α-d-Galacturonic Acid as Natural Ligand for Selective Copper-Catalyzed N-Arylation of N-Containing Heterocycles

Article abstract of DOI:10.1055/s-0039-1690226

The first application of α-d-galacturonic acid hydrate (GalA) is reported here, as a potential O-donor ligand. The C-N couplings of N-heterocycles with aryl halides or arylboronic acids could be readily conducted and exhibited good functional group tolerance with characters of selectivity. These N-Arylazoles allow rapid access to several pharmaceutical intermediates and can be easily transformed into a variety of other interesting scaffolds as well.

Full text of DOI:10.1055/s-0039-1690226

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–H
letter
A
en
C. Yuan et al.
Letter
Synlett
-D-Galacturonic Acid as Natural Ligand for Selective Copper-Cata-
lyzed N-Arylation of N-Containing Heterocycles
Chunling Yuan*
Yingdai Zhao
Li Zheng
0
0
0
0-0
0
0
2-9
2
8
6-7
0
9
5
NHet
X
CuBr (5 mol%)
GalA (10 mol%)
OH
H2O
Y
Y
abundant source
eco-friendly
selective
R
Het-NH
+
R
O
K2CO3 (3.0 equiv)
O
HO
in aq DMSO under Ar
X = I, Br, Cl, B(OH)2
Y = CH, O, S, N
R = e.g., –NH2, –CO2H,
HO
water soluble
80–120 o
C
OH
OH
41 examples
(50–99% yields)
Department of Medicinal Chemistry, Pharmacy School, Jinzhou
Medical University, Jinzhou 121001, Liaoning, P. R. of China
yutong8747@163.com
a-D-Galacturonic Acid Hydrate (GalA)
–CHO, –CN, –NO2
Submitted: 09.09.2019
Accepted after revision: 13.10.2019
Published online: 06.11.2019
into serious consideration for meeting the requirements of
green chemistry. As results, we are devoting to develop a
natural product as ligand for Cu-catalyzed C–N coupling re-
actions. Noteworthy is that abundant natural carbohydrates
have recently attracted a great many of interest in organic
synthesis due to the ability of increasing the efficiency of
the co-catalyst system by coordinating the metal center as
O,O-polydentate ligands.24,25 As a result, commercially
available monosaccharides and disaccharides were
screened by performing the Cu-catalytic N-arylation reac-
tion of bromobenzene with pyrazole under the basic condi-
tions, as described in Scheme 1. Accordingly, -D-galac-
turonic acid (GalA) L4 was identified as a potent Cu chelat-
ing ligand for C–N couplings with a yield of 90% for 3a. GalA
is the monomer of polygalacturonic acid which forms the
backbone of pectin in the plant cell walls.26 GalA also exhib-
its various biological activities, is used in the treatment of
cancer27,28 and as coloring agent.29 Herein, we show numer-
DOI: 10.1055/s-0039-1690226; Art ID: st-2019-l0478-l
Abstract The first application of -D-galacturonic acid hydrate (GalA)
is reported here, as a potential O-donor ligand. The C–N couplings of N-
heterocycles with aryl halides or arylboronic acids could be readily con-
ducted and exhibited good functional group tolerance with characters
of selectivity. These N-arylazoles allow rapid access to several pharma-
ceutical intermediates and can be easily transformed into a variety of
other interesting scaffolds as well.
Key words -D-galacturonic acid hydrate, C–N couplings, N-arylation,
Cu catalyst, ligand
N-Arylazoles provide access to important subunits and
precursors of numerous biologically active compounds,
natural products, and pharmaceuticals.1 Particularly, they
account for a crucial section of the top-selling drugs includ-
ing anti-inflammatory drug (celecoxib2 and tepoxalin3), an-
ticoagulant drug (apixaban4), antineoplastic medicine (nilo-
tinib5), and psychiatric medicine (sertindole6). For elabora-
tion of these synthetically challenging molecules, Ullmann-
type coupling reactions7 have becoming a practical and
flexible protocol due to the low cost and less toxicity of the
copper catalyst.8,9 Copper-catalyzed couplings promoted by
bidentate chelating ligands have been utilized to facilitate
N-arylations over the succeeding two decades,10 including
-keto ester,11 4,7-dimethoxy-1,10-phenanthroline,12,13
N,N′-dimethyl-1,2-cyclohexanediamine,14,15 amino acid,16,17
salicylaldoxime,18 pipecolinic acid,19 hippuric acid,20 8-hy-
droxyquinoline and its derivatives,21,22 and ethyl 2-oxocy-
clohexane-1-carboxylate.23
H
N
CuI (10 mol%)
L (10 mol%)
Br
N
+
N
N
K2CO3 (3 equiv)
in DMSO under Ar
100 °C, 8 h
2a
3a
1a
CH2OH
OH
CH2OH
OH
HOH2C
HO
H2O
O
OH
O
O
OH
O
O
HO
MeO
HO
OH
OH
OH
HO
OH
OH
OH
OH
OH
D-fructofuranose
methyl α-D-glucopyranoside
L3 (77%)
L1 (46%)
D-glucopyranose
α-D-galacturonic acid hydrate
L4 (90%)
L2 (39%)
OH
HOH2C
HO
CH2OH
O
O
HO
HO
HOH2C
HOH2C
O
OH
OH
O
O
OH
O
OH
HO
maltose
L6 (18%)
HO
HO
OH
lactose
OH
OH
Many reported useful ligands are not commercially
available in industrial scale, which might suffer from high
costs in large-scale manufacture. Besides, the toxicity, sus-
tainability, and pollution of these ligands must be taken
L5 (12%)
L7 (19%)
Scheme 1 Screening of O,O-type ligands for Cu-catalytic N-arylation
reaction of bromobenzene with pyrazole
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
C. Yuan et al.
Letter
Synlett
ous coupling reactions of N-containing heterocycles with
aryl halides or arylboronic acids catalyzed by Cu/GalA and
wish to disclose these results.
couplings of simple aryl bromides or aryl iodides with
azoles provided N-arylazoles in literally quantitative yields
(70–98%). It was found that the catalyst system was gener-
ally applicable to both electron-rich and electron-deficient
substrates. Moreover, a range of reactive functional groups
(e.g., NH2, CHO, COOH, CN) proved to be compatible, and
coupling products, such as 3–j,q, were obtained in moder-
ate to excellent yields. Noteworthy was that the coupling of
asymmetric imidazole with iodobenzene could give two
imidazole tautomers 3d and 3e with a ratio of 7.6:1 (from
1H NMR analysis) in 97% yield. The sterically hindered 2-
methylimidazole could also undergo N-arylation with 4-ni-
trobromobenzene to give 3c in 84% yield. Unfortunately,
chlorobenzene just resulted in trace amounts of 3a. At-
tempts to use electron-deficient chlorobenzene to couple
with pyrazole under standard conditions were successful,
yielding related N-arylazoles in excellent yields (3q–t). En-
couraged by these results, we focused on the challenging
substrates with poor nucleophilicity induced by neighbor-
ing heteroatom or heteroaryl amines.30 To our delight, the
inferior nucleophiles such as indole and pyridopyrrole were
found to be effective nucleophilic counterparts for the cou-
pling process (3k–o in 70–91% yield).
Optimal conditions were explored by examining the re-
action of bromobenzene and pyrazole at 100 °C under ar-
gon (Table 1). Initially, Cu(I) or Cu(II) sources were screened
in the presence of K2CO3, and GalA. The C–N coupling prod-
uct 3a was easily obtained in >80% yield using 10 mol%
Cu(I) as catalyst except of Cu2O (Table 1, entries 1–4). With
the use of Cu2SO4, no desired product was observed (Table
1, entry 5). Considering economy and stability, CuBr was
chosen, and it was also efficient with 5 mol% catalytic load-
ing (Table 1, entry 6). Further studies revealed a significant
effect of bases, with K2CO3 and Cs2CO3 proving to be opti-
mal in terms of yield (Table 1, entries 7–10). K2CO3 was
used for the following research as it was inexpensive. Polar
solvents (DMSO, H2O, and CH3CN) favored this reaction,
with 50% aq DMSO being the most effective (Table 1, entries
11–14). In order to investigate its effectiveness, a scale-up
experiment of 5 g loading was carried out to provide 3a in
93% yield, proving the stability of this catalyst system (Table
1, entry 15).
Table 1 Identification of Reaction Conditionsa
Table 2 Scope with Respect to Aryl Halides and N-Heterocyclesa,b
H
Br
N
Cu source, GalA, base
N
+
N
N
CuBr (5 mol%)
solvent under Ar
100 °C, 8 h
Y
X
+
Y
NHet
GalA (10 mol%)
2a
3a
1a
Het–NH
R
Ar
K2CO3 (3.0 equiv)
in aq DMSO under Ar
8–15 h, 80–100 °C
R
Ar
Entry Cu (mol%)
Base
K2CO3
Solvent
Yield (%)b
X = I, Br, Cl,
Y = CH, S, N
1
2
CuI (10)
DMSO
90
92
84
trace
0
Me
N
N
N
CuBr (10)
CuCl (10)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KHCO3
K3PO4·3H2O
KOH
DMSO
N
N
Me
N
N
N
N
N
3
DMSO
Me
O2N
4
Cu2O (10)
CuSO4 (10)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
DMSO
3a
3b
3d
3c
3e
X = I, 97%, 3d/3e = 7.6:1 (1H NMR)
5
DMSO
X = Br, 95%
X = Cl, trace
X = Br, 84%
X = Br, 98%
CHO
6
DMSO
92
94
0
NH2
N
N
N
7
DMSO
N
N
N
N
N
N
N
N
8
DMSO
CN
MeOC
O2N
3j
X = Br, 87%
CHO
3h
3i
X = Br, 88%
3f
3g
CHO
9
DMSO
77
17
95
31
70
trace
93
X = Br, 93%
X = Br, 80%
X = Br, 70%
10
11
12
13
14
15c
DMSO
CHO
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO–H2O
H2O
N
N
COOH
N
S
COOH
N
COOH
N
N
S
CH3CN
toluene
DMSO–H2O
3n
X = I, 89%
3o
X = I, 70%
3m
X = I, 91%
3l
3k
Cl
X = I, 87%
X = Br, 74%
N
COOH
N
NO2
N
N
Cl
N
N
N
N
N
COOH
N
a Standard conditions: 1a (0.8 mmol), 2a (1.0 mmol), 10 mol% GalA, base
(2.4 mmol), aq DMSO (50%, 2.0 mL), 100 °C, 8 h, unless noted otherwise.
b Isolated yield.
H2N
O2N
H2N
3p
Cl
3q
3r
3t
X = Cl, 97%
3s
X = Cl, 96%
X = Br, 86%
X = Cl, 89%
X = Cl, 86%
c The loading of 1a was 5 g, and the reaction time was prolonged to 24 h.
a Reaction conditions: aryl halide (0.8 mmol), N-heterocycle (1.0 mmol),
CuBr (5 mol%), GalA (10 mol%), K2CO3 (2.4 mmol), aq DMSO (50%, 2.0 mL),
80–100 °C, 8–15 h.
To exploit the potential of our established method, this
protocol was investigated with diverse aryl halides and N-
heterocycles, as described in Table 2. The Cu/GalA-catalyzed
b Isolated yield.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–H

C
C. Yuan et al.
Letter
Synlett
The preceding results revealed that 3p could be exclu-
sively obtained without formation of diaryl amine, indicat-
ing that the catalyst system may exhibit selectivity towards
construction of N-arylazoles. Subsequently, to further in-
vestigate the application of CuBr/GalA catalyst system, a se-
ries of nucleophiles were reacted with bromobenzene un-
der the standard conditions (Scheme 2). Only aliphatic
amines and aromatic amines were able to produce C–N
coupling products, with aniline and piperidine affording
the desired compounds in 46% and 90% yields, respectively.
However, neither phenols and thiols nor amides could per-
form such reactions.
Table 3 Coupling Reaction for the Synthesis of Highly Functional
Azoles with Aryl Halides and N-Heterocyclesa,b
CuBr (5 mol%)
X
Ar'
R'
Ar
N
GalA (10 mol%)
Ar'
R'
R
Ar
+
K2CO3 (3.0 equiv)
in aq DMSO under Ar
12–36 h, 100–120 °C
N
H
2.0 equiv
X = Br, I
1.0 equiv
R
3
COOEt
HO
HO
COOEt
HO
COOEt
Me
HO
N
Me
N
N
N
Me
OEt
Cl
Me
3u
X = Br, 85%
3v
X = I, 59%c
3w
3x
H
N
X = I, 62%c
X = I, 55%c
nucleophilic (1.0 equiv)
CuBr (5 mol%)
GalA (10 mol%)
N
H
Br
COOEt
HO
N
N
N
N
N
4a (46%)
4b (90%)
K2CO3 (3.0 equiv)
in aq DMSO under Ar
24 h, 100 °C
N
Me
N
1.0 equiv
HO
S
NH2
O
CF3
3z
X = Br, 99%
3ab
X = Br, 89%
3y
3aa
X = I, 87%
N
O
N
X = I, 63%c
O
a Reaction conditions: aryl halide (2.0 mmol), N-heterocycle (1.0 mmol),
CuBr (5 mol%), GalA (10 mol%), K2CO3 (3 mmol), aq DMSO (50%, 2.0 mL),
100 °C, 12 h, unless noted otherwise.
not observed
Scheme 2 Coupling reactions of bromobenzene and other nucleophiles
b Isolated yield.
using CuBr/GalA catalyst system
c Temperature was 120 °C, reaction time was extended to 36 h.
We then explored the selectivity by using bifunctional
reagents and aryl halides (2.0 equiv), and the results are
summarized in Table 3. Not surprisingly, most sensitive
functional groups (e.g., OH and NH2) were inferior to this
catalyst system, and the selective N-arylation products
from multifunctional substrates were obtained in moderate
to excellent yields. Remarkably, the 2-methyl-5-hydroxyin-
dolecarboxylate, of interest to us in the optimization of
NorA efflux pump inhibitors,31 is unusually resistant to hy-
drolysis due to the electron-donating indole. In these cases,
prolonged reaction time and elevated temperature (120 °C)
were required for benign conversion because of the large
steric hindrance and electron-deficient indole. Interesting-
ly, even under severe reaction conditions, the C–O coupling
products were not observed, only providing the N-
arylazoles in 55–63% yield along with unreacted starting
material. However, the coupling of iodobenzene (2.0 equiv)
with tryptamine provided diarylation products 3aa in 87%,
proving that CuBr /GalA catalytic system could also facili-
tate the C–N coupling reactions for assembly of aryl amines,
which was consistent with the result of competition reac-
tions.
imidazoles and benzoxazoles were conveniently obtained
in good yield (70–88%). Arguably, this protocol has offered a
new strategy for the synthesis of benzimidazoles and benz-
oxazoles which are ubiquitous structural motifs in numer-
ous biologically active compounds.32 Exceptionally, we
found that N-acetyl o-haloaniline mainly transformed to N-
arylazole 3ak in 50% yield along with a hydrolysis process
as acetamide was more easily hydrolyzed than benzamide.
Over the past decade, Chan–Evans–Lam (CEL) couplings
of arylboronic acids with nucleophiles in the presence of
catalytic amounts of copper have been developed.33 We
therefore decided to explore the feasibility for the CEL reac-
tion of arylboronic acids with azoles in aqueous solution
(Table 5). We were pleased to find that arylboronic acids af-
forded N-arylazoles in excellent yield (>89%) upon heating
to 40–60 °C for 3–6 hours. The Cu/GalA-catalyzed CEL reac-
tion typically run to quantitative conversion into products,
and the common side reactions such as deboration and ho-
mocoupling did not occur. In these cases, the workup pro-
cedure was convenient just through extraction with ethyl
acetate.
Ma et al. discovered that NHCOR groups in o-haloacet-
anilides could greatly promote the Ullmann-type biaryl for-
mation reaction, which in combination with the known li-
gand effect led to this reaction occurred at mild condition.19
Accordingly, several substituted o-haloanilides were uti-
lized to react with pyrazole via our catalyst system (Table
4). Surprisingly, intramolecular C–O or C–N bond formation
occurred more readily in most cases, and a series of benz-
Finally, to gain insight into the mechanism, the coupling
of the radical clock 1-allyloxy-2-iodobenzene with pyrazole
was performed to determine whether the aryl halide acti-
vation step proceeds via radical intermediates (Scheme 3).34
Results showed that no conversation of ring closure product
3ap was observed, and only the C–N coupling compound
3ao was afforded. Thus, this catalytic reaction might run via
a prototypical Cu(I)/Cu(III) catalytic cycle instead of a radi-
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–H

D
C. Yuan et al.
Letter
Synlett
Table 4 CuBr/GalA-Catalyzed Coupling Reaction of o-Haloanilides with
Table 5 CuBr/GalA-
Pyrazolea
Catalyzed Couplings of Arylboronic Acids with Pyrazolea,b
CuBr (5 mol%)
GalA (10 mol%)
Y
B(OH)2
+
CuBr (5 mol%)
N
H
N
Y
N
N
X
N
R
Ar
Y = CH, N
R1
R1
GalA (10 mol%)
HN
Y
R1
K2CO3 (3.0 equiv)
R
Ar
+
N
N
K2CO3 (3.0 equiv)
in aq DMSO under Ar
5–12 h, 80–100 °C
NH2
Y
in water under Ar
N
H
R2
or
3–6 h, 40–60 °C
3
X = Br, I
Y = O, NR3
R2
N
N
N
N
N
N
N
N
N
Entry Substrate
Product
Temp Time Yield
(°C) (h) (%)b
F3C
N
OMe
CF
Cl
3 3ai
95%
3aj
96%
3ak
90%
3ah
93%
Br
O
O
N
N
N
N
N
72c
86c
N
N
N
1
100 12
N
MeO
O2N
N
MeO
N
H
N
3ac
N
N
3al
96%
3am
3an
99%
Br
N
N
C2' = Cl, C5' = B(OH)2
96%c
2
80
80
12
5
N
N
O2N
H
3ad
a Reaction conditions: arylboronic acid (1.0 mmol), pyrazole (1.0 mmol),
CuBr (5 mol%), GalA (10 mol%), K2CO3 (3.0 mmol), H2O (2.0 mL), 40–60 °C,
3–6 h.
I
b Isolated yield.
c Pyrazole (2.0 mmol).
Me
70c
N
3
N
N
H
N
Me
N
3ae
OH
H2O
Br
O
Ar–N–Het
ArX
O
O
O
HO
N
4
80
80
5
5
50d
88c
O
Cu
HO
O2N
N
H
Me
HO
O2N
F3C
NH2
A
3af
Br
O
5
N
F3C
N
H
OH
OH
3ag
H2O
H2O
O
O
X
O
O
HO
HO
a Reaction conditions: o-haloanilide (0.8 mmol), pyrazole (1.0 mmol), CuBr
(5 mol%), GalA (10 mol%), K2CO3 (2.4 mmol), aq DMSO (50%, 2.0 mL), 80–
100 °C, 5–12 h.
O
O
Cu
HO
HO
HO
HO
Cu N–Het
B
D
Ar
Ar
b Isolated yield.
c No intermolecular coupling product with pyrazole was detected.
d Intramolecular coupling products were not observed.
B–HX
OH
H2O
O
NH–Het
O
HO
cal pathway.35 As shown in Scheme 4, the catalytic cycle ini-
tiated from a Cu(I) complex A. Then, coordinated Cu(III)
species B was produced via oxidative addition of an ArX and
A. Subsequently, ligand exchange would occur between A
and N-heterocycles to form intermediate C, which could be
converted into D with assistance of base. The N-arylazole
was afforded through final reductive elimination of D.
O
Cu
HO
HO
B
X
C
Ar
NH–Het
Scheme 4 Proposed mechanism for cross-coupling reactions of (hete-
ro)aryl halides with N-containing heterocycles
N-heterocycles, where a natural monosaccharide GalA was
first employed.59,60 This novel catalyst system has shown
high selectivity towards N-arylazole formation against
many other competitive nucleophiles, and enjoyed a large
scope with respect to N-containing heterocycles and aryl
halides or arylboronic acids. On the other hand, GalA con-
tains multiple chiral centers, which may open a new scope
for enantiopure synthesis of various important optically ac-
tive N-arylazoles in a cheap and environmentally friendly
way. Applications of GalA to other coupling reactions, along
with detailed mechanistic studies, are in progress.
O
O
CuBr (5 mol%)
O
GalA (10 mol%)
+
N
I
+
N
HN
K2CO3 (3.0 equiv)
in aq DMSO under Ar
10 h, 100 °C
N
1.2 equiv
not observed
observed
1.0 equiv
3ap
3ao
Scheme 3 Reaction of 2-(allyloxy)iodobenzene with pyrazole to deter-
mine if the aryl halide activation step proceeds via radical intermediates
In summary, we have developed an efficient and envi-
ronmentally friendly catalyst system for the assembly of N-
arylazoles with aryl halides or arylboronic acids and related
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–H

E
C. Yuan et al.
Letter
Synlett
Funding Information
(26) Tang, H. R.; Belton, P. S.; Davies, S. C.; Hughes, D. L. Carbohyd.
Res. 2001, 330, 391.
This research was funded by Natural Science Foundation of Liaoning
Province (Grant Number 2019-BS-102) and the College Students In-
novation Training Program of Liaoning Province (Grant Number
(27) Ippolito, M.; Girasolo, M. A.; Saiano, F.; Attanzio, A.; Rotondo, A.;
Rubino, S.; Mondello, L.; Capobianco, M. L.; Sabatino, P.;
Tesoriere, L.; Casella, G. J. Inorg. Biochem. 2018, 188, 102.
(28) Bermúdez-Oria, A.; Rodríguez-Gutiérrez, G.; Alaiz, M.; Vioque,
J.; Girón-Calle, J.; Fernández-Bolaños, J. Food Funct. 2019, 10,
4844.
201910160017).
N
aturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
L
i
a
o
n
i
n
g
Pro
v
i
n
c
e
(2
0
1
9-BS-1
0
2)
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(30) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13.
(31) Susan, L.; Buonerba, F.; Goracci, L.; Velilla, I.; Ruzziconi, R.;
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Chem. 2016, 59, 867.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690226.
S
u
p
p
orit
n
gInformati
o
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© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–H

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C. Yuan et al.
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Synlett
(56) Rampazzi, V.; Massard, A.; Richard, P.; Picquet, M.; Gendre, P. L.;
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J. Am. Chem. Soc. 2008, 130, 9971.
(59) General Procedure
121.1, 114.6, 13.7 ppm. MS (ESI+): m/z = 159.09 [M + H]+.
3-(1H-Pyrazol-1-yl)benzaldehyde (3f)41
Yield: 0.096 g (70%), off-white solid; mp 28–30 °C. 1H NMR (400
MHz, CDCl3):  = 10.08 (s, 1 H), 8.19 (t, J = 1.8 Hz, 1 H), 8.05–8.02
(m, 2 H), 7.81–7.76 (m, 2 H), 7.64 (t, J = 7.9 Hz, 1 H), 6.52 (t, J =
2.1 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3):  = 191.4, 141.6,
136.5, 135.8, 130.2, 127.6, 125.9, 124.6, 119.0, 108.3 ppm. MS
(ESI+): m/z = 173.08 [M + H]+.
All of the starting materials, reagents, and solvents are commer-
cially available and used without further purification. Melting
points were determined with a X-4 apparatus and were uncor-
rected. The nuclear magnetic resonance (NMR) spectra were
recorded on a Bruker 400 MHz spectrometer in CDCl3 or DMSO-
d6 using tetramethylsilane (TMS) as an internal standard. Elec-
trospray ionization mass spectrometry (MS (ESI)) analyses were
recorded in an Agilent 1100 Series MSD Trap SL (Santa Clara,
CA, USA). The reactions were monitored by thin-layer chroma-
tography (TLC: HG/T2354-92, GF254), and compounds were
visualized on TLC with UV light.
1-(4-(1H-Pyrazol-1-yl)phenyl)ethan-1-one (3g)42
Yield: 0.119 g (80%), white solid; mp 101–104 °C (lit. mp 108
1
°C). H NMR (400 MHz, CDCl3):  = 8.08–8.05 (m, 2 H), 8.02 (d,
J = 2.5 Hz, 1 H), 7.83–7.81 (m, 2 H), 7.78 (d, J = 1.5 Hz, 1 H), 6.52
(t, J = 2.0 Hz, 1 H), 2.63 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3):
 = 196.7, 143.2, 142.0, 134.7, 129.9, 126.8, 118.3, 108.5, 26.5
ppm. MS (ESI+): m/z = 187.09 [M + H]+.
1-(4-Nitrophenyl)-1H-pyrazole-4-carbaldehyde (3h)43
Yield: 0.162 g (93%), yellow solid; mp 158–160 °C (lit. mp 84 °C).
1H NMR (400 MHz, CDCl3):  = 10.02 (s, 1 H), 8.55 (s, 1 H), 8.41–
8.38 (m, 2 H), 8.23 (s, 1 H), 7.97–7.94 (m, 2 H) ppm. 13C NMR
(150 MHz, CDCl3):  = 183.7, 146.6, 143.3, 142.6, 130.3, 126.6,
125.5, 119.7 ppm. MS (ESI+): m/z = 218.34 [M + H]+.
(60) General Procedure for Catalytic Experiments
To a 10 mL vial was charged with aryl halide (0.8 mmol), N-con-
taining heterocycle (1.0 mmol), CuBr (0.04 mmol), GalA (0.08
mmol), K2CO3 (2.4 mmol), and 50% aq DMSO. The flask was
evacuated and backfilled with argon three times, and the reac-
tion mixture was stirred at appropriate temperature under oil
bath for the indicated time. After the complete consumption of
aryl halide monitored by TLC, the mixture was then cooled to
ambient temperature (if the product was acidic, the mixture
was acidified), diluted with ethyl acetate (5 mL), filtered via a
Celite pad, and washed with ethyl acetate (10–20 mL). The
organic layer was separated by the separating funnel, which
was washed successively with water (2 × 10 mL) and brine (2 ×
10 mL). The organic layer was dried over anhydrous MgSO4 and
concentrated by reduced pressure in a rotary evaporator, which
was then purified by column chromatography on silica gel to
provide the desired products.
3-(1H-Pyrazol-1-yl)pyridin-2-amine (3i)44
1
Yield: 0.112 g (88%), brown oil. H NMR (400 MHz, CDCl3):  =
10.68 (br, 1 H), 8.08–8.06 (dd, J = 5.0 Hz, 1.6 Hz, 1 H), 7.77–7.75
(m, 2 H), 7.48–7.46 (dd, J = 7.7 Hz, 1.6 Hz, 1 H), 6.74–6.71 (q, J =
7.7 Hz, 5.0 Hz, 1 H), 6.48 (t, J = 2.1 Hz, 1 H) ppm. 13C NMR (150
MHz, CDCl3):  = 152.7, 146.6, 140.9, 143.3, 130.4, 129.6, 121.6,
113.2, 107.1 ppm. MS (ESI+): m/z = 161.03 [M + H]+.
2-(1H-Pyrazol-1-yl)benzonitrile (3j)45
1
Yield: 0.118 g (87%), yellow oil. H NMR (400 MHz, CDCl3):  =
8.15 (d, J = 2.5 Hz, 1 H), 7.81–7.70 (m, 3 H), 7.73–7.69 (dt, J = 7.6
Hz, 1.5 Hz, 1 H), 7.45–7.41 (dt, J = 7.6 Hz, 1.0 Hz, 1 H), 6.55 (t, J =
2.1 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3):  = 142.3, 142.1,
134.5, 134.0, 129.5, 127.2, 124.3, 117.0, 108.5, 105.4 ppm. MS
(ESI+): m/z = 170.07 [M + H]+.
1-Phenyl-1H-pyrazole (3a)36
1-(4-Chlorophenyl)-1H-indole-2-carboxylic Acid (3k)
Yield: 0.160 g (74%), white to pale grey solid; mp 227–230 °C.
1H NMR (400 MHz, CDCl3):  = 7.75–7.73 (dt, J = 8.4 Hz, 0.9 Hz, 1
H), 7.57 (d, J = 0.7 Hz, 1 H), 7.50–7.47 (m, 2 H), 7.33–7.26 (m, 3
H), 7.23–7.19 (m, 1 H), 7.09–7.06 (m, 1 H) ppm. 13C NMR (150
MHz, DMSO-d6):  = 162.2, 140.4, 137.5, 132.7, 130.1, 129.4,
126.6, 125.9, 121.7, 111.6 ppm. MS (ESI–): m/z = 270.02 [M – H]–.
1-(Thiophen-2-yl)-1H-indole-2-carboxylic Acid (3l)
Yield: 0.169 g (87%), white solid; mp 175–176 °C. 1H NMR (400
MHz, CDCl3):  = 10.02 (s, 1 H), 8.55 (s, 1 H), 8.41–8.38 (m, 2 H),
8.23 (s, 1 H), 7.97–7.94 (m, 2 H) ppm. 13C NMR (150 MHz,
CDCl3):  = 165.8, 142.4, 138.9, 128.9, 126.5, 126.0, 125.9,125.5,
125.0, 122.6, 121.9, 114.6, 111.8 ppm. MS (ESI–): m/z = 241.99
[M – H]–.
Yield: 0.109 g (95%), colorless oil. 1H NMR (400 MHz, CDCl3):  =
7.93–7.92 (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 (t, J = 2.3 Hz, 1 H) ppm. 13C NMR
(150 MHz, CDCl3):  = 141.0, 129.3, 126.7, 126.4, 119.1, 107.5
ppm. MS (ESI+): m/z = 145.04 [M + H]+.
1-Phenyl-1H-imidazole (3b)37
Yield: 0.113 g (98%), colorless oil. 1H NMR (400 MHz, DMSO-d6):
 = 8.28 (s, 1 H), 7.77 (s, 1 H), 7.67–7.64 (m, 2 H), 7.54–7.50 (m,
2 H), 7.37 (t, J = 7.4 Hz, 1 H), 7.14 (s, 1 H) ppm. 13C NMR (150
MHz, CDCl3):  = 137.3, 135.5, 130.3, 129.8, 127.4, 121.4, 118.2
ppm. MS (ESI+): m/z = 145.04 [M + H]+.
2-Methyl-1-(4-nitrophenyl)-1H-imidazole (3c)38
Yield: 0.136 g (84%), light yellow solid; mp 128–130 °C (lit. mp
1
140–142 °C). H NMR (400 MHz, DMSO-d6):  = 8.38 (d, J = 9.0
1-(Thiophen-3-yl)-1H-indole-2-carboxylic Acid (3m)
Yield: 0.177 g (91%), white to a pale grey solid; mp 190–192 °C.
1H NMR (400 MHz, CDCl3):  = 7.74–7.71 (dt, J = 7.9 Hz, 1.0 Hz, 1
H), 7.55 (d, J = 0.6 Hz, 1 H), 7.43–7.41 (m, 1 H), 7.34–7.30 (m, 2
H), 7.22–7.17 (m, 2 H), 7.09–7.07 (q, J = 5.2 Hz, 1.4 Hz, 1 H) ppm.
13C NMR (150 MHz, CDCl3):  = 165.8, 141.2, 135.8, 127.8, 126.8,
126.2, 125.9, 124.9, 122.6, 121.5, 121.2, 113.7, 111.7 ppm. MS
(ESI–): m/z = 242.02 [M – H]–.
Hz, 2 H), 7.78 (d, J = 9.0 Hz, 2 H), 7.45 (d, J = 1.3 Hz, 2 H), 7.0 (d,
J = 1.2 Hz, 1 H), 2.38 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3):
 = 146.8, 144.4, 143.1, 128.7, 125.7, 125.1, 120.1, 14.1 ppm. MS
(ESI+): m/z = 204.05 [M + H]+.
4-Methyl-1-phenyl-1H-imidazole (3d)39 and 5-Methyl-1-
phenyl-1H-imidazole (3e)40
Yield: 0.123 g (97%), yellow oil. 1H NMR (400 MHz, CDCl3, 3d/3e
= 7.6:1):  = 7.76 (d, J = 1.3 Hz, 1 H), 7.57 (br, 0.13 H), 7.50–7.49
(m, 0.2 H), 7.48–7.43 (m, 2 H), 7.37–7.33 (m, 3 H), 7.32–7.28 (m,
0.5 H), 7.01 (t, J = 1.0 Hz, 1 H), 6.91 (br, 0.13 H), 2.31 (d, J = 1.0
Hz, 3 H), 2.18 (d, J = 1.0 Hz, 0.42 H) ppm. 13C NMR (150 MHz,
CDCl3):  = 139.5, 137.5, 134.6, 129.8, 129.5, 128.3, 127.1, 125.6,
1-Phenyl-1H-indole-3-carbaldehyde (3n)46
1
Yield: 0.157 g (89%), brown oil. H NMR (400 MHz, CDCl3):  =
10.12 (s, 1 H), 8.40–8.38 (m, 1 H), 7.92 (s, 1 H), 7.61–7.57 (m, 2
H), 7.54–7.47 (m, 4 H), 7.39–7.32 (m, 2 H) ppm. 13C NMR (150
MHz, CDCl3):  = 184.9, 138.2, 138.1, 137.5, 130.0, 128.3, 125.6,
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–H

G
C. Yuan et al.
Letter
Synlett
124.9, 124.6, 123.5, 122.3, 119.7, 111.1 ppm. MS (ESI+): m/z =
222.07 [M + H]+.
2.49 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (150 MHz,
DMSO-d6):  = 165.6, 153.6, 145.3, 136.5, 131.9, 130.3, 129.3,
128.4, 127.5, 112.5, 111.2, 105.9, 104.0, 59.4, 15.0, 13.3 ppm.
MS (ESI+): m/z = 296.12 [M + H]+.
Ethyl 1-(4-Ethoxyphenyl)-5-hydroxy-2-methyl-1H-indole-3-
carboxylate (3w)
Phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (3o)
Yield: 0.124 g (70%), yellow solid; mp 238–240 °C. 1H NMR (400
MHz, CDCl3):  = 10.10 (s, 1 H), 8.69–8.66 (dd, J = 7.8 Hz, 1.6 Hz,
1 H), 8.49-8.48 (dd, J = 4.8 Hz, 1.6 Hz, 1 H), 8.12 (s, 1 H), 7.76–
7.74 (m, 2 H), 7.62–7.57 (m, 2 H), 7.49–7.45 (m, 1 H), 7.36–7.33
(q, J = 7.8 Hz, 4.8 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3):  =
184.8, 148.5, 145.7, 137.5, 137.0, 130.8, 129.6, 128.0, 124.5,
119.5, 118.2, 117.6 ppm. MS (ESI+): m/z = 223.12 [M + H]+.
2-Chloro-4-(1H-pyrazol-1-yl)aniline (3p)
Yield: 0.210 g (62%), brown solid; mp 225–226 °C. 1H NMR (600
MHz, DMSO-d6):  = 9.02 (s, 1 H), 7.45 (d, J = 2.2 Hz, 1 H), 7.33
(d, J = 8.8 Hz, 2 H), 7.13 (d, J = 8.8 Hz, 2 H), 6.75 (d, J = 8.6 Hz, 1
H), 6.63–6.61 (dd, J = 8.7 Hz, 2.3 Hz, 1 H), 4.32–4.29 (q, J = 14.2
Hz, 7.1 Hz, 2 H), 4.13–4.10 (q, J = 13.7 Hz, 6.9 Hz, 2 H), 2.46 (s, 3
H), 1.39–1.36 (q, J = 14.1 Hz, 7.0 Hz, 6 H) ppm. 13C NMR (150
MHz, DMSO-d6):  = 165.6, 159.0, 153.5, 145.6, 132.3, 129.6,
128.8, 127.4, 115.8, 112.4, 111.2, 105.9, 103.6, 63.9, 59.3, 15.1,
15.0, 13.3 ppm. MS (ESI+): m/z = 340.16 [M + H]+.
Yield: 0.133 g (86%), light yellow solid; mp 70–73 °C. 1H NMR
(400 MHz, CDCl3):  = 7.77 (d, J = 2.4 Hz, 1 H), 7.70 (d, J = 1.5 Hz,
1 H), 7.61 (d, J = 2.5 Hz, 1 H), 7.39–7.36 (dd, J = 8.6 Hz, 2.5 Hz, 1
H), 6.81 (d, J = 8.6 Hz, 1 H), 6.42 (t, J = 2.1 Hz, 1 H), 4.09 (br, 2 H)
ppm. 13C NMR (150 MHz, CDCl3):  = 144.5, 141.2, 131.4, 128.4,
120.7, 119.9, 118.2, 116.7, 108.3 ppm. MS (ESI+): m/z = 194.05
[M + H]+.
Ethyl 5-Hydroxy-2-methyl-1-(p-tolyl)-1H-indole-3-carboxyl-
ate (3x)49
Yield: 0.170 g (55%), yellow solid; mp 190–192 °C. 1H NMR (600
MHz, DMSO-d6):  = 9.03 (s, 1 H), 7.45–7.41 (m, 3 H), 7.31 (d, J =
7.5 Hz, 2 H), 6.77 (d, J = 8.5 Hz, 1 H), 6.63 (d, J = 8.1 Hz, 1 H),
4.32–4.29 (q, J = 14.0 Hz, 7.1 Hz, 2 H), 2.47 (s, 3 H), 2.43 (s, 3 H),
1.37 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (150 MHz, DMSO-d6):  =
165.6, 153.5, 145.4, 138.9, 133.9, 132.0, 130.8, 128.2, 127.5,
112.4, 111.2, 105.9, 103.8, 59.4, 21.2, 15.0, 13.3 ppm. MS (ESI+):
m/z = 310.13 [M + H]+.
2-(1H-Pyrazol-1-yl)benzoic Acid (3q)47
Yield: 0.134 g (89%), white solid; mp 128–129 °C. 1H NMR (400
MHz, CDCl3):  = 11.41 (br, 1 H), 8.06–8.04 (dd, J = 7.8 Hz, 1.1 Hz,
1 H), 7.77–7.75 (m, 2 H), 7.63–7.59 (m, 1 H), 7.50–7.46 (t, J = 7.5
Hz, 1 H), 7.43 (d, J = 7.8 Hz, 1 H), 6.49–6.48 (t, J = 2.1 Hz, 1 H)
ppm. 13C NMR (150 MHz, CDCl3):  = 168.8, 141.0, 138.6, 132.7,
132.3, 131.0, 128.2, 127.1, 125.7, 107.6 ppm. MS (ESI–): m/z =
187.06 [M – H]–.
Ethyl 5-Hydroxy-2-methyl-1-[3-(trifluoromethyl)phenyl]-
1H-indole-3-carboxylate (3y)
1-(4-Nitrophenyl)-1H-pyrazole (3r)36
Yield: 0.130 g (86%), yellow solid; mp 167–168 °C (lit. mp
168.5–169 °C). 1H NMR (400 MHz, CDCl3):  = 8.37–8.33 (m, 2
H), 8.04 (d, J = 2.6 Hz, 1 H), 7.91–7.87 (m, 2 H), 7.81 (d, J = 1.5 Hz,
1 H), 6.57–5.56 (q, J = 2.4 Hz, 1.9 Hz, 1 H) ppm. 13C NMR (150
MHz, CDCl3):  = 140.8, 129.6, 125.6, 120.6, 119.3, 110.4 ppm.
MS (ESI+): m/z = 190.08 [M + H]+.
Yield: 0.229 g (63%), white solid; mp 199–201 °C. 1H NMR (600
MHz, DMSO-d6):  = 9.09 (s, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 7.92 (s,
1 H), 7.87 (t, J = 7.9 Hz, 1 H), 7.82 (d, J = 7.9 Hz, 1 H), 7.47 (d, J =
2.1 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 6.67–6.65 (dd, J = 8.7 Hz, 2.2
Hz, 1 H), 4.34–4.31 (q, J = 14.2 Hz, 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz,
3 H) ppm. 13C NMR (150 MHz, DMSO-d6):  = 165.5, 153.7,
145.4, 137.3, 132.9, 131.7, 131.6, 131.1 (J = 31.9 Hz), 127.6,
126.1 (J = 3.5 Hz), 125.4 (J = 3.8 Hz), 125.0, 123.2, 112.7, 111.0,
106.0, 104.5, 59.5, 15.0, 13.3 ppm. MS (ESI+): m/z = 364.15 [M +
H]+.
3-Nitro-4-(1H-pyrazol-1-yl)aniline (3s)
Yield: 0.156 g (96%), yellow solid; mp 135–136 °C. 1H NMR (400
MHz, CDCl3):  = 7.69 (d, J = 1.0 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H),
7.31 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 2.6 Hz, 1 H), 6.88–6.85 (dd,
J = 8.6 Hz, 2.6 Hz, 1 H), 6.44 (t, J = 2.0 Hz, 1 H), 3.85 (br, 2 H)
ppm. 13C NMR (150 MHz, CDCl3):  = 147.0, 145.7, 141.3, 130.3,
128.4, 124.3, 118.1, 109.9, 107.1 ppm. MS (ESI+): m/z = 205.06
[M + H]+.
4-(1H-Pyrazol-1-yl)phenol (3z)50
Yield: 0.158 g (99%), white solid; mp 99–101 °C (lit. mp 94–96
°C) 1H NMR (400 MHz, CDCl3):  = 7.77–7.72 (m, 2 H), 7.41–7.37
(m, 2 H), 6.82–6.78 (m, 2 H), 6.45 (t, J = 2.1 Hz, 1 H) ppm. 13C
NMR (150 MHz, CDCl3):  = 155.6, 140.3, 132.9, 127.8, 121.9,
116.2, 107.1 ppm. MS (ESI+): m/z = 161.02 [M + H]+.
N-[2-(1-phenyl-1H-indol-3-yl)ethyl]aniline (3aa)
Yield: 0.271 g (87%), yellow solid; mp 85–87 °C. 1H NMR (400
MHz, CDCl3):  = 7.67–7.65 (m, 1 H), 7.58–7.56 (m, 1 H), 7.53–
7.46 (m, 1 H), 7.35–7.30 (m, 1 H), 7.26–7.16 (m, 5 H), 6.73–6.69
(m, 1 H), 6.66–6.63 (m, 2 H), 3.98 (br, 1 H), 3.53 (t, J = 6.9 Hz, 2
H), 3.16–3.12 (m, 2 H) ppm. 13C NMR (150 MHz, CDCl3):  =
148.0, 139.7, 136.1, 129.6, 128.8, 126.2, 125.7, 124.1, 122.6,
120.0, 119.1, 117.4, 114.4, 113.0, 110.6, 43.9, 25.0 ppm. MS
(ESI+): m/z = 313.18 [M + H]+.
4-Chloro-2-(1H-pyrazol-1-yl)benzoic Acid (3t)
Yield: 0.172 g (97%), pale grey solid; mp 237–240 °C. 1H NMR
(400 MHz, DMSO-d6):  = 8.20 (d, J = 2.4 Hz, 1 H), 7.73–7.71 (m,
3 H), 7.57–7.54 (dd, J = 8.3 Hz, 2.0 Hz, 1 H), 6.51–6.50 (q, J = 2.4
Hz, 1.9 Hz, 1 H) ppm. 13C NMR (150 MHz, DMSO-d6):  = 168.5,
142.3, 140.4, 136.7, 132.5, 131.8, 128.5, 128.4, 125.4, 108.8
ppm. MS (ESI+): m/z = 220.94 [M + H]+, 222.93 [M + H]+.
1-(4-Nitrophenyl)-1H-indol-5-ol (3u)
Yield: 0.216 g (85%), yellow solid; mp 188–191 °C. 1H NMR (400
MHz, CDCl3):  = 8.40 (d, J = 9.0 Hz, 2 H), 7.67 (d, J = 9.0 Hz, 2 H),
7.53 (d, J = 8.8 Hz, 1 H), 7.36 (d, J = 3.3 Hz, 1 H), 7.09 (d, J = 2.4
Hz, 1 H), 6.87–6.84 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 6.66 (d, J = 3.2
Hz, 1 H), 4.60 (br, 1 H) ppm. 13C NMR (150 MHz, CDCl3):  =
152.8, 145.2, 144.2, 131.5, 129.2, 128.6, 125.9, 122.8, 113.2,
111.9, 105.8, 105.7 ppm. MS (ESI–): m/z = 253.06 [M – H]–.
Ethyl 5-Hydroxy-2-methyl-1-phenyl-1H-indole-3-carboxyl-
ate (3v)48
Yield: 0.174 g (59%), brown solid; mp 203–205 °C (lit. mp 203–
204 °C). 1H NMR (600 MHz, DMSO-d6):  = 9.06 (s, 3 H), 7.63 (t,
J = 7.4 Hz, 2 H), 7.57 (t, J = 7.3 Hz, 1 H), 7.47 (d, J = 2.3 Hz, 1 H),
7.45 (d, J = 7.3 Hz, 2 H), 6.78 (d, J = 8.7 Hz, 1 H), 6.65–6.63 (dd,
J = 8.8 Hz, 2.4 Hz, 1 H), 4.33–4.30 (q, J = 14.2 Hz, 7.1 Hz, 2 H),
3-(1H-Pyrazol-1-yl)aniline (3ab)51
1
Yield: 0.141 g (89%), brown oil. H NMR (400 MHz, CDCl3):  =
7.89 (d, J = 2.3 Hz, 1 H), 7.70 (d, J = 1.5 Hz, 1 H), 7.20 (t, J = 8.0 Hz,
1 H), 7.10 (t, J = 2.2 Hz, 1 H), 7.01–6.99 (m, 1 H), 6.61–6.58 (m, 1
H), 6.44 (t, J = 2.0 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3):  =
147.6, 140.8, 130.2, 126.8, 113.1, 109.0, 107.3, 106.1 ppm. MS
(ESI+): m/z = 160.07 [M + H]+.
5-Methoxy-2-phenylbenzo[d]oxazole (3ac)52
Yield: 0.129 g (72%), white solid; mp 66–69 °C (lit. mp 60–61
°C). 1H NMR (400 MHz, CDCl3):  = 8.24–8.22 (m, 2 H), 7.52–
7.51 (m, 3 H), 7.45 (d, J = 8.8 Hz, 1 H), 7.27 (d, J = 2.5 Hz, 1 H),
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–H

H
C. Yuan et al.
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Synlett
6.96–6.93 (dd, J = 2.6 Hz, 8.9 Hz, 1 H), 3.87 (s, 3 H) ppm. 13C
NMR (150 MHz, CDCl3):  = 163.7, 157.3, 145.3, 142.8, 131.3,
128.8, 128.7, 127.4, 127.2, 113.7, 110.6, 102.8, 55.9 ppm. MS
(ESI+): m/z = 226.10 [M + H]+.
3-Nitro-5a,6,7,8,9,10-hexahydro-5H-benzo[4,5]imidazo[1,2-
a]azepine (3ad)
0.9 Hz, 1 H), 7.76 (d, J = 1.4 Hz, 1 H), 7.60–7.53 (m, 2 H), 6.51 (t,
J = 1.9 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3):  = 141.7,
140.4, 131.9 (J = 32.7 Hz), 130.0, 126.7, 123.6 (J = 271.2 Hz),
122.8 (J = 3.4 Hz), 121.9, 115.9 (J = 3.6 Hz), 108.3 ppm. MS
(ESI+): m/z = 213.05 [M + H]+.
1-(3-Chlorophenyl)-1H-pyrazole (3aj)55
Yield: 0.160 g (86%), yellow solid; mp 171 °C (lit. mp 170–171
°C). 1H NMR (400 MHz, CDCl3):  = 8.58 (d, J = 2.1 Hz, 1 H), 8.18
(dd, J = 9.0, 2.2 Hz, 1 H), 7.32 (d, J = 9.0 Hz, 1 H), 4.24–4.21 (m, 2
H), 3.17–3.14 (m, 2 H), 2.02–1.96 (m, 2 H), 1.92–1.82 (m, 4 H)
ppm. 13C NMR (150 MHz, CDCl3):  = 161.2, 143.1, 141.6, 117.9,
115.8, 108.5, 45.1, 30.5, 30.1, 28.5, 25.1 ppm. MS (ESI+): m/z =
232.14 [M + H]+.
Yield: 0.171 g (96%), white solid; mp 27–29 °C. 1H NMR (400
MHz, CDCl3):  = 7.93 (br, 1 H), 7.75 (t, J = 1.9 Hz, 1 H), 7.74 (br, 1
H), 7.60–7.57 (m, 1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.27–7.24 (m, 1
H), 6.49 (br, 1 H) ppm. 13C NMR (150 MHz, CDCl3):  = 141.4,
141.0, 135.2, 130.4, 126.7, 126.3, 119.3, 116.9, 108.1 ppm. MS
(ESI+): m/z = 179.02 [M + H]+, 181.03 [M + H]+.
1-(3-Methoxyphenyl)-1H-pyrazole (3ak)36
2-Methyl-1-phenyl-1H-benzo[d]imidazole (3ae)53
Yield: 0.116 g (70%), white solid; mp 62–65 °C (lit. mp 68 °C). 1H
NMR (400 MHz, CDCl3):  = 7.76 (d, J = 7.9 Hz, 1 H), 7.60–7.56
(m, 2 H), 7.54–7.49 (m, 1 H), 7.38–7.35 (m, 2 H), 7.29–7.24 (m, 1
Yield: 0.156 g (90%), colorless oil. 1H NMR (400 MHz, CDCl3):  =
7.92–791 (dd, J = 2.4 Hz, 0.4 Hz, 1 H), 7.72 (d, J = 1.5 Hz, 1 H),
7.36–7.31 (m, 2 H), 7.24–7.21 (m, 1 H), 6.85–6.82 (m, 1 H),
6.46–6.45 (q, J = 2.4 Hz, 1.9 Hz, 1 H), 3.87 (s, 3 H) ppm. 13C NMR
(150 MHz, CDCl3):  = 160.5, 141.3, 140.9, 130.1, 126.9, 112.3,
111.1, 107.5, 105.0, 55.4 ppm. MS (ESI+): m/z = 175.10 [M + H]+.
5-(1H-Pyrazol-1-yl)pyrimidine (3al)56
H), 7.21–7.17 (m, 1 H), 7.14–7.12 (m, 1 H), 2.51 (s, 3 H) ppm. 13
C
NMR (150 MHz, CDCl3):  = 151.6, 142.7, 136.5, 136.1, 129.9,
128.8, 127.1, 122.6, 122.4, 119.0, 109.9, 14.5 ppm. MS (ESI+):
m/z = 209.11 [M + H]+.
Yield: 0.140 g (96%), white solid; mp 88–90 °C. 1H NMR (400
MHz, CDCl3):  = 9.16 (s, 1 H), 8.00 (d, J = 2.5 Hz, 1 H), 7.83 (d, J =
1.6 Hz, 1 H), 6.59 (t, J = 1.9 Hz, 1 H) ppm. 13C NMR (150 MHz,
CDCl3):  = 156.1, 147.0, 142.8, 134.6, 126.6, 109.2 ppm. MS
(ESI+): m/z = 147.05 [M + H]+.
5-Nitro-2-(1H-pyrazol-1-yl)aniline (3af)
Yield: 0.081 g (50%), red solid; mp 100 °C. 1H NMR (400 MHz,
CDCl3):  = 7.83–7.80 (m, 2 H), 7.69 (d, J = 2.4 Hz, 1 H), 7.63–7.60
(dd, J = 8.7 Hz, 2.5 Hz, 1 H), 7.33 (d, J = 8.7 Hz, 1 H), 6.52 (t, J = 2.3
Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3):  = 147.0, 141.3,
141.2, 129.9, 129.7, 123.1, 112.5, 111.9, 107.5 ppm. MS (ESI+):
m/z = 205.10 [M + H]+.
2,5-Di(1H-pyrazol-1-yl)pyridine (3am)57
Yield: 0.202 g (96%), white solid; mp 160–161 °C (lit. mp 162
°C). 1H NMR (400 MHz, CDCl3):  = 8.78 (d, J = 1.5 Hz, 1 H), 8.59
(d, J = 2.4 Hz, 1 H), 8.19–8.10 (m, 2 H), 7.96 (d, J = 2.4 Hz, 1 H),
7.79 (d, J = 1.6 Hz, 1 H), 7.77 (s, 1 H), 6.54 (t, J = 2.1 Hz, 1 H), 6.50
(t, J = 2.0 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3):  = 149.6,
142.2, 141.8, 138.5, 134.8, 129.5, 127.1, 126.7, 112.8, 108.3,
108.0 ppm. MS (ESI+): m/z = 212.10 [M + H]+.
2-Phenyl-5-(trifluoromethyl)benzo[d]oxazole (3ag)52
Yield: 0.185 g (88%), white solid; mp 83 °C (lit. mp 86–87 °C). 1H
NMR (400 MHz, CDCl3):  = 8.95 (d, J = 1.9 Hz, 1 H), 8.56 (br, 1
H), 7.96–7.93 (m, 2 H), 7.73–7.70 (m, 1 H), 7.64–7.60 (m, 1 H),
7.57–7.51 (m, 2 H), 7.29–7.26 (m, 1 H) ppm. 13C NMR (150 MHz,
CDCl3):  = 136.4, 133.9, 132.6, 132.5, 131.0 (J = 33.0 Hz), 129.0,
128.8, 127.0, 123.5 (J = 271.0 Hz), 121.5 (J = 3.5 Hz), 118.3 (J =
3.7 Hz), 116.8 ppm. MS (ESI+): m/z = 264.05 [M + H]+.
4-(1H-Pyrazol-1-yl)pyridine (3an)55
Yield: 0.143 g (99%), white solid; mp 72–74 °C. 1H NMR (400
MHz, CDCl3):  = 8.71 (br, 2 H), 8.05 (d, J = 2.4 Hz, 1 H), 7.79 (d,
J = 1.5 Hz, 1 H), 7.67 (d, J = 4.0 Hz, 2 H), 6.55–6.54 (q, J = 2.6 Hz,
1.8 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3):  = 151.1, 145.9,
142.5, 126.5, 112.5, 109.0 ppm. MS (ESI+): m/z = 146.02 [M + H]+.
1-(2-(Allyloxy)phenyl)-1H-pyrazole (3ao)58
5-(1H-Pyrazol-1-yl)-2-(trifluoromethyl)pyridine (3ah)
Yield: 0.198 g (93%), white solid; mp 115–117 °C. 1H NMR (400
MHz, CDCl3):  = 9.10 (d, J = 2.4 Hz, 1 H), 8.26–8.23 (dd, J = 8.5
Hz, 2.2 Hz, 1 H), 8.04 (d, J = 2.6 Hz, 1 H), 7.82 (d, J = 1.6 Hz, 1 H),
7.80 (d, J = 8.5 Hz, 1 H), 6.58–6.57 (q, J = 2.4 Hz, 1.8 Hz, 1 H)
ppm. 13C NMR (150 MHz, CDCl3):  = 145.4 (J = 36.0 Hz), 142.8,
140.1, 138.2, 126.8, 126.7, 121.3 (J = 273.1 Hz), 121.2 (J = 2.3
Hz), 109.3 ppm. MS (ESI+): m/z = 214.08 [M + H]+.
Yield: 0.160 g (84%), colorless oil. 1H NMR (400 MHz, CDCl3):  =
8.09 (s, 1 H), 7.77–7.74 (dd, J = 7.9 Hz, 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 Hz, 1.5 Hz, 2 H) ppm. 13C NMR (150 MHz, CDCl3):  =
148.6, 140.6, 140.2, 131.4, 128.8, 127.6, 125.0, 123.1, 116.4,
108.4, 106.5, 69.7 ppm. MS (ESI+): m/z = 201.12 [M + H]+.
1-[3-(Trifluoromethyl)phenyl]-1H-pyrazole (3ai)54
Yield: 0.201 g (95%), colorless oil. 1H NMR (400 MHz, CDCl3):  =
8.00 (br, 1 H), 7.98 (d, J = 1.9 Hz, 1 H), 7.90–7.88 (dt, J = 7.8 Hz,
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–H