K. P. Chem. Rev. 2015, 115,
6687.
(10) (a) Hajipour, A. R.; Check, M.; Khorsandi, Z. Appl. Organomet.
Chem. 2017, 31, e3769. (b) Nasrollahzadeh, M.; Zahraei, A.;
Pourbasheer, E. Monatsh. Chem. 2015, 146, 1329. (c) Kodicherla,
B.; Perumgani, C. P.; Mandapati, M. R. Appl. Catal., A 2014, 483,
110. (d) Hirai, Y.; Uozumi, Y. Chem. Lett. 2011, 40, 934.
(11) (a) Islam, S. M.; Mondal, S.; Mondal, P.; Roy, A. S.; Tuhina, K.;
Salam, N.; Mobarak, M. J. Organomet. Chem. 2012, 696, 4264.
(b) Islam, S. M.; Mondal, S.; Mondal, P.; Roy, A. S.; Tuhina, K.;
Mobarok, M. Inorg. Chem. Commun. 2011, 14, 1352. (c) Kantam,
M. L.; Roy, M.; Roy, S.; Sreedhar, B.; Lal De, R. Catal. Commun.
2008, 9, 2226.
(18) Scholz, U.; Schlummer, B. Tetrahedron 2005, 61, 6379.
(19) Ding, X.; Huang, M.; Yi, Z.; Du, D.; Zhu, X.; Wan, Y. J. Org. Chem.
2017, 82, 5416.
(20) Wan, Y.; Fu, L.; Lin, X.; Zhu, X.; Wang, S.; Liang, Y. Chinese Patent
CN102276612A, 2011.
(21) Yang, B.; Mao, Z.; Zhu, X.; Wan, Y. Catal. Commun. 2015, 60, 92.
(22) Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.; Sproules, S.;
Watson, A. J. B. J. Am. Chem. Soc. 2017, 139, 4769.
(23) Lan, X.-B.; Li, Y.; Li, Y.-F.; Shen, D.-S.; Ke, Z.; Liu, F.-S. J. Org.
Chem. 2017, 82, 2914.
(24) Hatakeyama, T.; Imayoshi, R.; Yoshimoto, Y.; Ghorai, S. K.; Jin,
M.; Takaya, H.; Norisuye, K.; Sohrin, Y.; Nakamura, M. J. Am.
Chem. Soc. 2012, 134, 20262.
(25) Mostafalu, R.; Kaboudin, B.; Kazemi, F.; Yokomatsu, T. RSC Adv.
2014, 4, 49273.
(26) Yonekura, K.; Yoshimura, Y.; Akehi, M.; Tsuchimoto, T. Adv.
Synth. Catal. 2018, 360, 1159.
(27) Marcoux, J.-F.; Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1997, 62,
1568.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J