Methyl-α-d-glucopyranoside as Green Ligand for Selective Copper-Catalyzed N-Arylation

Article abstract of DOI:10.1055/s-0039-1690702

In the selective N-arylation of amines or azoles with aryl halidesa-, methyl-α-d-glucopyranoside (MG) was found to function as a green ligand of copper powder. In addition, nitrogen heterocyclic amine compounds can also undergo the N-arylation coupling with heterocyclic aryl chlorides. This process allows access to a variety of aromatic amines and aryl azoles under mild reaction conditions, has good tolerance, and proceeds in moderate to high yield.

Full text of DOI:10.1055/s-0039-1690702

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–K
paper
A
en
Y. Chen et al.
Paper
Synthesis
Methyl--D-glucopyranoside as Green Ligand for Selective
Copper-Catalyzed N-Arylation
Yuanguang Chen
Fangyu Du
10 mol% Cu powder,
20 mol% MG,
3.0 equiv Cs2CO3
N
N
Het
R
R
Het-NH
NHR'R''
Y
X
+
or
Fengyang Chen
Qifan Zhou
R
Y
DMSO–H2O (1:1), 100 °C,
10–24 h
HO
HO
R'R''
O
O
Y = CH, N
Y
Guoliang Chen*
0
0
0
0-
0
0
0
3-3
6
7
4-5
2
2
6
R = OCH3, CH3, CHO,
CN, NO2, etc.
HO
OH
Key Laboratory of Structure-Based Drug Design & Discovery of
Ministry of Education, Shenyang Pharmaceutical University,
Shenyang 110016, P. R. of China
10 mol% Cu powder,
20 mol% MG,
3.0 equiv Cs2CO3
N
Het
Methyl-a-D-
glucopyranoside
(MG)
R
R
Cl
X
X
Y
Y
Het-NH
R
or
+
spucgl@163.com
N
NR'R''
X
Y
NHR'R''
DMSO–H2O (1:1), 110 °C,
14 h
X, Y = CH, N
Received: 28.08.2019
Accepted after revision: 17.09.2019
Published online: 14.10.2019
celerate the C–N coupling reaction, fewer catalysts could
promote the coupling of nitrogen-containing aromatic het-
erocyclic chlorides. Some ligands are expensive and diffi-
cult to obtain, leading to high costs in large-scale produc-
tion.9 Therefore, we wanted to find a ligand with a wide
range of sources, that was also green and readily commer-
cially available. Carbohydrates are one of the most naturally
abundant organic molecules and they generally exist in the
form of disaccharides and polysaccharides. Many natural
products and biological molecules are synthesized using
monosaccharide as precursors.10 In 2011, Krishna et al.11 re-
ported that D-glucose and D-aminosaccharides act as green
ligands for selective copper-catalyzed halogenated aromatic
synthesis of phenol and primary aromatic amines. To date,
there are no reports on the use of monosaccharides as li-
gands that can promote the coupling of aryl halides with
secondary amines, aromatic amines, and azoles. According
to the screening, we found methyl--D-glucopyranoside
(L6), which has a wide range of sources, was inexpensive,
green, and readily commercially available (Figure 1). The
Cu(0)/MG catalytic system has good applicability for nitro-
gen-containing aromatic heterocyclic chlorides, amines,
and azoles. The introduction of a heterocyclic structure into
a drug molecule can play an important role in improving its
selectivity and availability, liposolubility, water solubility,
and molecular polarity.12 Herein, we report our initial find-
ing of the study of MG as a green ligand for copper-cata-
lyzed synthesis of N-arylated compounds. This procedure is
very simple, economic, and environmentally friendly.
DOI: 10.1055/s-0039-1690702; Art ID: ss-2019-f0486-op
Abstract In the selective N-arylation of amines or azoles with aryl
halides, methyl--D-glucopyranoside (MG) was found to function as a
green ligand of copper powder. In addition, nitrogen heterocyclic
amine compounds can also undergo the N-arylation coupling with het-
erocyclic aryl chlorides. This process allows access to a variety of aro-
matic amines and aryl azoles under mild reaction conditions, has good
tolerance, and proceeds in moderate to high yield.
Key words N-arylation, ligands, catalysts, nitrogen heterocycles,
azoles
Metal-catalyzed Ullmann type C–N coupling reactions
represent one of the most efficient methods available for
the formation of various C–N bond-containing compounds,
which have important biological activity.1 Nitrogen-con-
taining heterocycles such as N-arylpyrroles, N-arylindoles,
and N-arylimidazoles are ubiquitous synthons in numerous
natural products and biologically active pharmaceuticals.2
The synthetic methods for these pharmaceutical ingredi-
ents have mainly depended on using highly activated aryl
halides (SNAr reaction),3 classical Ullmann type coupling re-
actions,4 Buchwald–Hartwig reactions,5 and Chan–Lam re-
actions.6 Although these coupling reactions have attracted
considerable attention, they suffer from harsh reaction con-
ditions, such as large excess amounts of copper catalyst,
high temperature (150–250 °C), and strong base, leading to
restrictions in industrial application.7
We commenced with 4-chlorine pyridine hydrochloride
with piperidine (3.0 equiv) in the presence of 10 mol % cop-
per catalyst and 20 mol% MG at 100 °C in a sealed vessel
without inert gas protection, as described in Table 1. Initial-
ly, in the presence of MG, when CuSO4, CuI, CuCl and Cu2O
were used as catalysts (entries 1–3), only a small amount of
To overcome the shortcomings of classical Ullmann re-
action, various improved Ullmann catalytic systems, espe-
cially ligands, have been reported over the past decades.
These efficient ligands include 1,10-phenanthroline deriva-
tives,8a–c diamines,8d–f amino acid derivatives,8g–i 8-hydroxy-
quinoline,8j etc. Although these ligands could effectively ac-
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K
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B
Y. Chen et al.
Paper
Synthesis
Table 1 Identification of Reaction Conditionsa
OH
OH
O
OH
OH
O
O
Cl
10 mol% Cu source
OH
OH
OH
O
HO
OH HO
20 mol% MG
HO
HO
OH
OH
3.0 equiv base
HCl
+
N
N
O
N
N
solvent, 100 °C, 14 h
H
HO
OH
1a
2a
3w
HO
OH
L1
L2
L3
Entry
Cu (mol%)
Base
Cs2CO3
Solvent
Yield (%)b
HO
1
2
CuSO4 (10)
CuI (10)
Cu2O (10)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
20
50
45
75
65
60
50
60
55
88
40
OH
O
OH
O
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
HO
HO
O
OH
OH
3
O
O
OH
HO
HO
OH O
OH
4
OH
5
HO
OH
OH
6
7
KOH
L4
L5
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
HO
HO
O
9
dioxane
OH
OH
O
10
11c
DMSO–H2O (1:1)
DMSO–H2O (1:1)
HO
OH
HO
HO
OH
a Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), Cu powder (10
mol%), MG (20 mol%), DMSO–H2O, 1:1 (2 mL), 100 °C, 14 h; the reaction
was run in a sealed vessel, unless noted otherwise.
b Isolated yield.
L6
L7
L8
O
H
c Reaction system without MG.
N
OH
N
N
L9
L10
Table 2 Screening of Ligandsa
Figure 1 Some bidentate ligands for copper-catalyzed coupling reac-
tions, and the chemical structure of MG
Cl
10 mol% Cu powder
20 mol% Ligand
3.0 equiv Cs2CO3
HCl
N
N
+
target product 4-piperidine-1-pyridine (3w) (< 50% yield)
and unreacted starting materials were observed. Surpris-
ingly, the C–N coupling product was obtained in 75% yield
under the catalysis of copper powder (entry 4). Further
studies showed that base had a significant effect, and
Cs2CO3 was the best in yield (entries 5–7). Polar solvents
(DMSO, DMF) are beneficial to this reaction, and DMSO–
H2O (1:1) is the most effective (entries 8–10). To prove the
effectiveness of the ligand, a control reaction (entry 11) was
carried out with a yield of only 40%, which fully proves the
effectiveness of MG.
N
H
N
DMSO–H2O (1:1, 2 mL),
110 °C, 14 h
1b
2b
3w
Ligand
L1
L2
65
L7
50
L3
60
L8
55
L4
70
L9
54
L5
Yield (%)b
Ligand
68
L6
88
58
L10
56
Yield (%)b
a Reaction conditions: 1b (1.0 mmol), 2b (3.0 mmol), ligand (20 mol%), Cu
powder (10 mol%), DMSO–H2O, (1:1, 2 mL), 100 °C, 14 h; the reaction was
run in a sealed vessel, unless noted otherwise.
b Isolated yield.
At the same time, we systematically examined other li-
gands used in copper-catalyzed N-arylation (Table 2).
Whereas the yield was only 50% with reported glycol as li-
gand,13 it was found that L4 or MG could promote the cou-
pling reaction at 100 °C in yields of more than 70%. Other
carbohydrates also gave moderate yields of the product, but
lower than with MG. We speculated that the good water
solubility and rigid six-membered ring of MG is conducive
to fixing hydroxyl groups and better binding with copper.
With the reported tridentate ligand 1,1,1-tri(hydroxymeth-
yl)ethane14 (L8, Figure 1), we found that the target product
was obtained in 55% yield. Similarly, ligands L7, L9 and L10
led to yield of the product of only around 50%, which fur-
ther demonstrates the effectiveness of MG.
With optimized conditions in hand, we explored the
scope of the coupling reactions of aryl halides with aliphat-
ic amines in the presence of Cu powder (10 mol%), MG (20%
mol) and Cs2CO3 (3 equiv); the results are summarized in
Table 3. We obtained 3a in high yield (95%) with active bro-
mides, and the inactive bromide with electron-donor react-
ed with 2-(piperazin-1-yl)ethan-1-ol and piperidine to give
3b (90%) and 3c (91%), respectively. Recently, Mudithana-
pelli et al. 15 reported that 3c was obtained from palladium
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

C
Y. Chen et al.
Paper
Synthesis
Table 4 Scope with Respect to N-Containing Heterocyclesa
Table 3 Copper/MG Catalyzed Coupling Reactions of Aryl Halides with
Aminesa
X = CH, N
10 mol% Cu powder, 20 mol%
MG, 3.0 equiv Cs2CO3
Br
X
10 mol% Cu powder, 20 mol%
MG, 3.0 equiv Cs2CO3
R
Het-NH
+
NH Het
+
HNRR'
ArBr
Ar NRR'
X
R
DMSO-H2O (1:1), 100 °C,
12–24 h
DMSO–H2O (1:1), 100 °C, 10–16 h
1c
2c
3
1d
2d
3
OH
O
N
N
O
N
N
N
N
N
N
NO2
N
3a (95%)
3b (90%)
3c (91%)
N
O2N
N
O
O
N
O
O
NO2
H
NO2
3m (84%)
N
N
3k (96%)
3j (96%)
3l (90%)
3f (84%)
O
O
3e (83%)
HO
3d (85%)
O
HN
N
N
N
N
N
N
N
N
N
N
S
N
N
H
3o (85%)
3n (80%)
3h (80%)
3g (90%)
3p (82%)
3q (80%)
CHO
3i (90%)
CHO
a Standard conditions: 1c (1.0 mmol), 2c (3.0 mmol), MG (20 mol%), Cu
powder (10 mol%), DMSO–H2O (1:1, 2 mL), 100 °C; the reaction was run in
a sealed vessel, unless noted otherwise.
CHO
b Isolated yield.
N
COOH
N
N
N
N
N
and sodium tert-butanol, with 95% yield. The sterically hin-
dered 2-bromoanisole reacted with tetrahydropyrrole,
3r (75%)
3s (80%)
NO2
3t (91%)
NO2
3u (66%)
NO2
piperidine and morpholine, affording the coupling product
16
in high yield (>80%). Similarly, de Lange et al.
reported
a Standard conditions: 1d (1.0 mmol), 2d (1.5 mmol), MG (20 mol%), Cu
powder (10 mol%), DMSO–H2O (1:1, 2 mL), 100 °C; the reaction was run in
a sealed vessel, unless noted otherwise.
that 3e was obtained in only 38% yield catalyzed by CuI/
2-propionylcyclohexan-1-one (130 °C, 16 hours). Then, 2-
bromothiophene was coupled with piperidine to give 3g in
90% yield. To further expand the scope of substrates, prima-
ry amines were investigated in the reaction; thus, 3h was
delivered in 80% yield, with no secondary or tertiary amines
being found. Surprisingly, bromobenzene could also partic-
ipate in the reaction with D-valine to give 3i in 90% yield.
Surprisingly, the reaction of bromobenzene with pyra-
zole yielded 3j in 96% yield. To investigate the applicability
of substrates, a number of inactive azoles were coupled
with aryl halides and found to give the corresponding prod-
uct 3k (96%) and 3l (90%) (Table 4). Compound 3m was ob-
tained from p-nitrobromobenzene and pyrrole in 84% yield,
and 3n was also obtained in 80% yield by using 2-bromo-
anisole and pyrrole as starting material. The reaction of 2-bro-
mopyridine with imidazole, 2-methylimidazole, 4-formal-
dehyde pyrazole and pyrrole was then carried out to afford
3o (85%), 3p (82%), 3q (80%), and 3r (75%), respectively. Not
surprisingly, electron-rich azoles are superior to electron-
deficient azoles, such as 3s and 3u, with the yield of 80%
and 66%, respectively. When indole-2-carboxylic acid was
used, the yield was increased to 91%. It is possible that in-
dole-2-carboxylic acid could function as a ligand, which
promoted the coupling reaction. The system is not neces-
sarily optimal for azoles, but it is also well tolerated for pyr-
roles, imidazoles and benzimidazoles.
b Isolated yield.
To investigate the catalytic ability of the system, first, 4-
chloropyridine hydrochloride and tetrahydropyrrole were
used as starting material; surprisingly, 3v was obtained in
89% yield (Table 5). The reaction with piperidine also pro-
ceeded in 88% yield to give 3w. 2-Chloropyridine, a less ac-
tive halide, coupled with tetrahydropyrrole, piperidine and
morpholine, affording the desired product 3x (82%), 3y
(80%) and 3z (76%), respectively. The reaction of p-chloro-
benzaldehyde with tetrahydropyrrole and piperidine gave
3aa (78%) and 3ab (76%) in satisfactory yield. Next, 2-chlo-
ropyrimidine, a nitrogen-containing heterocyclic chloride,
reacted with secondary amines contained within rings. No-
tably, 3ac (90%) and 3ad (89%) were obtained in higher
yields. We speculated that water could form intermolecular
hydrogen bonds with 2-chloropyrimidine, thus facilitating
the coupling reaction. Based on the previous reaction of
bromobenzene with L-valine, a satisfactory yield was ob-
tained. Therefore, L-valine and methionine coupled with 2-
chloropyrimidine, affording the corresponding product in a
surprisingly high yield for 3ae (92%) and 3af (93%). 2-Chlo-
ropyrimidine could also react with imidazole and 2-me-
thylimidazole, to give the desired product 3ag (86%) and
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

D
Y. Chen et al.
Paper
Synthesis
Table 6 Copper/MG Catalyzed Coupling Reactions of Aromatic Halides
Table 5 Copper/MG Catalyzed Coupling Reactions of Nitrogenous
with Aromatic Aminesa
Heterocyclic Aryl Chlorides with Amines and Azolesa
10 mol% Cu powder,
X, Y = CH, N
H
20 mol% MG,
NH2
N
10 mol% Cu powder, 20 mol%
MG, 3.0 equiv Cs2CO3
Cl
3.0 equiv Cs2CO3
Br
+
NH-Het
R'
R
R
+
HCl
HNR'R''
X
Y
R
DMSO–H2O (1:1), 110 °C, 14 h
R'
DMSO–H2O (1:1), 110 °C,
20–30 h
2e
3
1e
H
1f
2f
N
R'R''
N
Het
R
R
or
HOOC
HN
X
Y
X
Y
3
3
H
N
H
N
O2N
O
N
N
N
3ak (75%)
3aj (85%)
3al (66%)
NO2
N
N
N
N
H
N
N
O
N
O
N
3v (89%)
3w (88%)
3x (82%)
3y (80%)
3z (76%)
N
H
3an (78%)
O
O
3am (64%)
HO
N
N
N
N
a Reaction conditions: 1f (1.0 mmol), 2f (0.8 mmol), MG (20 mol%), Cu
powder (10 mol%), base (3.0 mmol), DMSO–H2O (1:1, 2 mL), 110 °C; the
reaction was run in a sealed vessel, unless noted otherwise.
b Isolated yield.
N
N
N
HN
N
N
N
CHO
CHO
3aa (78%) 3ab (76%)
3ac (90%)
3ad (89%)
3ae (92%)
O
3ao in 38% yield.17 The reaction time was long and the yield
was low. Under catalysis with copper, 70% of 3ao was ob-
tained at 110 °C after 24 hours. The system not only reduces
the reaction time, but also increases the yield by 32%, which
greatly reduces the cost. The scalability of this scheme was
demonstrated by the synthesis of 5 grams of 3ao, which
shows the stability of the system.
To identify a plausible mechanism for the coupling reac-
tion, 1-allyloxy-2-iodobenzene (a radical probe) was used
to determine whether the coupling reaction involved free
radicals,18 as shown in Scheme 2. The results revealed that
no closure compound was obtained, and only the C–N cou-
pling product 3ap and 3ar were found. Therefore, the reac-
tion was probably carried out through the copper(I)/
copper(III) catalytic cycle,19 as shown in Scheme 3. First,
copper(I) is formed in situ by oxidation of copper(0), and
then dealcoholic complex (MG-A) is formed with the two
cis-hydroxyl groups of MG. Next, MG-A and ArX are oxi-
dized to give MG-B. The metathesis of MG-B and NHRR′ af-
fords MG-C, and removal HX delivers MG-D under the ac-
tion of base. Finally, N-aryl compounds are obtained by the
reductive elimination of MG-D.
In summary, we have developed a catalytic system for
N-arylation that utilizes existing heterocyclic aromatic
chlorides (bromides) and related aliphatic amines, azoles,
aromatic amines and amino acids. The mild, environmen-
tally friendly reaction conditions and high turnover rates
are positive attributes of the present method for the prepa-
ration of aryl amines, particularly in large-scale production.
This reaction converts simple starting materials into com-
plex aminated structural fragments, which are important
S
N
N
N
N
OH
N
N
HN
N
N
N
CN
N
N
N
3af (93%)
3ag (86%) 3ah (80%)
3ai (88%)
a Reaction conditions: 1e (1.0 mmol), 2e (3.0 mmol), MG (20 mol%), Cu
powder (10 mol%), Cs2CO3 (3.0 mmol), DMSO–H2O (1:1, 2 mL), 110 °C; the
reaction was run in a sealed vessel, unless noted otherwise.
b Isolated yield.
3ah (80%) in good yield. Compound 3ai was also obtained in
88% yield using o-chlorobenzenitrile and pyrazole as start-
ing material.
To establish the feasibility of this method, aromatic
amines and halides with different properties were exam-
ined to achieve the desired coupling; the results are sum-
marized in Table 6. When o-bromobenzoic acid reacted
with aniline, 3aj (85%) was obtained, which may be due to
the increased solubility of the salt formed by the acid and
the promotion of the reaction. When we changed the sub-
stituents of the bromides, stable coupling was achieved,
and the yield was over 64%.
Methyl--D-glucopyranoside is a cheap, widely avail-
able, green and commercialized ligand. To investigate the
application of this system to pharmaceutical processes, the
key intermediate of tofacitinib (3ao), was prepared by using
the copper catalyst with the assistance of MG (Scheme 1).
According to the literature, (3S,4S)-1-benzyl-N-4-dimethyl-
piperidine-3-amine and 4-chloro-7H-pyrrolidone[2,3-d]-
pyrimidine reacted in triethylamine for four days, and gave
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

E
Y. Chen et al.
Paper
Synthesis
N
Cl
N
N
H
N
N
10 mmol% Cu powder, 20 mmol% MG,
3.0 equiv Cs2CO3
N
N
N
O
N
N
+
N
N
N
DMSO–H2O (1:1), 110 °C, 24 h
70%
N
H
N
H
N
tofacitinib
H
3an
Scheme 1 Synthesis of tofacitinib (3ao)
10 mol% Cu powder,
20 mol% MG,
3.0 equiv Cs2CO3
O
O
O
+
N
I
HN
N
+
N
DMSO–H2O = 1:1, 110 °C, 14 h
not observed
observed
3aq
3ap
10 mol% Cu powder,
20 mol% MG,
3.0 equiv Cs2CO3
O
O
O
+
N
I
+
HN
DMSO–H2O = 1:1, 110 °C, 14 h
observed
not observed
3ar
3as
Scheme 2 Reaction of 2-allyloxyiodobenzene with piperidine and pyrazole
HO
base
H
OH
HO
H
O
Ar
O
OH
H
ArX
O
O
O
Cu((III)
Copper precursor
X
O
Cu(I)
OCH3
MG
OCH3
MG-B
MG-A
NHRR'
Ar-NRR'
HO
HO
OH
O
H
OH
O
H
base
–HX
Ar
O
Ar
O
O
O
Cu((III)
Cu((III)
R'RN
R'RN
OCH3
OCH3
X
MG-C
MG-D
Scheme 3 Reaction mechanism of copper-catalyzed N-arylamination
synthetic intermediates for the preparation of biologically
active molecules such as tofacitinib. Given that MG is a
commercially sourced, cheap, green ligand, the approach
opens a road for the application of such ligands in industry.
On the other hand, MG contains many chiral centers, which
may open new fields for cheap and environmentally friend-
ly chiral synthesis of various important optically active aro-
matic amines. The application of water-soluble MG as a li-
gand for other organic reactions, and detailed mechanistic
studies on the N-arylation are in progress.
All starting materials, reagents and solvents are commercially avail-
able and were used without further purification. Melting points were
determined with an X-4 detector without correction. NMR spectra
were recorded with a Bruker 400-MHz spectrometer as samples in
CDCl3 or DMSO-d6 with tetramethylsilane (TMS) as internal standard.
Electrospray ionization mass spectrometry (ESI-MS) analyses were
recorded with an Agilent 1100 Series MSD Trap SL (Santa Clara, CA,
USA). The reactions were monitored by thin-layer chromatography
(TLC: HG/T2354-92, GF254), and compounds were visualized on TLC
with UV light.
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F
Y. Chen et al.
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Synthesis
General Procedure
1-(2-Methoxyphenyl)piperidine (3e)24
All the reactions were carried out in DMSO–H2O (1:1, 2 mL) in a
sealed vessel. To a 10 mL hydrothermal synthesis reactor was charged
Cu powder (6 mg, 0.1 mmol), MG (39 mg, 0.2 mmol), Cs2CO3 (980 mg,
3.0 mmol), nitrogen-containing heterocycle (1.5 mmol), amine (3.0
mmol), and aryl halide (0.8 mmol). The reaction mixture was stirred
for a specified time at 100–110 °C. After TLC analysis confirmed the
complete consumption of aryl halides, the mixture was cooled to r.t.
(the pH was adjusted if the product was acidic), diluted with EtOAc
(10 mL), filtered through a Celite pad, and washed with EtOAc (20–30
mL). The organic layer was dried and concentrated. The residue was
purified by silica gel column chromatography to give the product.
The reaction was performed with 1-bromo-2-methoxybenzene (0.19
g, 1.0 mmol), piperidine (0.26 g, 3.0 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.16 g (83%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 6.97–6.95 (m, 3 H), 6.84 (d, J = 6.6 Hz,
1 H), 3.86 (s, 3 H), 2.98 (t, J = 4.8 Hz, 4 H), 1.78–1.73 (m, 4 H), 1.59–
1.54 (m, 2 H).
ESI-MS: m/z = 192.17 [M + H]–.
4-(2-Methoxyphenyl)morpholine (3f)25
1-(4-Nitrophenyl)pyrrolidine (3a)20
The reaction was performed with 1-bromo-2-methoxybenzene (0.19
g, 1.0 mmol), morpholine (0.26 g, 3.0 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
The reaction was performed with 1-bromo-4-nitrobenzene (0.20 g,
1.0 mmol), pyrrolidine (0.21 g, 3.0 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol), in
DMSO–H2O (1:1; 2 mL).
Yield: 0.18 g (95%); yellow solid; mp 160–162 °C (lit.20 165–167 °C).
1H NMR (400 MHz, CDCl3):  = 8.12 (dd, J = 7.2, 2.1 Hz, 2 H), 6.47 (dd,
J = 7.4, 2.1 Hz, 2 H), 3.42–3.39 (m, 4 H), 2.09–2.06 (m, 4 H).
Yield: 0.16 g (84%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.03–6.99 (m, 1 H), 6.93 (d, J = 4.1 Hz,
2 H), 6.87 (d, J = 7.9 Hz, 1 H), 3.89 (t, J = 4.6 Hz, 4 H), 3.86 (s, 3 H), 3.07
(t, J = 4.7 Hz, 4 H).
ESI-MS: m/z = 194.16 [M + H]+.
ESI-MS: m/z = 193.14 [M + H]+.
1-(Thiophen-2-yl)piperidine (3g)26
2-[4-(4-Methoxyphenyl)piperazin-1-yl]ethan-1-ol (3b)21
The reaction was performed with 2-bromothiophene (0.16 g, 1.0
mmol), piperidine (0.26 g, 3.0 mmol), Cu powder (6.0 mg, 0.1 mmol),
MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O
(1:1, 2 mL).
The reaction was performed with 1-bromo-4-methoxybenzene (0.19
g, 1.0 mmol), 2-(piperazin-1-yl)ethan-1-ol (0.39 g, 3.0 mmol), Cu
powder (6.0 mg, 0.1 mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98
g, 3.0 mmol) in DMSO–H2O (1:1, 2 mL).
Yield: 0.15 g (90%); colorless oil.
Yield: 0.21 g (90%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 6.77 (dd, J = 5.4, 3.7 Hz, 1 H), 6.57 (d, J =
5.2 Hz, 1 H), 6.12 (br, 1 H), 3.12 (t, J = 5.5 Hz, 4 H), 1.75–1.69 (m, 4 H),
1.58–1.54 (m, 2 H).
1H NMR (400 MHz, CDCl3):  = 6.92–6.89 (m, 2 H), 6.85–6.83 (m, 2 H),
3.77 (s, 3 H), 3.67 (t, J = 5.3 Hz, 2 H), 3.12 (t, J = 4.8 Hz, 4 H), 2.70 (t, J =
5.0 Hz, 4 H), 2.65–2.61 (m, 3 H). ESI-MS: m/z 237.22 [M + H]+.
ESI-MS: m/z = 168.11 [M + H]+.
1-(4-Methoxyphenyl)piperidine (3c)22
The reaction was performed with 1-bromo-4-methoxybenzene (0.19
g, 1.0 mmol), piperidine (0.26 g, 3.0 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
(S)-4-Methyl-N-(1-phenylethyl)aniline (3h)27
The reaction was performed with 1-bromo-4-methylbenzene (0.17 g,
1.0 mmol), (S)-1-phenylethan-1-amine (0.36 g, 3.0 mmol), Cu powder
(6.0 mg, 0.1 mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0
mmol) in DMSO–H2O (1:1, 2 mL).
Yield: 0.17 g (91%); colorless solid; mp 62–64 °C (lit.22 64–65 °C).
1H NMR (400 MHz, CDCl3):  = 6.92 (br, 2 H), 6.84–6.82 (m, 2 H), 3.76
(s, 3 H), 3.03 (t, J = 5.0 Hz, 4 H), 1.73 (s, 4 H), 1.57–1.53 (m, 2 H).
ESI-MS: m/z = 192.17 [M + H]+.
Yield: 0.17 g (80%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.37–7.35 (m, 2 H), 7.30 (t, J = 7.3 Hz,
2 H), 7.23–7.19 (m, 1 H), 6.90–6.89 (m, 2 H), 6.46 (d, J = 8.2 Hz, 2 H),
4.45 (q, J = 13.5, 6.8 Hz, 1 H), 2.18 (s, 3 H), 1.51 (d, J = 6.7 Hz, 3 H).
1-(2-Methoxyphenyl)pyrrolidine (3d)23
ESI-MS: m/z = 212.21 [M + H]+.
The reaction was performed with 1-bromo-2-methoxybenzene (0.19
g, 1.0 mmol), pyrrolidine (0.21 g, 3.0 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Phenyl-D-valine (3i)
The reaction was performed with bromobenzene (0.16 g, 1.0 mmol),
D-valine (0.35 g, 3.0 mmol), Cu powder (6.0 mg, 0.1 mmol), MG (39
mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O (1:1, 2
mL).
Yield: 0.15 g (85%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 6.90–6.80 (m, 4 H), 3.83 (s, 3 H), 3.29
(t, J = 6.4 Hz, 4 H), 1.96–1.90 (m, 4 H).
Yield: 0.17 g (90%); colorless oil.
1H NMR (400 MHz, DMSO-d6):  = 12.40 (br, 1 H), 7.05 (dd, J = 8.5,
7.3 Hz, 2 H), 6.61 (d, J = 7.7 Hz, 2 H), 6.53 (t, J = 7.2 Hz, 1 H), 5.64 (br,
1 H), 3.61 (d, J = 6.7 Hz, 1 H), 2.08–2.02 (m, 1 H), 0.98 (dd, J = 13.8,
7.3 Hz, 6 H).
ESI-MS: m/z = 178.16 [M + H]+.
ESI-MS: m/z = 194.16 [M + H]+.
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Synthesis
1-Phenyl-1H-pyrazole (3j)28
Yield: 0.12 g (85%); colorless solid; mp 40–42 °C (lit.32 38–40 °C).
1H NMR (400 MHz, CDCl3):  = 8.50–8.48 (m, 1 H), 8.35 (s, 1 H), 7.85–
7.81 (m, 1 H), 7.65–7.64 (m, 1 H), 7.36 (d, J = 8.2 Hz, 1 H), 7.28–7.23
(m, 1 H), 7.20 (s, 1 H).
The reaction was performed with bromobenzene (0.16 g, 1.0 mmol),
1H-pyrazole (0.10 g, 1.5 mmol), Cu powder (6.0 mg, 0.1 mmol), MG
(39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O (1:1,
2 mL).
ESI-MS: m/z = 146.06 [M + H]+.
Yield: 0.14 g (96%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.92 (d, J = 2.4 Hz, 1 H), 7.73–7.68 (m,
3 H), 7.47–7.43 (m, 2 H), 7.30–7.25 (m, 1 H), 6.46 (d, J = 2.3 Hz, 1 H).
ESI-MS: m/z = 145.04 [M + H]+.
2-(2-Methyl-1H-imidazol-1-yl)pyridine (3p)33
The reaction was performed with 2-bromopyridine (0.16 g, 1.0
mmol), 2-methyl-1H-imidazole (0.12 g, 1.5 mmol), Cu powder (6.0
mg, 0.1 mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol)
in DMSO–H2O (1:1, 2 mL).
2-Methyl-1-(4-nitrophenyl)-1H-imidazole(3k)29
Yield: 0.13 g (82%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.57–8.55 (m, 1 H), 7.87–7.83 (m, 1 H),
7.33–7.28 (m, 3 H), 7.02 (d, J = 1.4 Hz, 1 H), 2.60 (s, 3 H).
The reaction was performed with 1-bromo-4-nitrobenzene (0.20 g,
1.0 mmol), 2-methyl-1H-imidazole (0.12 g, 1.5 mmol), Cu powder
(6.0 mg, 0.1 mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0
mmol) in DMSO–H2O (1:1, 2 mL).
ESI-MS: m/z = 160.09 [M + H]+.
Yield: 0.20 g (96%); colorless solid; mp 140–143 °C (lit.29 140–142 °C).
1H NMR (400 MHz, DMSO-d6):  = 8.38–8.36 (m, 2 H), 7.78–7.76 (m,
2 H), 7.45 (d, J = 1.3 Hz, 1 H), 6.98 (d, J = 1.2 Hz, 1 H), 2.38 (s, 3 H).
ESI-MS: m/z = 204.11 [M + H]+ .
1-(Pyridin-2-yl)-1H-pyrazole-4-carbaldehyde (3q)
The reaction was performed with 2-bromopyridine (0.16 g,
1.0 mmol), 1H-pyrazole-4-carbaldehyde (0.14 g, 1.5 mmol), Cu pow-
der (6.0 mg, 0.1 mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0
mmol) in DMSO–H2O (1:1, 2 mL).
1-(4-Nitrophenyl)-1H-pyrazole-4-carbaldehyde (3l)30
Yield: 0.14 g (80%); colorless solid; mp 101–103 °C.
The reaction was performed with 1-bromo-4-nitrobenzene (0.20 g,
1.0 mmol), 1H-pyrazole-4-carbaldehyde (0.14 g, 1.5 mmol), Cu pow-
der (6.0 mg, 0.1 mmol), MG (4.8 mg, 0.2 mmol), and Cs2CO3 (0.98 g,
3.0 mmol) in DMSO–H2O (1:1, 2 mL).
1H NMR (400 MHz, CDCl3):  = 10.00 (s, 1 H), 9.09 (d, J = 0.6 Hz, 1 H),
8.47–8.46 (m, 1 H), 8.17 (s, 1 H), 8.04–8.02 (m, 1 H), 7.90–7.86 (m,
1 H), 7.31–7.27 (m, 1 H).
Yield: 0.20 g (90%); yellow solid; mp 148–150 °C (lit.30 150–151 °C).
ESI-MS: m/z = 174.10 [M + H]+.
1H NMR (400 MHz, CDCl3):  = 10.01 (s, 1 H), 8.55 (s, 1 H), 8.40 (d, J =
9.1 Hz, 2 H), 8.23 (s, 1 H), 7.95 (d, J = 9.1 Hz, 2 H).
2-(1H-Pyrrol-1-yl)pyridine (3r)34
ESI-MS: m/z = 218.34 [M + H]+.
The reaction was performed with 2-bromopyridine (0.16 g, 1.0
mmol), 1H-pyrrole (0.10 g, 1.5 mmol), Cu powder (6.0 mg, 0.1 mmol),
MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol), and DMSO–
H2O (1:1, 2 mL).
1-(4-Nitrophenyl)-1H-pyrrole (3m)31
The reaction was performed with 1-bromo-4-nitrobenzene (0.20 g,
1.0 mmol), 1H-pyrrole (0.10 g, 1.5 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.11 g (75%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.43–8.41 (m, 1 H), 7.75–7.70 (m, 1 H),
7.51 (t, J = 2.3 Hz, 2 H), 7.30 (d, J = 8.3 Hz, 1 H), 7.10–7.07 (m, 1 H),
6.35 (t, J = 2.3 Hz, 2 H).
Yield: 0.16 g (84%); yellow solid; mp 178–180 °C (lit. 180–183 °C).
1H NMR (400 MHz, CDCl3):  = 8.33–8.30 (m, 2 H), 7.53–7.51 (m, 2 H),
7.18 (t, J = 2.2 Hz, 2 H), 6.42 (t, J = 2.2 Hz, 2 H).
ESI-MS: m/z = 145.06 [M + H]+.
1-(4-Nitrophenyl)-1H-indole-3-carbaldehyde (3s)35
ESI-MS: m/z = 189.13 [M + H]+.
The reaction was performed with 1-bromo-4-nitrobenzene (0.20 g,
1.0 mmol), 1H-indole-3-carbaldehyde (0.22 g, 1.5 mmol), Cu powder
(6.4 mg, 0.1 mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0
mmol) in DMSO–H2O (1:1, 2 mL).
1-(2-Methoxyphenyl)-1H-pyrrole (3n)31
The reaction was performed with 1-bromo-2-methoxybenzene (0.19
g, 1.0 mmol), 1H-pyrrole (0.10 g, 1.5 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.21 g (80%); colorless solid; mp 160–162 °C (lit.35 165–167 °C).
1H NMR (400 MHz, DMSO-d6):  = 10.09 (s, 1 H), 8.77 (s, 1 H), 8.48 (d,
J = 8.9 Hz, 2 H), 8.26–8.24 (m, 1 H), 8.03 (d, J = 8.9 Hz, 2 H), 7.73–7.71
(m, 1 H), 7.44–7.38 (m, 2 H).
Yield: 0.14 g (80%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.30–7.23 (m, 2 H), 7.03–6.98 (m, 4 H),
6.30 (t, J = 2.2 Hz, 2 H), 3.82 (s, 3 H).
ESI-MS: m/z = 267.06 [M + H]+.
ESI-MS: m/z = 174.11 [M + H]+.
1-(4-Nitrophenyl)-1H-indole-2-carboxylic Acid (3t)36
The reaction was performed with 1-bromo-4-nitrobenzene (0.20 g,
1.0 mmol), 1H-indole-2-carboxylic acid (0.24 g, 1.5 mmol), Cu pow-
der (6.0 mg, 0.1 mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0
mmol) in DMSO–H2O (1:1, 2 mL).
2-(1H-imidazol-1-yl)pyridine (3o)32
The reaction was performed with 2-bromopyridine (0.16 g, 1.0
mmol), 1H-imidazole (0.10 g, 1.5 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (4.8 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.26 g (91%); colorless solid; mp 163–165 °C (lit.36 165–167 °C).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

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Synthesis
1H NMR (400 MHz, DMSO-d6):  = 13.02 (br, 1 H), 8.39–8.37 (m, 2 H),
7.80 (d, J = 7.9 Hz, 1 H), 7.73–7.71 (m, 2 H), 7.50 (s, 1 H), 7.36–7.32 (m,
1 H), 7.24 (t, J = 7.2 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H).
1H NMR (400 MHz, CDCl3):  = 8.17–8.16 (m, 1 H), 7.45–7.40 (m, 1 H),
6.63 (d, J = 8.6 Hz, 1 H), 6.55–6.52 (m, 1 H), 3.53–3.51 (m, 4 H), 1.63 (s,
6 H).
ESI-MS: m/z = 281.07 [M-H]–.
ESI-MS: m/z = 163.13 [M + H]+.
1-(4-Nitrophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (3u)
4-(Pyridin-2-yl)morpholine (3z)41
The reaction was performed with 1-bromo-4-nitrobenzene (0.20 g,
1.0 mmol), 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.22 g, 1.5
mmol), Cu powder (6.0 mg, 0.1 mmol), MG (39 mg, 0.2 mmol), and
Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O (1:1, 2 mL).
The reaction was performed with 2-chloropyridine (0.11 g, 1.0
mmol), morpholine (0.26 g, 3.0 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (4.8 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.18 g (66%); colorless oil.
Yield: 0.12 g (76%); colorless oil.
1H NMR (400 MHz, DMSO-d6):  = 10.09 (s, 1 H), 9.11 (s, 1 H), 8.57
(dd, J = 7.8, 1.6 Hz, 1 H), 8.51 (dd, J = 4.8, 1.6 Hz, 1 H), 8.50 (d, J =
2.1 Hz, 1 H), 8.48 (d, J = 2.2 Hz, 1 H), 8.37–8.35 (m, 2 H), 7.51–7.48 (m,
1 H).
1H NMR (400 MHz, CDCl3):  = 8.21–8.19 (m, 2 H), 7.51–7.47 (m, 1 H),
6.67–6.62 (m, 2 H), 3.81 (t, J = 4.8 Hz, 4 H), 3.49 (t, J = 5.0 Hz, 4 H).
ESI-MS: m/z = 165.11 [M + H]+.
ESI-MS: m/z 268.07 [M + H]+.
4-(Pyrrolidin-1-yl)benzaldehyde (3aa)42
The reaction was performed with 4-chlorobenzaldehyde (0.14 g, 1.0
mmol), pyrrolidine (0.21 g, 3.0 mmol), Cu powder (6.4 mg, 0.1 mmol),
MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O
(1:1, 2 mL).
Yield: 0.14 g (78%); colorless solid; mp 80–81 °C (lit.42 78–79 °C).
1H NMR (400 MHz, CDCl3):  = 9.72 (s, 1 H), 7.72 (d, J = 8.8 Hz, 2 H),
6.57 (d, J = 8.8 Hz, 2 H), 3.40–3.37 (m, 4 H), 2.07–2.03 (m, 4 H).
4-(Pyrrolidin-1-yl)pyridine (3v)37
The reaction was performed with 4-chloropyridine hydrochloride
(0.15 g, 1.0 mmol), pyrrolidine (0.21 g, 3.0 mmol), Cu powder (6.0 mg,
0.1 mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.13 g (89%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.10 (d, J = 5.0 Hz, 2 H), 6.27 (dd, J = 5.8,
1.5 Hz, 2 H), 3.21 (t, J = 6.6 Hz, 4 H), 1.95–1.92 (m, 4 H).
ESI-MS: m/z = 176.13 [M + H]+.
ESI-MS: m/z = 149.09 [M + H]+.
4-(Piperidin-1-yl)benzaldehyde (3ab)43
The reaction was performed with 4-chlorobenzaldehyde (0.14 g, 1.0
mmol), piperidine (0.26 g, 3.0 mmol), Cu powder (6.0 mg, 0.1 mmol),
MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O
(1:1, 2 mL).
Yield: 0.14 g (76%); colorless solid; mp 60–61 °C (lit.43 65–66 °C).
1H NMR (400 MHz, CDCl3):  = 9.74 (s, 1 H), 7.72 (d, J = 9.0 Hz, 2 H),
6.88 (d, J = 8.9 Hz, 2 H), 3.40 (s, 4 H), 1.67 (m, 6 H).
4-(Piperidin-1-yl)pyridine (3w)38
The reaction was performed with 4-chloropyridine hydrochloride
(0.15 g, 1.0 mmol), piperidine (0.26 g, 3.0 mmol), Cu powder (6.0 mg,
0.1 mmol), MG (39 mg, 0.12 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.14 g (88%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.22 (dd, J = 5.1, 1.4 Hz, 2 H), 6.62 (dd,
J = 5.0, 1.5 Hz, 2 H), 3.31 (d, J = 5.1 Hz, 4 H), 1.64 (s, 6 H).
ESI-MS: m/z = 190.16 [M + H]+.
ESI-MS: m/z = 163.13 [M + H]+.
2-(Pyrrolidin-1-yl)pyrimidine (3ac)44
The reaction was performed with 2-chloropyrimidine (0.11 g, 1.0
mmol), pyrrolidine (0.21 g, 3.0 mmol), Cu powder (6.0 mg, 0.1 mmol),
MG (4.8 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O
(1:1, 2 mL).
2-(Pyrrolidin-1-yl)pyridine (3x)39
The reaction was performed with 2-chloropyridine (0.11 g, 1.0
mmol), pyrrolidine (0.21 g, 3.0 mmol), Cu powder (6.0 mg, 0.1 mmol),
MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O
(1:1, 2 mL).
Yield: 0.13 g (90%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.31 (d, J = 4.8 Hz, 2 H), 6.45 (t, J =
4.8 Hz, 1 H), 3.59–3.56 (m, 4 H), 2.02–1.98 (m, 4 H).
ESI-MS: m/z = 150.11 [M + H]+.
Yield: 0.12 g (82%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.16–8.14 (m, 1 H), 7.44–7.39 (m, 1 H),
6.51–6.48 (m, 1 H), 6.34 (d, J = 8.5 Hz, 1 H), 3.46–3.43 (m, 4 H), 2.02–
1.98 (m, 4 H).
2-(Piperidin-1-yl)pyrimidine (3ad)45
ESI-MS: m/z = 149.12 [M + H]+.
The reaction was performed with 2-chloropyrimidine (0.11 g, 1.0
mmol), piperidine (0.26 g, 3.0 mmol), Cu powder (6.0 mg, 0.1 mmol),
MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O
(1:1, 2 mL).
2-(Piperidin-1-yl)pyridine (3y)40
The reaction was performed with 2-chloropyridine (0.11 g, 1.0
mmol), piperidine (0.26 g, 3.0 mmol), Cu powder (6.0 mg, 0.1 mmol),
MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O
(1:1, 2 mL).
Yield: 0.15 g (89%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.28 (d, J = 4.7 Hz, 2 H), 6.41 (t, J =
6.2 Hz, 1 H), 3.78 (t, J = 5.7 Hz, 4 H), 1.69–1.65 (m, 2 H), 1.63–1.59 (m,
4 H).
Yield: 0.13 g (80%); colorless oil.
ESI-MS: m/z = 164.14 [M + H]+.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

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Y. Chen et al.
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Synthesis
Pyrimidin-2-yl-D-valine (3ae)
2-(Phenylamino)benzoic Acid (3aj)49
The reaction was performed with 2-chloropyrimidine (0.11 g, 1.0
mmol), D-valine (0.35 g, 3.0 mmol), Cu powder (6.0 mg, 0.1 mmol),
MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O
(1:1, 2 mL).
The reaction was performed with 2-bromobenzoic acid (0.20 g, 1.0
mmol), aniline (0.07 g, 0.8 mmol), Cu powder (6.0 mg, 0.1 mmol), MG
(39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O (1:1,
2 mL).
Yield: 0.18 g (92%); colorless solid; mp 113–115 °C.
Yield: 0.15 g (85%); colorless solid; mp 175–178 °C (lit.49 185–187 °C).
1H NMR (400 MHz, CDCl3):  = 11.23 (br, 1 H), 8.25 (s, 2 H), 7.21 (d, J =
8.1 Hz, 1 H), 6.55 (t, J = 4.9 Hz, 1 H), 4.62–4.59 (m, 1 H), 2.37–2.29 (m,
1 H), 1.06 (t, J = 7.2 Hz, 6 H).
1H NMR (400 MHz, DMSO-d6):  = 13.03 (br, 1 H), 9.67 (br, 1 H), 7.90
(dd, J = 8.0, 1.6 Hz, 1 H), 7.41–7.34 (m, 3 H), 7.25–7.22 (m, 3 H), 7.07
(t, J = 7.2 Hz, 1 H), 6.78 (t, J = 7.8 Hz, 1 H).
ESI-MS: m/z = 196.16 [M + H]+.
ESI-MS: m/z = 214.15 [M + H]+.
Pyrimidin-2-ylmethionine (3af)
4-Nitro-N-phenylaniline (3ak)50
The reaction was performed with 2-chloropyrimidine (0.11 g, 1.0
mmol), methionine (0.45 g, 3.0 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
The reaction was performed with 1-bromo-4-nitrobenzene (0.20 g,
1.0 mmol), aniline (0.07 g, 0.8 mmol), Cu powder (6.0 mg, 0.1 mmol),
MG (4.8 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in DMSO–H2O
(1:1, 2 mL).
Yield: 0.21 g (93%); colorless solid; mp 139–141 °C.
Yield: 0.13 g (75%); colorless solid; mp 130–132 °C (lit.50 135–136 °C).
1H NMR (400 MHz, CDCl3):  = 13.30 (br, 1 H), 8.27 (br, 2 H), 7.90 (d,
J = 7.2 Hz, 1 H), 6.60 (t, J = 4.9 Hz, 1 H), 4.84 (q, J = 12.2, 6.0 Hz, 1 H),
2.72–2.59 (m, 2 H), 2.39–2.30 (m, 1 H), 2.26–2.16 (m, 1 H), 2.09 (s,
3 H).
1H NMR (400 MHz, CDCl3):  = 8.14–8.11 (m, 2 H), 7.41–7.37 (m, 2 H),
7.22–7.19 (m, 2 H), 7.17–7.15 (m, 1 H), 6.95–6.93 (m, 2 H), 6.27 (br,
1 H).
ESI-MS: m/z = 215.10 [M + H]+.
ESI-MS: m/z = 228.13 [M + H]+.
4-Methoxy-N-phenylaniline (3al)51
2-(1H-Imidazol-1-yl)pyrimidine (3ag)46
The reaction was performed with 1-bromo-4-methoxybenzene (0.19
g, 1.0 mmol), aniline (0.07 g, 0.8 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.11 g (66%); colorless solid; mp 100–102 °C (lit.51 104–105 °C).
1H NMR (400 MHz, CDCl3):  = 7.22 (s, 2 H), 7.10 (br, 2 H), 6.94 (br,
2 H), 6.86 (d, J = 8.9 Hz, 3 H), 3.80 (s, 3 H).
The reaction was performed with 2-chloropyrimidine (0.11 g, 1.0
mmol), 1H-imidazole (0.20 g, 3.0 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.13 g (86%); colorless solid; mp 129–131 °C (lit.46 124 °C).
1H NMR (400 MHz, CDCl3):  = 8.70 (d, J = 4.8 Hz, 2 H), 8.64 (s, 1 H),
7.90 (s, 1 H), 7.21 (t, J = 4.8 Hz, 1 H), 7.18 (s, 1 H).
ESI-MS: m/z = 200.15 [M + H]+.
ESI-MS: m/z = 147.06 [M + H]+.
N-(4-Methoxyphenyl)-3-nitroaniline (3am)
2-(2-Methyl-1H-imidazol-1-yl)pyrimidine (3ah)47
The reaction was performed with 1-bromo-4-methoxybenzene (0.19
g, 1.0 mmol), 3-nitroaniline (0.11 g, 0.8 mmol), Cu powder (6.0 mg,
0.1 mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol),
DMSO–H2O (1:1, 2 mL).
The reaction was performed with 2-chloropyrimidine (0.11 g, 1.0
mmol), 2-methyl-1H-imidazole (0.25 g, 3.0 mmol), Cu powder (6.0
mg, 0.1 mmol), MG (4.8 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol)
in DMSO–H2O (1:1, 2 mL).
Yield: 0.13 g (64%); yellow solid; mp 115–116 °C.
Yield: 0.13 g (80%); colorless solid; mp 87–88 °C (lit.47 90.3–90.8 °C).
1H NMR (400 MHz, CDCl3):  = 7.64 (t, J = 2.1 Hz, 1 H), 7.61–7.59 (m,
1 H), 7.30 (t, J = 8.1 Hz, 1 H), 7.13–7.08 (m, 3 H), 6.93–6.91 (m, 2 H),
5.77 (br, 1 H), 3.83 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 8.71 (d, J = 4.8 Hz, 2 H), 7.86 (d, J =
1.4 Hz, 1 H), 7.19 (t, J = 4.8 Hz, 1 H), 6.97 (d, J = 1.3 Hz, 1 H), 2.83 (s,
3 H).
ESI-MS: m/z = 245.11 [M + H]+.
ESI-MS: m/z = 161.10 [M + H]+.
1-(4-(Phenylamino)phenyl)ethan-1-one (3an)52
2-(1H-pyrazol-1-yl)benzonitrile (3ai)48
The reaction was performed with 1-(4-bromophenyl)ethan-1-one
(0.20 g, 1.0 mmol), aniline (0.07 g, 0.8 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
The reaction was performed with 2-chlorobenzonitrile (0.14 g, 1.0
mmol), 1H-pyrazole (0.20 g, 3.0 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.13 g (78%); colorless oil.
Yield: 0.15 g (88%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 8.07 (d, J = 2.5 Hz, 1 H), 7.74–7.70 (m,
3 H), 7.65–7.62 (m, 1 H), 7.38–7.34 (m, 1 H), 6.48 (t, J = 2.1 Hz, 1 H).
1H NMR (400 MHz, CDCl3):  = 7.89–7.85 (m, 2 H), 7.37–7.32 (m, 2 H),
7.20–7.17 (m, 2 H), 7.11–7.06 (m, 1 H), 7.01–6.98 (m, 2 H), 2.53 (s,
3 H).
ESI-MS: m/z = 170.10 [M + H]+.
ESI-MS: m/z = 212.16 [M + H]+.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

J
Y. Chen et al.
Paper
Synthesis
N-((3S,4S)-1-Benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-amine (3ao)15
(2) (a) Lange, J. H. M.; van Stuivenberg, H. H.; Coolen, H. K. A. C.;
Adolfs, T. J. P.; McCreary, A. C.; Keizer, H. G.; Wals, H. C.;
Veerman, W.; Borst, A. J. M.; de Looff, W.; Verveer, P. C.; Kruse,
C. G. J. Med. Chem. 2005, 48, 1823. (b) Quan, M. L.; Lam, P. Y. S.;
Han, Q.; Pinto, D. J. P.; He, M. Y.; Li, R.; Ellis, C. D.; Clark, C. G.;
Teleha, C. A.; Sun, J. H.; Alexander, R. S.; Bai, S.; Luettgen, J. M.;
Knabb, R. M.; Wong, P. C.; Wexler, R. R. J. Med. Chem. 2005, 48,
1729. (c) Wiglenda, T.; Gust, R. J. Med. Chem. 2007, 50, 1475.
(d) Shi, W.; Nacev, B. A.; Aftab, B. T.; Head, S.; Rudin, C. M.; Liu, J.
O. J. Med. Chem. 2011, 54, 7363. (e) Jiang, J.; Ghoreschi, K.;
Deflorian, F.; Chen, Z.; Perreira, M.; Pesu, M.; Smith, J.; Nguyen,
D.; Liu, E.; Leister, W.; Costanzi, S.; O’Shea, J.; Thomas, C. J. Med.
Chem. 2008, 51, 8012. (f) Chan, C. M.; Jing, X.; Pike, L. A.; Zhou,
Q.; Lim, D.-J.; Sams, S. B.; Lund, G. S.; Sharma, V.; Haugen, B. R.;
Schweppe, R. E. Clin. Cancer Res. 2012, 18, 3580. (g) Heinrich, M.
C.; Griffith, D. J.; Druker, B. J.; Wait, C. L.; Ott, K. A.; Zigler, A. J.
Blood 2000, 96, 925.
(3) (a) Kwan, E. E.; Zeng, Y.; Besser, H. A.; Jacobsen, E. N. Nat. Chem.
2018, 10, 917. (b) Neumann, C. N.; Hooker, J. M.; Ritter, T.
Nature 2016, 534, 369.
(4) (a) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48,
6954. (b) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008,
108, 3054. (c) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
(d) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13.
The reaction was performed with (bromomethyl)benzene (3.64 g,
21.29 mmol), N-methyl-N-((3S,4S)-4-methylpiperidin-3-yl)-7H-pyr-
rolo[2,3-d]pyrimidin-4-amine (5.22 g, 21.29 mmol), Cu powder (6.0
mg, 0.1 mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol)
in DMSO–H2O (1:1, 2 mL).
Yield: 5 g (70%); colorless oil.
1H NMR (400 MHz, DMSO-d6):  = 11.57 (s, 1 H), 8.06 (s, 1 H), 7.31 (d,
J = 4.4 Hz, 4 H), 7.25–7.20 (m, 1 H), 7.11–7.09 (m, 1 H), 6.55 (s, 1 H),
5.10 (br, 1 H), 3.50 (s, 5 H), 2.80–2.77 (m, 1 H), 2.63 (s, 2 H), 2.33–2.30
(m, 1 H), 2.14 (s, 1 H), 1.71 (s, 1 H), 1.64–1.58 (m, 1 H), 0.90–0.88 (m,
3 H).
ESI-MS: m/z = 336.30 [M + H]+.
1-(2-(Allyloxy)phenyl)-1H-pyrazole (3ap)
The reaction was performed with 1-(allyloxy)-2-iodobenzene (0.21 g,
1.0 mmol), 1H-pyrazole (0.10 g, 1.5 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
Yield: 0.17 g (85%); colorless liquid.
1H NMR (400 MHz, CDCl3):  = 8.09 (s, 1 H), 7.77–7.74 (dd, J = 7.9,
1.4 Hz, 1 H), 7.73 (s, 1 H), 7.30–7.25 (m, 1 H), 7.10–7.03 (m, 2 H), 6.44
(s, 1 H), 6.06–5.96 (m, 1 H), 5.39–5.33 (m, 1 H), 5.29–5.25 (m, 1 H),
4.61–4.59 (dt, J = 5.1, 1.5 Hz, 2 H).
(5) (a) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (b) Yang, B. H.;
Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
(6) (a) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829. (b) Rao, D. N.;
Rasheed, S.; Vishwakarma, R. A.; Das, P. Chem. Commun. 2014,
50, 12911. (c) Reddy, A. S.; Reddy, K. R.; Rao, D. N.; Jaladanki, C.
K.; Bharatam, P. V.; Lam, P. Y. S.; Das, P. Org. Biomol. Chem. 2017,
15, 801. (d) Duparc, V. H.; Bano, G. L.; Schaper, F. ACS Catal.
2018, 8, 7308. (e) Vantourout, J. C.; Miras, H. N.; Isidro-Llobet,
A.; Sproules, S.; Watson, A. J. B. J. Am. Chem. Soc. 2017, 139,
4769.
ESI-MS: m/z = 201.12 [M + H]+.
1-(2-(Allyloxy)phenyl)piperidine (3ar)
The reaction was performed with 1-(allyloxy)-2-iodobenzene (0.21 g,
1.0 mmol), piperidine (0.26 g, 3.0 mmol), Cu powder (6.0 mg, 0.1
mmol), MG (39 mg, 0.2 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in
DMSO–H2O (1:1, 2 mL).
(7) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.
(8) (a) Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657. (b) Kuil, M.; Bekedam, E. K.; Visser, G. M.; van
den Hoogenband, A.; Terpstra, J. W.; Kamer, P. C. J.; Kamer van
Leeuwen, P. W. N. M.; van Strijdonck, G. P. F. Tetrahedron Lett.
2005, 46, 2405. (c) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006,
8, 2779. (d) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727. (e) Alcalde, E.; Dinarès, I.;
Rodríguez, S.; Garcia de Miguel, C. Eur. J. Org. Chem. 2005, 1637.
(f) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org.
Chem. 2004, 69, 5578. (g) Ma, D.; Cai, Q. Synlett 2004, 128.
(h) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164. (i) Lv,
X.; Wang, Z.; Bao, W. Tetrahedron 2006, 62, 4756. (j) Liu, L.;
Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider, P. J. J. Org.
Chem. 2005, 70, 10135.
Yield: 0.20 g (88%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 6.95–6.88 (m, 3 H), 6.86–6.82 (m, 1 H),
6.14–6.04 (m, 1 H), 5.49–5.43 (m, 1 H), 5.28–5.24 (m, 1 H), 4.57–4.55
(m, 2 H), 3.03–2.99 (q, J = 9.9, 5.5 Hz, 4 H), 1.78–1.72 (m, 4 H), 1.60–
1.53 (m, 2 H).
ESI-MS: m/z = 218.12 [M + H]+.
Funding Information
This work was financially supported by Natural Science Foundation of
Liaoning Province (No. 201602707), Discipline Construction Program
of Shenyang Pharmaceutical University (No. 52134606)
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(9) (a) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 11684. (b) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.;
Taillefer, M. Eur. J. Org. Chem. 2004, 695.
Supporting Information
(10) (a) Deshpande, P. P.; Danishefsky, S. J. Nature 1997, 387, 164.
(b) Tatsuta, K.; Hosokawa, S. Sci. Technol. Adv. Mater. 2006, 7,
397. (c) David, A. Isr. J. Chem. 2010, 50, 204.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690702.
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(11) (a) Thakur, K. G.; Ganapathy, D.; Sekar, G. Chem. Commun. 2011,
47, 5076. (b) Thakur, K. G.; Sekar, G. Chem. Commun. 2011, 47,
6692.
References
(12) Hargreaves, M. B.; Jones, B. C.; Smith, D. A.; Gescher, A. Drug
Metab. Dispos. 1994, 22, 806.
(13) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793.
(14) Chen, Y. J.; Chen, H. H. Org. Lett. 2006, 8, 5609.
(1) (a) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42,
5400. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
(c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004,
248, 2337.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

K
Y. Chen et al.
Paper
Synthesis
(15) Mudithanapelli, C.; Dhorma, L. P.; Kim, M. Org. Lett. 2019, 21,
3098.
(16) de Lange, B.; Lambers-Verstappen, M. H.; Schmieder-van de
Vondervoort, L.; Sereinig, N.; de Rijk, R.; de Vries, A. H. M.; de
Vries, J. G. Synlett 2006, 3105.
(17) Flanagan, M. E.; Blumenkopf, T. A.; Brissette, W. H.; Brown, M.
F.; Casavant, J. M.; Chang, S. P.; Doty, J. L.; Elliott, E. A.; Fisher, M.
B.; Hines, M.; Kent, C.; Kudlacz, E. M.; Lillie, B. M.; Magnuson, K.
S.; McCurdy, S. P.; Munchhof, M. J.; Perry, B. D.; Sawyer, P. S.;
Strelevitz, T. J.; Subramanyam, C.; Sun, J.; Whipple, D. A.;
Changelian, P. S. J. Med. Chem. 2010, 53, 8468.
(30) dos Santos, M. S.; Gomes, A. O.; Bernardino, A. M. R.; de Souza,
M. C.; Khan, M. A.; de Brito, M. A.; Castro, H. C.; Abreu, P. A.;
Rodrigues, C. R.; de Leo, R. M. M.; Leon, L. L.; Canto-Cavalheiro,
M. M. J. Braz. Chem. Soc. 2011, 22, 352.
(31) Reddy, V. P.; Kumar, A. V.; Rao, K. R. Tetrahedron Lett. 2011, 52,
777.
(32) Lv, X.; Wang, Z.; Bao, W. Tetrahedron 2006, 62, 4756.
(33) Liang, L.; Li, Z.; Zhou, X. Org. Lett. 2009, 11, 3294.
(34) Ma, H. C.; Jiang, X. Z. J. Org. Chem. 2007, 72, 8943.
(35) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Eur. J. Org.
Chem. 2007, 2147.
(18) (a) Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig, J.
F. J. Am. Chem. Soc. 2008, 130, 9971. (b) Cohen, T.; Cristea, I.
J. Org. Chem. 1975, 40, 3649.
(19) (a) Giri, R.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 15860.
(b) Casitas, A.; Canta, M.; Sola, M.; Costas, M.; Ribas, X. J. Am.
Chem. Soc. 2011, 133, 19386. (c) Ribas, X.; Güell, I. Pure Appl.
Chem. 2014, 86, 345.
(20) Yang, K.; Qiu, Y.; Li, Z.; Wang, Z.; Jiang, S. J. Org. Chem. 2011, 76,
3151.
(21) Gao, J.; Bhunia, S.; Wang, K.; Gan, L.; Xia, S.; Ma, D. Org. Lett.
2017, 19, 2809.
(36) Khan, M. A.; Rocha, E. K. Chem. Pharm. Bull. 1977, 25, 3110.
(37) Wei, Y.; Sastry, G. N.; Zipse, H. J. Am. Chem. Soc. 2008, 130, 3473.
(38) Hashimoto, S.; Otani, S.; Okamoto, T.; Matsumoto, K. Heterocy-
cles 1988, 27, 319.
(39) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34,
2069.
(40) Kauffmann, T.; Boettcher, F. P. H. II. Chem. Ber. 1962, 95, 1528.
(41) Pedersen, E. B.; Carlsen, D. P. VIII. Synthesis 1978, 844.
(42) Rasburn, J. W.; Stewart, F. H. C. J. Chem. Soc. 1957, 2237.
(43) Abdel-Aziz, H. A.; Abdel-Wahab, B. F.; El-Sharief, M. A. M. Sh.;
Abdulla, M. M. Monatsh. Chem. 2009, 140, 431.
(22) Zhang, Z. J.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B. Tetrahe-
dron 2006, 62, 4465.
(23) Shim, S. C.; Huh, K. T.; Park, W. H. Tetrahedron 1986, 42, 259.
(24) Sommers, A. H.; Aaland, S. E. J. Am. Chem. Soc. 1953, 75, 5280.
(25) Lu, B.; Li, P. B.; Fu, C. L.; Xue, L. Q.; Lin, Z. Y.; Ma, S. M. Adv. Synth.
Catal. 2011, 353, 100.
(26) Lu, Z. K.; Twieg, R. J. Tetrahedron 2005, 61, 903.
(27) Wang, Z. Y.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett.
2006, 8, 999.
(44) Ho, L. A.; Raston, C. L.; Stubbs, K. A. Eur. J. Org. Chem. 2016, 5957.
(45) Narayan, S.; Seelhammer, T.; Gawley, R. E. Tetrahedron Lett.
2004, 45, 757.
(46) Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Venkanna, G. T.;
Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 9948.
(47) Xie, Y. X.; Pi, S. F.; Wang, J.; Yin, D. L.; Li, J. H. J. Org. Chem. 2006,
71, 8324.
(48) Jia, X. F.; Yang, D. P.; Wang, W. H.; Luo, F.; Cheng, J. J. Org. Chem.
2006, 74, 9470.
(28) Finar, I. L.; Hurlock, R. J. J. Chem. Soc. 1957, 3024.
(29) Jammi, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.; Mandal, S.;
Mitra, R.; Saha, P.; Punniyamurthy, T. J. Org. Chem. 2009, 74,
1971.
(49) Neukom, J. D.; Aquino, A. S.; Wolfe, J. P. Org. Lett. 2011, 13, 2196.
(50) Liu, Z. J.; Larock, R. C. J. Org. Chem. 2006, 71, 3198.
(51) Fors, B. P.; Davis, N. R.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 5766.
(52) Rao, H. H.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2005, 70, 8107.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K