L -(-) -Quebrachitol as a Ligand for Selective Copper(0)-Catalyzed N-Arylation of Nitrogen-Containing Heterocycles

Article abstract of DOI:10.1021/acs.joc.9b00997

l-(-)-Quebrachitol (QCT) has been found as a ligand of copper powder for selective N-arylation of nitrogen-containing heterocycles with aryl halides. Furthermore, another potential catalytic system (copper powder/QCT/t-BuOK) was successfully adapted to unactivated aryl chlorides.

Full text of DOI:10.1021/acs.joc.9b00997

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Article
L-(-)-Quebrachitol as a Ligand for Selective Copper (0)-
Catalyzed N-Arylation of Nitrogen-Containing Heterocycles
Qifan Zhou, Fangyu Du, Yuanguang Chen, Yang Fu, Wenjiao Sun, Ying Wu, and Guoliang Chen
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 Jun 2019
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L-(-)-Quebrachitol as a Ligand for Selective Copper (0)-
Catalyzed N-Arylation of Nitrogen-Containing Heterocycles
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Qifan Zhou,‡ Fangyu Du,‡ Yuanguang Chen,‡ Yang Fu,‡ Wenjiao Sun,‡ Ying Wu*† and
Guoliang Chen*‡
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education,
Shenyang Pharmaceutical University, Shenyang 110016, China, and Yunnan Institute
of Tropical Crops, Jinghong 666100, China.
Correspondence: spucgl@163.com (GL Chen); ynbnwy@163.com (Y Wu)
‡ Shenyang Pharmaceutical University
† Yunnan Institute of Tropical Crops
Abstract
L-(-)-quebrachitol has been found as a ligand of copper powder for selective N-
arylation of nitrogen-containing heterocycles with aryl halides. Furthermore, another
potential catalytic system (copper powder/QCT/t-BuOK) was successfully adapted to
unactivated aryl chlorides.
Introduction
N-arylazoles are ubiquitous structural motifs in numerous biologically active
compounds, natural products and pharmaceuticals and also as precursors of versatile N-
1
heterocyclic carbines and auxiliary ligands for transition-metal catalysis. Traditional
synthetic approaches of N-arylazoles often depend on using highly activated aryl
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halides (SNAr reaction),
the classical Ullmann-type coupling reactions,3or the
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Buchwald-Hartwig reactions. 4 The classical Ullmann reactions normally requires harsh
reaction conditions (high temperature, long reaction time, the narrow substrate and
erratic yields). 5 However, due to the low cost and toxicity of the copper catalyst, Cu-
catalyzed N-arylation is still attractive in synthetic applications.
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To overcome the drawbacks in classical Ullmann reactions, various modified
Ullmann catalytic systems have been reported continuously over the past decades, for
example, the use of bidentate ligands, which allowed the coupling reaction to be
6
conducted smoothly under the mild conditions (Figure 1). However, because many
ligands are not commercially available in industrial-scale, it seriously hampers their
6c
synthetic application. Notably, the toxicity and sustainability of these ligands must
been taken in consideration for meeting the requirements of green chemistry.
On the other hand, quebrachitol (1-L-(-)-2-O-methyl-chiro-inositol, QCT, Figure 1)
is an optically active inositol with superior water solubility, existing in a variety of
plants, could be used as a chiral source in organic synthesis. 7 QCT is mainly extracted
from waste water of natural rubber industry by using the matured extraction technology.
8
Arguably, developing the use of QCT could also contribute to facilitate problem
solving like waste water of natural rubber industry.
Herein, we discovered that Cu (0)-catalyzed N-arylation could be smoothly carried
out under the mild condition with the assistance of QCT. Due to its stable
physicochemical properties and good water solubility, QCT could be employed as a
green auxiliary ligand in Ullmann-type reaction, which simultaneously extends the
industrial application of natural rubber.
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Figure 1. Chemical structures of general bidentate ligands and QCT.
Results and Discussion
As described in Table 1, we chose Cu-catalyzed coupling of bromobenzene and
pyrazole as model substrates to explore optimal conditions. Initially, under basic
conditions in the presence of CuI, CuBr, CuCl or Cu2O, only a small quantity target
product 3a was observed, along with unreacted starting material (Table 1, entries 1-4).
With the use of Cu2SO4, no desired product was seen (entry 5). Surprisingly, the C-N
coupling product was obtained in 90% yield when the Cu powder was used as catalyst,
and the loading of catalyst could be reduced to 10 mol % (entries 6, 7). Further studies
revealed a significant effect of bases, with Cs2CO3 or K2CO3 being proved to be optimal
in terms of yield (entries 7-12). Subsequent evidence showed that Cs2CO3 was more
potential in the coupling reaction of 1-bromo-4-methoxybenzene and pyrazole (data not
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shown). Polar solvents (DMSO, DMF and ethylene glycol) favored this reaction, with
DMSO-H2O being the most effective (entries 13-18). We postulated that the addition
of water promoted oxidization of copper powder into Cu (I) specie. In order to
investigate its effectiveness, the coupling reaction was conducted on a 10 gram scale,
and 8.50 g of 3a was obtained in 92% yield (entry 19).
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Table 1. Identification of Reaction Conditions a
entry
1
Cu (mol %)
CuI (20)
CuBr (20)
CuCl (20)
Cu2O (20)
CuSO4 (20)
Cu (20)
base
solvent
DMSO
yield (%) b
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
56
55
21
trace
0
2
DMSO
3
DMSO
4
DMSO
5
DMSO
6
DMSO
90
90
75
0
7
Cu (10)
DMSO
.
8
Cu (10)
K3PO4 3H2O
DMSO
9
Cu (10)
Et3N
DMSO
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18
Cu (10)
Cs2CO3
NaHCO3
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMSO
93
0
Cu (10)
DMSO
Cu (10)
DMSO
86
94
88
0
Cu (10)
DMSO-H2O (1:1)
DMF
Cu (10)
Cu (10)
dioxane
Cu (10)
dichloroethane
toluene
0
Cu (10)
0
Cu (10)
ethylene glycol
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19 c
Cu (10)
Cs2CO3
DMSO-H2O (1:1)
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a Standard condition: 1a (0.8 mmol), 2a (1.0 mmol), 20 mol % QCT, solvent (2.0 mL),
100 oC, 10 h, Ar. b Isolated yield. c The loading of 1a was 10 gram.
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With optimized conditions in hand, we explored the scope of the coupling reactions
of aryl halides with pyrazole in the presence of Cu powder (10 mol %), QCT (20 mol %)
and Cs2CO3 (3.0 equiv), and the results were summarized in Table 2. Notably, the
catalytic system could facilitate the coupling reactions of aryl iodides and pyrazole in
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o
excellent yields at 80 C, while the aryl bromides also proceeded well at higher
o
temperature (100 C) to afford products in 68-99% yields. Furthermore, electron-rich
substitutions on aryl bromides were not conducive and led to lower yields (3a vs. 3b).
A range of reactive functional groups (e.g. NH2, CHO, COOH, CN.) was proved to be
compatible, and the coupling products (e.g. 3d, 3e, 3h, 3i) were obtained in excellent
yields from corresponding aryl halides and pyrazole. Consequently, this protocol has
offered an alternative scheme for the synthesis of highly functional azoles.
Table 2. Scope with Respect to Aryl Halides a
entry
1
X
temp (oC)/time (h)
100/10
product
yield (%) b
94
Br
2
3
Br
I
110/20
80/10
68
93
4
Br
80/10
99
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Br
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I
I
95 c
8
9
I
80/10
110/24
110/24
96 c
Br
Br
82
10
89
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12
Br
I
110/16
80/10
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a Reaction conditions: 1 (0.8 mmol), 2a (1.0 mmol), 10 mol % Cu powder, 20 mol %
QCT, Cs2CO3 (2.4 mmol), DMSO-H2O (1 mL: 1 mL). b Isolated yield. c DMSO (2 mL)
as solvent to avoid hydrolysis of esters.
The reaction also enjoys wide substrate scope with respect to N-heterocycles (Table
3). The coupling reactions also could go smoothly by changing pyrazole with pyrroles,
imidazoles, indoles, benzimidazoles. Not surprisingly, the electron-rich aryls were
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superior to electron-deficient aryls, for example, 3t and 3u with the yield of 65% and
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95%, respectively. Pyrrole gave the desired compound in moderate yield (54%), which
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might result from the acidity of pyrrole. Sufficient evidence showed that the reaction
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with unsymmetrical heterocycles proceeded with regioselectivity.
Accordingly,
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using asymmetric imidazole afforded two imidazole tautomers 3r and 3s with a ratio of
12:1 in 89% yield. As evidenced by the example presented in Table 3, the catalytic
system displayed more regioselectivity than using CuI system. 6c Not suppursingly, the
C-N coupling reactions were hindered in steric pyrroles, it explained the fact that
affording 3m only in 47% and 3n was not observed. In our cases, bi-functional
compound 2-mercaptobenzimidazole was selectively S-arylated (3v) without N-
arylation (entry 10). The 5-hydroxyindole was selectively N-arylated by providing 3w
6b
in excellent yield without O-arylation (entry 11). However, utilizing CuI/L-Proline
gave 3w and 3ah in 65% and 20% yield, respectively (Scheme 1A). For 2-
indolecarboxylic acid substrates, N-arylation reactions were readily conducted in
excellent yields, from 84% to 98%. According to the reports that pyrrole-2-carboxylic
acid and 2-picolinic acid could be generally applied as chelating ligands of transition
metal, 9 we postulated that 2-indolecarboxylic acid also acted as an efficient auxiliary
ligand of copper, and it accounted for the excellent yields. The imidazole could also
participate in C-N coupling reaction, especially the unactivated aryl bromines, for
example,
4-bromoanisole, 2-bromoanisole and 3-bromoaniline
yielded
corresponding desire compounds in moderate yield (3ab, 3ac, and 3ad). Moreover, the
sterically hindered 2-methyl-1H-benzo[d]imidazole afforded the product (3ag) only in
54% yield.
Table 3. Scope with Respect to N-Containing Heterocyclic a
entry
product (yield) b
entry
product (yield) b
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2c
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a Reaction conditions: Aryl bromides (0.8 mmol), 2 (1.0 mmol), 10 mol % Cu powder,
20 mol % QCT, Cs2CO3 (2.4 mmol), DMSO-H2O (1 mL: 1 mL), 100 C, unless
otherwise noted. b Isolated yield. c DMSO (2 mL) as solvent.
o
Inspired by the excellent performance of Cu/QCT catalytic system, the inert aryl
chlorides were also examined for the coupling reactions (Table 4). Regrettably, only a
trace of 3a was observed using chlorobenzene and pyrazole as starting materials. After
o
subsequent optimization, the coupling reaction could proceed at 120 C with Cu/QCT
catalytic system by replacing Cs2CO3 with t-BuOK. The scope of Cu-catalyzed reaction
has been further tested using a wide range of aryl chlorides. The corresponding N-
arylazoles were formed in 70-92% yields in relatively short time (8-16 h). Apparently,
aryl chlorides and aryl bromides could undergo the N-arylation reaction with
quantitative conversion except for the aryl fluorides (entries 2, 5, 7). Notably, only a
trace (<5%) of 3t was detected when p-nitrochlorobenzene was reacted with the
unactivated 7-azaindole-3-carbaldehyde. The major product was Ullmann biaryl
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homocoupling compound 3aq (30% yield).
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Table 4. Cu/QCT-catalyzed Coupling of Aryl Chloride with Pyrazol in the Presence of
t-BuOK a
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time
(h)
yield (%)
entry
1
substrate
product
b
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--
a Reaction conditions: Aryl chlorides (0.8 mmol), 2 (1.0 mmol), 10 mol % Cu powder,
20 mol % QCT, t-BuOK (2.4 mmol), DMSO (2 mL). b Isolated yield. c The loading of
pyrazole was 2.0 mmol. Control experiment conditions: 2-chlorobenzonitrile (0.8
mmol), pyrazole (1.0 mmol), 20 mol % QCT, t-BuOK (2.4 mmol), DMSO (2 mL).
d
To further explore the selectivity, competition reactions among different nucleophiles
using bromobenzene in Cu/QCT catalytic system were next investigated in Scheme 1B.
When the competitive reaction was conducted between pyrazole and piperidine, it was
encouraging to observe the sole formation of 3a in good yield at 110 °C. Consistent
results were also obtained for pyazole competing with aniline and phenol.
Scheme 1. Competition Reactions
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Scheme 2. Reaction between 2-(Allyloxy)iodobenzene and Pyrazole
Finally, to gain insight into the mechanism of cross coupling reaction, we used the
radical clock 1-allyloxy-2-iodobenzene as substrate to determine if the aryl halide
activation step proceeds via radical intermediate.10 Results showed that no conversation
of ring closure product 3as was observed, only affording the C-N coupling compound
3ar (Scheme 2). Thus, this catalytic reaction might run via a prototypical Cu (I)/Cu (III)
catalytic cycle instead of a radical pathway. 11
Conclusion
In summary, we have developed an efficient and environmentally friendly catalytic
system for assemble of N-arylazoles with aryl halides and related N-heterocycles, where
the inexpensive copper powder and a green ligand QCT were employed. Herein, the
direct usage of readily available QCT in ligand-promoted Ullmann-type is
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unprecedented. This catalytic system has displayed highly selectivity towards the
formation of N-arylazoles against other competitive nucleophiles, and enjoyed a large
scope with respect to N-containing heterocyclics and aryl halides. Applications of QCT
to other coupling reactions, along with detailed mechanistic studies, are under progress.
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Experimental Section
General information
All of the starting materials, reagents, and solvents are commercially available and
used without further purification. Melting points were determined with a X-4 apparatus
and were uncorrected. 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. Electrospray ionization mass spectrometry (ESI-MS)
analyses were recorded in 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.
General Procedure for Catalytic Experiments.
To a 10 mL vial was charged with Cu powder (5 mg, 0.08 mmol), QCT (30 mg, 0.16
mmol), Cs2CO3 (78 mg, 2.4 mmol) or t-BuOK (0.27 g, 2.4 mmol), nitrogen-containing
heterocycle (1.0 mmol), aryl halide (0.8 mmol), and DMSO-H2O (1:1, 2 mL) or DMSO
(2 mL). The flask was evacuated and backfilled with argon three times, and the resulting
suspension was heated in appropriate temperature oil bath with rapid stirring for the
indicated time. After the complete consumption of aryl halide monitored by TLC, the
reactor was cooled to rt, the flask was opened to air and the reaction mixture was the
mixture (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
combined organic phase was concentrated, and the resulting residue was purified by
column chromatography on silica gel to provide the desired product.
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Larg scale synthesis of 1-phenyl-1H-pyrazole (3a)
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To a solution of Cu powder (0.41 g, 6.40 mmol), QCT (2.49 g, 12.8 mmol), Cs2CO3
(62.7 g, 0.19 mol), pyrazole (5.06 g, 80.1 mmol), DMSO (25 mL) and H2O (25 mL)
were added bromobenzene (10 g, 64.1 mmol). The flask was evacuated and backfilled
with argon three times, and the resulting suspension was heated in a 100 °C oil bath
with rapid stirring for 10 h. The reactor was cooled to room temperature, the flask was
opened to air and the reaction mixture was diluted with ethyl acetate (50 mL), filtered
via a celite pad, washed with ethyl acetate (50 mL). The combined organic phase was
concentrated, and the resulting residue was purified by column chromatography on
silica gel to provide the 3a as colorless liquid (8.50 g, 92%).
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Compound characterization data
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1-Phenyl-1H-pyrazole (3a). According to the general procedure, the 3a was
obtained as colorless liquid (0.11 g, 94%). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.93-
7.92 (d, J=2.4 Hz, 1 H), 7.73-7.68 (m, 3H), 7.47-7.43 (m, 2H), 7.30-7.25 (m, 1H), 6.46
(t, J=2.3 Hz, 1H). MS (ESI+): m/z 145.04 [M+H]+.
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1-(4-Methoxyphenyl)-1H-pyrazole (3b). According to the general procedure,
the 3b was obtained as white solid (0.13 g, 93% ). m.p. 40-42 oC (lit. 42 oC). 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.83 (d, J=2.4 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.61-7.57
(m, 2H), 6.99-6.95 (m, 2H), 6.44 (t, J=1.9 Hz, 1H), 3.84 (s, 3H). MS (ESI+): m/z 175.12
[M+H]+.
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1-(4-Nitrophenyl)-1H-pyrazole (3c). According to the general procedure, the 3c
o
o
1
was obtained as yellow solid (0.15 g, 99%). m.p. 167-168 C (lit. 168.5-169 C). H
NMR (400 MHz, CDCl3): δ (ppm) 8.37-8.33 (m, 2H), 8.04 (d, J=2.6 Hz, 1H), 7.91-
7.87 (m, 2H), 7.81 (d, J=1.5 Hz, 1H), 6.57-5.56 (q, J=2.4 Hz, 1.9 Hz, 1H). MS (ESI+):
m/z 190.08 [M+H]+.
3-(1H-Pyrazol-1-yl)benzaldehyde (3d)16. According to the general procedure, the 3d
o
1
was obtained as off-white solid (0.13 g, 93%). m.p. 28-30 C. H NMR (400 MHz,
CDCl3): δ (ppm) 10.08 (s, 1H), 8.19 (t, J=1.8 Hz, 1H), 8.05-8.02 (m, 2H), 7.81-7.76 (m,
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2H), 7.64 (t, J=7.9 Hz, 1H), 6.52 (t, J=2.1 Hz, 1H). MS (ESI+): m/z 173.07 [M+H]+.
2-(1H-Pyrazol-1-yl)benzoic acid (3e) 17. According to the general procedure, the 3e
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o
was obtained as white solid (0.15 g, 98%). m.p. 128-129 C. 1H NMR (400 MHz,
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CDCl3): δ (ppm) 11.41 (br, 1H), 8.06-8.04 (dd, J=7.8 Hz, 1.1 Hz, 1H), 7.77-7.75 (m,
2H), 7.63-7.59 (m, 1H), 7.50-7.46 (t, J=7.5 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 6.49-6.48
(t, J=2.1 Hz, 1H). MS (ESI-): m/z 187.05 [M-H]-.
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Ethyl 3-(1H-Pyrazol-1-yl)benzoate (3f) 18. According to the general procedure, the
3f was obtained as yellow liquid (0.16 g, 95%). 1H NMR (400 MHz, CDCl3): δ (ppm)
8.32 (t, J=1.9 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.98-7.94 (m, 2H), 7.76 (d, J=1.6 Hz,
1H), 7.54 (t, J=7.9 Hz, 1H), 6.50 (t, J=2.0 Hz, 1H), 4.45-4.39 (q, J=14.3 Hz, 7.1 Hz,
2H), 1.42 (t, J=7.2 Hz, 3H). MS (ESI+): m/z 217.10 [M+H]+.
Methyl 4-(1H-pyrazol-1-yl)benzoate (3g) 19. According to the general procedure, the
3g was obtained as white solid (0.16 g, 96% ). m.p. 103-105 oC. 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.15-8.12 (m, 2H), 8.01 (d, J=2.4 Hz, 1H), 7.81-7.78 (m, 2H), 7.77 (d,
J=1.4 Hz, 1H), 6.51 (t, J=2.1 Hz, 1H), 3.94 (s, 3H). MS (ESI+): m/z 203.11 [M+H]+.
2-(1H-Pyrazol-1-yl)aniline (3h). 20 According to the general procedure, the 3h was
obtained as brown oil (0.10 g, 82%). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.75-7.72
(dd, J=8.6 Hz, 1.2 Hz, 2H), 7.20-7.13 (m, 2H), 6.86-6.84 (dd, J=8.0 Hz, 0.9 Hz, 1H),
6.81-6.77 (dt, J=7.7 Hz, 1.1 Hz, 1H), 6.45 (t, J=2.0 Hz, 1H), 4.63 (br, 2H). MS (ESI+):
m/z 160.09 [M+H]+.
2-(1H-Pyrazol-1-yl)benzonitrile (3i) 21. According to the general procedure, the 3i
was obtained as yellow oil (0.12 g, 89%). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.15
(d, J=2.5 Hz, 1H), 7.81-7.70 (m, 3H), 7.73-7.69 (dt, J=7.6 Hz, 1.5 Hz, 1H), 7.45-7.41
(dt, J=7.6 Hz, 1.0 Hz, 1H), 6.55 (t, J=2.1 Hz, 1H). MS (ESI+): m/z 170.10 [M+H]+.
1-(4-(1H-Pyrazol-1-yl)phenyl)ethan-1-one (3j).22 According to the general
o
procedure, the 3j was obtained as white solid (0.13 g, 90%). m.p. 93-94 C (lit. 106-
108 oC). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.08-8.05 (m, 2H), 8.02 (d, J=2.5 Hz,
1H), 7.83-7.81 (m, 2H), 7.78 (d, J=1.5 Hz, 1H), 6.52 (t, J=2.0 Hz, 1H), 2.63 (s, 3H).
MS (ESI+): m/z 187.13 [M+H]+.
1-(4-Bromo-2-nitrophenyl)-1H-pyrazole (3k)23. According to the general procedure,
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the 3k was obtained as yellow solid (0.19 g, 91%). m.p. 74-75 oC. 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.00 (d, J=2.1 Hz, 1H), 7.81-7.78 (dd, J=8.5 Hz, 2.2 Hz, 1H), 7.75 (d,
J=1.6 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 6.51 (t, J=2.1 Hz, 1H).
MS (ESI+): m/z 267.98 [M+H]+ , 269.97 [M+H]+.
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1-(4-Nitrophenyl)-1H-pyrrole (3l). 24 According to the general procedure, the 3l was
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obtained as yellow solid (51 mg, 54%). m.p. 180-182 C (lit. 179-180 C). H NMR
(400 MHz, CDCl3): δ (ppm) 8.33-8.30 (m, 2H), 7.54-7.50 (m, 2H), 7.18 (t, J=2.2 Hz,
2H), 6.43 (t, J=2.2 Hz, 2H). MS (ESI+): m/z 189.13 [M+H]+.
Ethyl 2,4-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate (3m) 25. According to the
general procedure, the 3m was obtained as yellow solid (91 mg, 47%). 1H NMR (400
MHz, CDCl3): δ (ppm) 7.47-7.36 (m, 3H), 7.26-7.23 (m, 2H), 6.48 (s, 1H), 4.33-4.28
(q, J=14.2 Hz, 7.1 Hz, 2H), 2.41 (s, 3H), 2.28 (s, 3H), 1.37 (t, J=7.1 Hz, 3H). MS (ESI+):
m/z 244.18 [M+H]+.
1-(4-Nitrophenyl)-1H-pyrazole-4-carbaldehyde (3o).26 According to the general
procedure, the 3o was obtained as yellow solid (0.16 g, 93%). m.p. 158-160 oC (lit. 84
oC). 1H NMR (400 MHz, CDCl3): δ (ppm) 10.02 (s, 1H), 8.55 (s, 1H), 8.41-8.38 (m,2
H), 8.23 (s, 1H), 7.97-7.94 (m, 2H). MS (ESI+): m/z 218.34 [M+H]+.
27
Ethyl 1-phenyl-1H-pyrazole-4-carboxylate (3p).
According to the general
procedure, the 3p was obtained as brown solid (0.16 g, 91%). m.p. 90-91 oC (lit. 96-99
oC). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.41 (s, 1H), 8.10 (s, 1H), 7.72-7.70 (m, 2H),
7.49 (t, J=7.6 Hz, 2H), 7.36 (t, J=7.2 Hz, 1H), 4.37-4.32 (q, J=14.3 Hz, 7.1 Hz, 2H),
1.38 (t, J=7.1 Hz, 3H). MS (ESI+): m/z 217.09 [M+H]+.
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2-Methyl-1-(4-nitrophenyl)-1H-imidazole (3q).
According to the general
o
procedure, the 3q was obtained as light yellow solid (0.14 g, 88%). m.p. 128-130 C
(lit. 140-142 oC). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.38 (d, J=9.0 Hz, 2H), 7.78
(d, J=9.0 Hz, 2H), 7.45 (d, J=1.3 Hz, 2H), 7.0 (d, J=1.2 Hz, 1H), 2.38 (s, 3H). MS
(ESI+): m/z 204.11 [M+H]+.
4-Methyl-1-(4-nitrophenyl)-1H-imidazole (3r) and 5-Methyl-1-(4-nitrophenyl)-
1H-imidazole (3s) 29. According to the general procedure, the 3r and 3s was obtained
o
1
as light yellow solid (0.14 g, 89%). m.p. 125-133 C (mixture solid). H NMR (3r:
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3s=12:1, 400 MHz, CDCl3): δ (ppm) 8.42-8.39 (m, 0.18 H), 8.38-8.34 (m, 2H), 7.92 (d,
J=1.0 Hz, 1H), 7.67 (br, 0.07 H), 7.56-7.52 (m, 2H), 7.52-7.49 (m, 0.17H), 7.10 (s, 1H),
6.99 (br, 0.07 H), 2.32 (d, J=0.6 Hz, 3H), 2.26 (s, 0.26 H). MS (ESI+): m/z 204.09
[M+H]+.
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1-(4-Nitrophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (3t). According to
the general procedure, the 3t was obtained as yellow solid (0.14 g, 65%). m.p. 150-152
oC. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.09 (s, 1H), 9.12 (s, 1H), 8.59-8.56 (dd,
J=7.8 Hz, 1.6 Hz, 1H), 8.53-8.52 (dd, J=7.8 Hz, 1.6 Hz, 1H), 8.51-8.47 (m, 2H), 8.38-
8.34 (m, 2H), 7.51-7.48 (q, J=7.8 Hz, 4.8 Hz, 1H). 13C {1H} NMR (400 MHz, CDCl3):
δ (ppm) 184.8, 150.7, 146.1, 142.3, 135.9, 131.7, 126.0, 125.2, 124.0, 123.8, 119.0,
118.7. MS (ESI+): m/z 268.07 [M+H]+.
22
1-(4-Nitrophenyl)-1H-indole-3-carbaldehyde (3u).
According to the general
o
procedure, the 3u was obtained as yellow solid (0.20 g, 95%). m.p. 251-252 C (lit.
251-252 oC). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.09 (s, 1H), 8.77 (s, 1H), 8.50
(d, J=9.0 Hz, 2H), 8.26-8.24 (m, 1H), 8.04 (d, J=9.0 Hz, 2H), 7.73-7.71 (m, 1H), 7.45-
7.38 (m, 2H). MS (ESI+): m/z 267.06 [M+H]+.
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2-((4-nitrophenyl)thio)-1H-benzo[d]imidazole(3v).
According to the general
o
1
procedure, the 3v was obtained as yellow solid (0.21 g, 97%). m.p. 166-169 C. H
NMR (400 MHz, DMSO-d6): δ (ppm) 13.22 (br, 1H), 8.22 (d, J=7.6 Hz, 2H), 7.70-7.51
(m, 4H), 7.30-7.24 (m, 2H). ESI-MS: m/z 272.04 [M+H]+.
1-(4-Nitrophenyl)-1H-indol-5-ol (3w). According to the general procedure, the 3w
o
1
was obtained as yellow solid (0.18 g, 89%). m.p. 188-191 C. H NMR (400 MHz,
CDCl3): δ (ppm) 8.40 (d, J=9.0 Hz, 2H), 7.67 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.8 Hz, 1H),
7.36 (d, J=3.3 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 6.87-6.84 (dd, J=8.8 Hz, 2.4 Hz, 1H),
6.66 (d, J=3.2 Hz, 1H), 4.60 (br, 1H). 13C {1H} NMR (400 MHz, DMSO-d6): δ (ppm)
152.8, 145.2, 144.2, 131.5, 129.2, 128.6, 125.8, 122.8, 113.2, 111.9, 105.8, 105.7. MS
-
(ESI-): m/z 253.06 [M-H]-. HRMS (ESI): C14H9N2O3 [M-H]- calcd for 253.0619; found:
253.0631.
1-(4-Methoxyphenyl)-1H-indole-2-carboxylic acid (3x). 31 According to the general
procedure, the 3x was obtained as white solid (0.18 g, 84% ). m.p. 208-211 oC. 1H NMR
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(400 MHz, CDCl3): δ (ppm) 7.74-7.72 (dt, J=8.0 Hz, 1.0 Hz, 1H), 7.54 (d, J=0.8 Hz,
1H), 7.31-7.26 (m, 2H), 7.24-7.23 (m, 1H), 7.21-7.17 (m,1 H), 7.09-7.06 (m, 1H), 7.03-
6.99 (m, 2H), 3.90 (s, 3H). MS (ESI-): m/z 266.09 [M-H]-.
9
1-(3-Carboxyphenyl)-1H-indole-2-carboxylic acid (3y). 32According to the general
procedure, the 3y was obtained as white solid (0.22 g, 98%). m.p. 245-246 oC. 1H NMR
(400 MHz, DMSO-d6): δ (ppm) 8.07-8.02 (m, 1H), 7.82-7.81 (m, 1H), 7.80-7.77 (dt,
J=7.9 Hz, 1.1 Hz, 1H), 7.70-6.63 (m, 2H), 7.44 (d, J=0.6 Hz, 1H), 7.32-7.28 (m, 1H),
7.22-7.18 (m, 1H), 7.05-7.03 (m, 1H). 13C {1H} NMR (400 MHz, DMSO-d6): δ (ppm)
167.2, 162.3, 140.3, 138.9, 132.6, 132.3, 130.3, 129.9, 129.1, 128.7, 126.4, 126.0, 123.0,
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121.8, 111.9, 111.4. MS (ESI-): m/z 280.08 [M-H]-. HRMS (ESI): C16H10NO4 [M-H]-
calcd for 280.0615; found: 280.0612.
32
1-(4-Nitrophenyl)-1H-indole-2-carboxylic acid (3z). According to the general
procedure, the 3z was obtained as yellow solid (0.22 g, 98%). m.p. 243-244 oC (lit. 263-
264 oC). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 13.02 (br, 1H), 8.40-8.36 (m, 2H),
7.81-7.79 (d, J=7.9 Hz, 1H), 7.74-7.70 (m, 2H), 7.50 (s, 1H), 7.36-7.32 (m, 1H), 7.24
(t, J=7.2 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H). MS (ESI-): m/z 281.07 [M-H]-.
33
1-Phenyl-1H-imidazole (3aa). According to the general procedure, the 3aa was
1
obtained as colorless liqud (0.10 g, 88% ). H NMR (400 MHz, DMSO-d6): δ (ppm)
8.28 (s, 1H), 7.77 (s, 1H), 7.67-7.64 (m, 2H), 7.54-7.50 (m, 2H), 7.37 (t, J=7.4 Hz, 1H),
7.14 (s, 1H). MS (ESI+): m/z 145.04 [M+H]+.
1-(4-Methoxyphenyl)-1H-imidazole (3ab). 28 According to the general procedure,
the 3ab was obtained as white solid (96 mg, 69% ). m.p. 55-57 oC. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.75 (s, 1H), 7.30 (d, J=9.0 Hz, 2H), 7.20 (d, J=7.6 Hz, 2H),6.97 (t,
J=6.8 Hz, 2H). MS (ESI+): m/z 175.07 [M+H]+.
1-(2-Methoxyphenyl)-1H-imidazole (3ac). 34 According to the general procedure,
the 3ac was obtained as colorless liqud (88 mg, 63% ). 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.78 (s, 1H), 7.37-7.33 (m, 1H), 7.28-7.26 (dd, J=7.7 Hz, 1.5 Hz, 1H), 7.20-7.16
(m, 2H), 7.06-7.01 (m, 2H), 3.84 (s, 3H). MS (ESI+): m/z 175.06 [M+H]+.
3-(1H-Imidazol-1-yl)aniline (3ad). 6a According to the general procedure, the 3ad
o
1
was obtained as white solid (92 mg, 72% ). m.p. 110-111 C. H NMR (400 MHz,
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CDCl3) δ (ppm): 7.82 (s, 3H), 7.26-7.17 (m, 3H), 6.67-6.74 (m, 1H), 6.68-6.64 (m, 2H),
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3.66 (br, 2H). MS (ESI+): m/z 160.05 [M+H]+.
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1-(2-(1H-Imidazol-1-yl)phenyl)ethan-1-one (3ae).
According to the general
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procedure, the 3ae was obtained as white solid (0.13 g, 85% ). m.p. 183-184 C. H
NMR (400 MHz, CDCl3) δ (ppm): 7.62-7.60 (dd, J=7.4 Hz, 0.4 Hz, 1H), 7.37-7.33 (m,
1H), 7.27-7.19 (m, 3H), 7.13 (s, 1H), 1.88 (s, 3H). MS (ESI+): m/z 187.09 [M+H]+.
1-(Thiophen-2-yl)-1H-imidazole (3af). 34 According to the general procedure, the
3af was obtained as colorless liqud (97 mg, 81%). 1H NMR (400 MHz, CDCl3) δ (ppm):
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7.74 (s, 3H), 7.19-7.11 (m, 3H), 7.00-6.96 (m, 2H). MS (ESI+): m/z 151.03 [M+H]+.
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2-Methyl-1-phenyl-1H-benzo[d]imidazole (3ag).
According to the general
procedure, the 3ag was obtained as white solid (90 mg, 54%). m.p. 62-65 oC. 1H NMR
(400 MHz, CDCl3): δ (ppm) 7.76 (d, J=7.9 Hz, 1H), 7.60-7.56 (m, 2H), 7.54-7.49 (m,
1H), 7.38-7.35 (m, 2H), 7.29-7.24 (m, 1H), 7.21-7.17 (m, 1H), 7.14-7.12 (m, 1H), 2.51
(s, 3H). MS (ESI+): m/z 209.11 [M+H]+.
5-(4-Nitrophenoxy)-1-(4-nitrophenyl)-1H-indole (3ah). According to the general
o
1
procedure, the 3ah was obtained as yellow solid (0.16 g, 20%). m.p. 161-162 C. H
NMR (400 MHz, CDCl3): δ (ppm) 8.80-8.42 (m, 2H), 8.21-8.18 (m, 2H), 7.73-7.69 (m,
2H), 7.68 (d, J=8.9 Hz, 1H), 7.47-7.42 (dd, J=17.8 Hz, 3.3 Hz, 2H), 7.06-7.03 (dd,
J=9.0 Hz, 2.4 Hz, 2H), 7.03-7.00 (m, 2H), 6.77 (d, J=3.2 Hz, 1H). 13C {1H} NMR (400
MHz, CDCl3): δ (ppm) 164.4, 149.3, 145.5, 144.8, 142.4, 133.0, 131.1, 128.8, 125.9,
125.6, 123.5, 116.9, 116.5, 113.1, 112.0, 106.1. HRMS (ESI): Not responding.
1,4-Di(1H-pyrazol-1-yl)benzene (3ai). 37 According to the general procedure, the 3ai
o
o
1
was obtained as white needle solid (0.13 g, 75%). m.p. 103-104 C (lit. 180 C). H
NMR (400 MHz, CDCl3): δ (ppm) 7.95 (d, J=1.8 Hz, 2H), 7.80 (s, 4H), 7.75 (d, J=1.3
Hz, 2H), 6.50 (t, J=1.8 Hz, 2H). MS (ESI+): m/z 211.13 [M+H]+.
38
1-(4-(Trifluoromethyl)phenyl)-1H-pyrazole (3aj).
According to the general
procedure, the 3aj was obtained as white solid (0.12 g, 72%). m.p. 42-44 oC (lit. 93 oC).
1H NMR (400 MHz, CDCl3): δ (ppm) 8.03 (br, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.78 (br,
1H), 7.72 (d, J=8.4 Hz, 2H), 6.54 (br, 1H). MS (ESI+): m/z 213.07 [M+H]+.
3-(1H-Pyrazol-1-yl)benzonitrile (3ak). 39 According to the general procedure, the
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3ak was obtained as yellow oil (0.11 g, 85%). 1H NMR (400 MHz, CDCl3): δ (ppm)
8.20 (t, J=1.8 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.77-7.73 (m, 2H),
7.55 (t, J=7.9 Hz, 1H), 6.52 (t, J=2.0 Hz, 1H). MS (ESI+): m/z 170.06 [M+H]+.
1-(3-Fluorophenyl)-1H-pyrazole (3al). 40 According to the general procedure, the
3al was obtained as colorless oil (91 mg, 70%). 1H NMR (400 MHz, CDCl3): δ (ppm)
7.97 (br, 1H), 7.75 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.44-7.38 (m, 1H), 7.01-6.97 (m,
1H), 6.52 (br, 1H). MS (ESI+): m/z 163.07 [M+H]+.
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1,1'-(4-Nitro-1,2-phenylene)bis(1H-pyrazole) (3am). According to the general
procedure, the 3am was obtained as yellow solid (0.17 g, 81%). m.p. 65-66 oC (lit. 93
oC). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.55 (d, J=2.5 Hz, 1H), 8.38-8.35 (dd, J=8.9
Hz, 2.6 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.80-7.76 (dd, J=12.7 Hz, 1.6 Hz, 2H), 7.16
(d, J=2.4 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 6.42 (t, J=2.2 Hz, 1H), 6.36 (t, J=2.4 Hz,
13
1H). C {1H} NMR (400 MHz, CDCl3): δ (ppm) 146.7, 142.5, 142.3, 139.4, 133.6,
130.7, 130.3, 127.0, 123.9, 123.4, 109.0, 108.6. MS (ESI+): m/z 256.10 [M+H]+. HRMS
(ESI): C12H9N5O2Na+ [M+Na]+ calcd for 278.0648; found: 278.0663.
1-(4-Fluorophenyl)-1H-indole-2-carboxylic acid (3an). 41 According to the general
o
1
procedure, the 3an was obtained as white solid (0.16 g, 79%). m.p. 188-190 C. H
NMR (400 MHz, CDCl3): δ (ppm) 7.75-7.73 (dt, J=8.4 Hz, 0.9 Hz, 1H), 7.56 (d, J=0.7
Hz 1H), 7.33-7.17 (m, 3H), 7.23-7.17 (m, 3H), 7.07-7.04 (m, 1H). MS (ESI-): m/z
254.06 [M-H]-.
1-(4-Carboxyphenyl)-1H-indole-2-carboxylic acid (3ao). According to the general
procedure, the 3ao was obtained as off-white solid (0.19 g, 85%). m.p. 185-186 oC. 1H
NMR (400 MHz, CDCl3): δ (ppm) 8.29-8.26 (m, 2H), 7.71-7.63 (m, 4H), 7.40 (d, J=3.3
Hz, 1H), 7.30-7.28 (m, 1H), 7.23-7.19 (m, 1H), 6.75 (d, J=3.3 Hz, 1H). MS (ESI-): m/z
280.07 [M-H]-.
Ethyl 1-(2-cyanophenyl)-1H-pyrazole-4-carboxylate (3ap). According to the
general procedure, the 3ap was obtained as yellow solid (0.17 g, 90%). m.p. 68-70 oC.
1H NMR (400 MHz, CDCl3): δ (ppm) 8.54 (d, J=0.4 Hz, 1H), 8.19 (s, 1H), 7.84-7.81
(m, 1H), 7.78-7.72 (m, 2H), 7.54-7.50 (m, 1H), 4.38-4.33 (q, J=14.3 Hz, 7.1 Hz, 2H),
1.38 (t, J=7.1 Hz, 3H). 13C {1H} NMR (400 MHz, CDCl3): δ (ppm) 162.3, 143.1, 141.2,
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134.6, 134.1, 132.8, 128.4, 124.7, 117.9, 116.2, 106.3, 60.7, 14.4. MS (ESI+): m/z
242.09 [M+H]+. HRMS (ESI): C13H11N3O2Na+ [M+Na]+ calcd for 264.0743; found:
264.0753.
9
4,4'-Dinitro-1,1'-biphenyl (3aq). 42 According to the general procedure, the 3aq was
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obtained as yellow solid (59 mg, 30%). m.p. 237-238 C (lit. 238-239 °C). H NMR
(400 MHz, CDCl3): δ (ppm) 8.23-8.19 (m, 4H), 7.51-7.48 (m, 4H).
43
1-(2-(Allyloxy)phenyl)-1H-pyrazole (3ar). According to the general procedure,
the 3ar was obtained as colorless liquid (0.24 g, 30%). 1H NMR (400 MHz, CDCl3): δ
(ppm) 8.09 (s, 1H), 7.77-7.74 (dd, J=7.9 Hz, 1.4 Hz, 1H), 7.73 (s, 1H), 7.30-7.25 (m,
1H), 7.10-7.03 (m, 2H), 6.44 (s, 1H), 6.06-5.96 (m, 1H), 5.39-5.33 (m, 1H), 5.29-5.25
(m, 1H), 4.61-4.59 (dt, J=5.1 Hz, 1.5 Hz, 2H). MS (ESI+): m/z 201.12 [M+H]+.
Associated content
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
at DOI:
1H NMR and ESI-MS spectra for all products; 1H NMR, 13C NMR, ESI-MS and HRMS
spectra for new products.
Author information
Corresponding Author
*E-mail: spucgl@163.com (GL Chen); ynbnwy@163.com (Y Wu)
ORCID
Guoliang Chen: 0000-0003-3674-5226
Qifan Zhou: 0000-0002-5738-3511
Fangyu Du: 0000-0001-7975-7775
Notes
The authors declare no competing financial interest.
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Acknowledgments
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This work was financially supported by Liaoning Provincial Natural Science
Foundation of China (No. 201602707), Discipline Construction Program of Shenyang
Pharmaceutical University (No. 52134606) and Program of Yunnan Science and
Technology Department (No. 2017jkys03).
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