One-Pot, Multistep Reactions for the Modular Synthesis of N, N′-Diarylindazol-3-ones

Article abstract of DOI:10.1021/acs.joc.8b02548

The pot-economic synthesis of N,N′-diarylindazol-3-ones has been developed using readily available isatoic anhydrides, aryl amines, and aryl boronic acids. A Cu-catalyzed oxidative C-N cross-coupling and dehydrogenative N-N formation sequence under an air atmosphere affords indazol-3-one derivatives in good to excellent yields. Such process merges well with the preceding decarboxylative amination reaction, resulting in a more modular and straightforward approach.

Full text of DOI:10.1021/acs.joc.8b02548

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Note
One-Pot, Multi-Step Reactions for Modular
Synthesis of N,N’-Diarylindazol-3-ones
Shuai Liu, Liang Xu, and Yu Wei
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02548 • Publication Date (Web): 26 Dec 2018
Downloaded from http://pubs.acs.org on January 2, 2019
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The Journal of Organic Chemistry
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One-Pot, Multi-Step Reactions for Modular Synthesis of N,N’-
Diarylindazol-3-ones
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Shuai Liu, Liang Xu, Yu Wei*
School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of Chemical Engineering of
Xin-jiang Bingtuan, Shihezi University
Ar1NH
Ar2B(OH)
(i) decarboxylative amination, +
2
O
O
(ii) Cu-catalyzed C-N cross-coupling, +
2
(iii) Cu-catalyzed dehydrogenative N-N formation
N
N
Ar2
Ar1
O
O
NH
One-pot, two-step or three-step synthesis
31 examples, up to 94% yield
ABSTRACT: Pot-economic synthesis of N,N’-diarylindazol-3-ones has been developed using readily available isatoic
anhydrides, aryl amines and aryl boronic acids. A Cu-catalyzed oxidative C−N cross-coupling and dehydrogenative N−N
formation sequence under air atmosphere affords indazol-3-one derivatives in good to excellent yields. Such process
merges well with the preceding decarboxylative amination reaction, resulting in a more modular and straightforward
approach.
Indazol-3-one derivatives represent an important class of nitrogen heterocycles. They possess unique bioactivity and
have potential medicinal application.1 The main methods for the assembly of indazol-3-one skeleton include two types of
intramolecular ring closure pathways. Conventionally, copper-catalyzed Ullmann2 or metal-free3 condensation was
employed to assemble this skeleton through the use of hydrazine and its derivatives that may present considerable
hazards, with the N−N bond already in place. Another approach constructed the N−N bond during cyclization process,
including oxidative dehydrogenative coupling of N−H4 and cyclization of nitro and nitroso groups.5,6 As for the synthesis
of N,N’-diarylindazol-3-ones, only the oxidative dehydrogenative coupling approach was workable from prefabricated
N,N’-diaryl-2-aminobenzamides (Scheme 1A).4c Such strategy suffered from multiple synthetic steps and pre-
functionalized starting materials. Thus, the development of a more straightforward and efficient approach is highly
desirable.
Combining traditional purification-dependent stepwise catalyzed reactions into one-pot strategies, which incorporate
multiple synthetic transformations and bond-forming steps in a single vessel without isolation and purification of any
intermediates represent a practical means to approach atom economy and green chemistry.7 In this context, Cu-catalyzed
oxidative C−N cross-coupling reactions, also known as Chan-Evans-Lam (CEL) reactions, natively have the potential to
match up with aerobic Cu-catalyzed cross dehydrogenative cyclization reactions. Then, elegant integration of these two
processes should benefit the quick construction of heterocycles. However, limited success has been achieved in this field,
relative to the wide application of Cu-catalyzed one-pot sequential, cascade or tandem cyclization reactions.8 In fact, most
of Cu-catalyzed one-pot cyclization reactions were developed based on Ullmann reactions.9 To our knowledge, only
benzimidazole10 and acridone11 derivatives have been constructed via the oxidative CEL coupling/dehydrogenation
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process. With these issues in mind, we became interested in applying this protocol into the synthesis of indazol-3-ones.
Herein, we demonstrated the one-pot modular assembly of N,N’-diarylindazol-3-ones from readily available isatoic
anhydrides, aryl amines and aryl boronic acids. (Scheme 2).
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2
3
4
Scheme 1. (A) Representative approaches to form indazol-3-one derivatives; (B) One-pot Cu-catalyzed oxidative Chan-
5
6
7
Evans-Lam coupling/dehydrogenation sequence.
O
8
9
R1
(A)
OH
NH
NO2
or
+ R1NH2
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NO2
O
Oxidative
dehydrogenation
R1
Ullmann
coupling
O
R1
NH
O
X
R1
N
N
NH
R2
or
SNAr
N
R2
NH
R2
O
OH
CO2Et
OMe
NH
or
N
R1
N
R2
N
O
R1, R2 = H, alkyl, or aryl
R2
(i) Cu(OAc)2, air, 50 oC
(ii) O2, 120 o
(B)
NH
N
N
(HO)2B
C
+
+
NH
R
H
R
O
O
Cu(NO3)2, O2, 130 o
C
(HO)2B
H
CH3
O
O
N
H
NH2
C
H
N
Scheme 2. One-pot sequential synthesis of N,N’-diarylindazol-3-ones.
(i) Ar1-NH2 (1.0 equiv), 70 o
(ii) Ar2-B(OH)2 (1.5 equiv)
CuCl (20 mol%), rt
C
O
O
(iii) DMSO, 120 o
C
Ar1
O
N
N
Ar2
O
NH
decarboxylative
amination
dehydrogenative
N-N formation
O
Ar1
Chan-Evans-Lam
C-N cross-coupling
O
Ar1
NH
NH
NH
Ar2
NH2
To examine the feasibility of the proposed strategy, N-phenyl-2-aminobenzamide 1a and phenylboronic acid 2a were
used as model reaction components. The reactions were carried out in open flasks using air as oxidant. After screening of
catalysts, additives, solvents and operation procedures, we discovered a Cu-catalyzed sequential C−N12 and N−N
formation13 process afforded the target product 3a in 94% yield (Table 1, Entry 6). Firstly, the reactants, 0.2 equivalent of
CuCl and 0.5 equivalent of Et3N were mixed in MeOH and stirred for 3 hours at room temperature. Then, simple addition
o
of DMSO and adjustment of reaction temperature to 120 C gave 94% of 3a after stirring for 4 hours and purification by
column chromatography. Although 1,4-benzodiazepine skeleton had been synthesized via oxidative C−N bond formation
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from 2-(arylamino)benzamides,14 such type of product was not observed with indazol-3-one structure formed
preferentially.
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7
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9
Although the sequence worked more or less in the present of several common copper salts (54%-94%, Entries 1-6),
cuprous halide generally afforded more product than their cupric analogs (Entry 6 vs. Entry 3 and Entry 5 vs. Entry 2). In
the meanwhile, Cu(OAc)2 was found to be quite ineffective. When inorganic base K2CO3 was used in place of Et3N, no
target product can be observed after the reaction sequence (Entry 7). It was supposed that organic bases, such as TEA and
pyridine, might act as not only bases but also ligands for copper catalysts. A slightly decreased yield was obtained when
the solvent of the second step was changed to DMF (Entry 10). Notably, when only MeOH or DMSO was used as solvent
for both steps, significant decreased yields were obtained (Entry 11 and 12), indicating the different demand of solvent for
C−N and N−N formation steps.
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Table 1. Optimization of reaction conditions[a]
O
O
(i) catalyst (20 mol%), base (50 mol%)
MeOH (4.0 mL), rt, 3 h
B(OH)2
Ph
NH
N
Ph
+
N
NH2
(ii) DMSO (1.0 mL)
120 oC, 4 h
Ph
2a
3a
1a
Entry
1
2
3
4
5
6
7
8
9
10
11
12
Catalyst
Cu(OAc)2
CuBr2
CuCl2
CuI
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
Base
Et3N
Et3N
Et3N
Et3N
Solvent
Yields (%)[b]
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
MeOH/DMSO
MeOH/DMF
MeOH[c]
10
61
55
54
82
94
N.R.
17
68
89
17
Et3N
Et3N
K2CO3
DBU
pyridine
Et3N
Et3N
Et3N
CuCl
DMSO
28
[a] Reaction conditions: 0.2 mmol 1a (1.0 equiv), 0.3 mmol 2a (1.5 equiv), 0.04 mmol copper catalyst (20 mol%), 0.1 mmol base (0.5 equiv), MeOH
(4.0 mL), rt, open flask, 3 h. Then DMSO (1.0 mL), 120 oC, 4h. [b] Isolated yields. [c] 70 oC.
The substrate scope of this protocol was subsequently investigated under the optimal conditions. The results
were summarized in Scheme 3. A variety of N-phenyl-2-aminobenzamides were converted into the desired
products in moderate to excellent yields. Aryl boronic acids containing electron-donating/withdrawing groups
were all compatible with these reaction conditions, including methyl (3b and 3d), methoxyl (3c and 3e),
methylthio (3f), trifluoromethyl (3j), alkenyl (3k), trimethylsilyl (3l) and carboxylic ester (3m). The electronic
nature of the substituent had no obvious influence on the outcome of the reactions. The halogen atoms (such as
Cl and Br) on the phenyl rings of the boronic acids, were also well tolerated and no competitive Cu-catalyzed
Ullmann reactions were observed, which enabled further decoration of the obtained products. The variation of
2-aminobenzamide component with 4-Me, 3-OMe or 3-NO2 led to 92%,87%, 69% yield of the corresponding
products (3n, 3s, 3r) respectively. The halogen atoms on the 2-aminobenzamide moiety were also well tolerated
(3o, 3p, 3q). The heteroaryl boronic acids and alkyl boronic acids were not suitable starting materials for this
one-pot procedure, probably due to their incompatibility towards CuCl-catalyzed C
such conditions.
−
N coupling reactions under
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As illustrated in Scheme 3, the substituent on amide group remained as phenyl. When we tried to change the
phenyl to other aryl groups. It occurred to us to combine the synthesis of N-aryl-2-aminobenzamides with the
established Cu-catalyzed CEL coupling/dehydrogenation sequence. Such one-pot, three-step protocol might
further enhance the operation convenience and enable modular assembly of disubstituted indazol-3-ones.
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2
3
4
5
6
7
Scheme 3. Substrate scope of Cu-catalyzed one-pot construction of indazol-3-ones.
8
9
(i) CuCl (20 mol%)
O
O
B(OH)2
Et3N (50 mol%)
Ph
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11
12
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NH
MeOH (4.0 mL), rt, 3 h
N
+
N
NH2
R1
R1
R2
(ii) DMSO (1.0 mL)
120 oC, 4 h
R2
0.2 mmol
1.5 equiv
O
O
O
O
N
Ph
N
Ph
N
Ph
N
N
N
N
N
Me
3c
3a
, 72%
, 94%
3d
, 89%
3b
, 78%
Me
OMe
Ph
O
O
O
O
N
Ph
N
Ph
N
N
Ph
N
N
N
N
OMe
3e
, 81%
3h
, 81%
3f
3g
, 82%
O
, 85%
Cl
SMe
F
O
O
O
N
Ph
N
Ph
N
Ph
N
Ph
N
N
N
N
Br
3i
3l
, 87%
, 88%
3j
SiMe3
, 83%
3k
, 69%
CF3
O
O
O
O
Cl
N
Ph
N
Ph
N
Ph
N Ph
N
N
N
N
Me
Cl
3o
3p
, 87%
3n
, 91%
3m
, 92%
O2N
, 62%
Br
COOMe
O
O
O
MeO
N
Ph
N Ph
N
Ph
N
N
N
3q
, 79%
3r
, 69%
3s
, 87%
Previously, a Cu-catalyzed Ullmann protocol had been identified to enable the arylation of amide groups in 2-
aminobenzamides, so a Cu-catalyzed sequential Ullmann/CEL/dehydrogenation reaction was firstly tested.
However, no target product could be obtained after such sequence maybe due to the incompatibility between
Ullmann and CEL conditions. The preparation of N-aryl-2-aminobenzamide could also be easily achieved by
metal-free decarboxylative amination of isatoic anhydrides with aryl amines. The metal-free procedure, in
combination with the elimination of by-product CO2, should be helpful to relieve the complexity and
incompatibility problem of the desired one-pot reactions. Fortunately, this decarboxylative amination reaction
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could be combined well with the following two steps, affording the target product 3a in 68% yield with two
phenyl groups derived from phenylamine and phenylboronic acid separately.
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3
4
5
6
7
8
Scheme 4. Substrate scope of one-pot, three-step construction of indazol-3-ones.
O
O
(i) Ar1-NH2 (1.0 equiv), EtOAc, 70 o
C
O
N
Ar1
N
Ar2
(ii) Ar2-B(OH)2 (1.5 equiv), CuCl (20 mol%)
Et3N (50 mol%), MeOH (4.0 mL), rt
O
NH
(iii) DMSO, 120 o
C
0.2 mmol
9
O
O
10
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O
O
N
N
N
Me
N
N
N
N
N
Me
Br
3a
, 68% (68%)
O
4a
, 71% (68%)
OMe
4b
, 58% (54%)
O
4c
, 52% (70%)
O
O
N
N
OMe
N
N
N
Cl
N
N
Cl
N
OMe
, 40% (44%)
Cl
Cl
4g
4f
, 46% (63%)
O
4e
4d
, 41% (59%)
, 65% (70%)
O
O
O
N
N
Me
N
N
F
N
N
N
N
Cl
OMe
4j,
20% (30%)
4k
, 42% (55%)
4h
, 30% (42%)
4i
, 70% (75%)
Scheme 5. Further exploration.
O
O
B(OH)2 (i) CuCl (20 mol%), Et3N (50 mol%)
MeOH (60 mL), rt, 12 h
Ph
NH
N
Ph
+
N
NH2
(ii) DMSO (10 mL)
120 oC, 12 h
Ph
1.5 equiv
3 mmol
3a, 73%, 626 mg
O
O
(i) Ar-NH2 (1.0 equiv), EtOAc, 70 oC, 24 h
O
N
Ph
(ii) Ar-B(OH)2 (3.0 equiv), CuCl (20 mol%)
Et3N (50 mol%), MeOH (60 mL), rt, 12 h
(iii) DMSO (10 mL), 120 oC, 12 h
N
O
NH
Ph
3 mmol
3a, 65%, 558 mg
O
Ph-B(OH)2 (3.0 equiv)
O
(i) CuCl (40 mol%), Et3N (1.0 equiv)
N
N
HN
MeOH (4.0 mL), rt, 3 h
O
NH2
O
N
HN
H2N
Ph
(ii) DMSO (1.0 mL)
120 oC, 4 h
N
Ph
68%
0.1 mmol
Substrate scope of such protocol was then explored (Scheme 4). Generally, aryl amines with electron-donating
groups gave better yields than those ones bearing electron-withdrawing groups, when the use of aryl boronic
acid remained unchanged (4a: 71%, 4b: 58%, 4f: 46%). In contrast, electron-rich boronic acid gave relative lower
yield (4f vs. 4g). Therefore, the combination of electron-deficient aryl amines and electron-rich boronic acid led
to significant decreased yields, compared with the yield of 3a (4g: 40%, 4h: 30%). Additionally, alkyl amines were
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also tested. While benzylamine led to a greatly decreased yield (4j: 20%), β-phenylethylamine could participate
in this one-pot sequence and afforded 4k in 42% yield. To improve the efficiency, additional CuBr catalyst could
be added to the reaction mixture after the second step, along with the addition of solvent DMSO. Isolated yields
could be increased by 5-18% yield (the yields in parenthesis in Scheme 4) based on different substrate
combinations.
1
2
3
4
5
6
7
8
9
In addition, this one-pot protocol proved to be readily scalable. Simple amplification of the synthesis of 3a
without further optimization to a gram scale afforded 0.63 gram of product (73% yield, Scheme 5). Three-step
synthesis was also easily amplified, in spite of the need of a larger amount of boronic acid. When a compound
containing two N-aryl-2-aminobenzamide fragments was used as the starting material, two C−N bonds and two
N−N bonds could be constructed simultaneously, affording final product in 68% yield.
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In summary, this one-pot synthetical sequence enables fast modular assembly of indazol-3-one skeleton from
readily available isatoic anhydrides, aryl amines and aryl boronic acids. Such pot-economical protocol
circumvents isolation and purification processes and complements the existing synthetical methods of indazol-3-
one derivatives. Furthermore, this disclosed methodology is expected to shed lights on developing other one-pot
sequential, cascade or tandem transformations, which make best use of CEL C−N coupling reactions.
EXPERIMENTAL SECTION
General Information.
Unless otherwise noted, all reactions were carried out under an air atmosphere. Analytical thin-layer
chromatography (TLC) was performed on glass plates coated with 0.25 mm 230–400 mesh silica gel containing a
fluorescent indicator. Visualization was accomplished by exposure to a UV lamp. All the products in this article
are compatible with standard silica gel chromatography. Column chromatography was performed on silica gel
(200–300 mesh) using standard methods.
NMR spectra were measured on a Bruker Ascend 400 spectrometer and chemical shifts (δ) are reported in
1
parts per million (ppm). H NMR spectra were recorded at 400 MHz in NMR solvents and referenced internally
to corresponding solvent resonance, and 13C NMR spectra were recorded at 101 MHz and referenced to
corresponding solvent resonance. Coupling constants are reported in Hz with multiplicities denoted as s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). Infrared spectra were collected on a
Thermo Fisher Nicolet 6700 FT-IR spectrometer using ATR (Attenuated Total Reflectance) method. Absorption
maxima (ν max) are reported in wavenumbers (cm-1). High resolution mass spectra (HRMS) were acquired on
Thermo Scientific LTQ Orbitrap XL with an ESI source.
Commercial reagents including N-phenyl-2-aminobenzamide 1a and solvent were purchased from Adamas, J&K,
Energy, Sigma-Aldrich, Alfa Aesar, Acros Organics, TCI and used as received unless otherwise stated.
Preparation of 1n, 1o, 1p, 1q, 1r, and 1s.
According to a literature procedure,15 1n, 1o and 1p were prepared via Cu-catalyzed C−N cross coupling
reactions. A Schlenk tube was charged with CuI (9.7 mg, 0.050 mmol, 5.0 mol%), 2-aminobenzamide (1.2 mmol),
K2CO3 (276 mg, 2.0 equiv), evacuated and backfilled with nitrogen. N,N'-dimethylethylenediamine (11 µL, 0.10
mmol, 10 mol%), bromobenzenes (1.0 mmol) and toluene (1.0 mL) were then added under nitrogen. The Schlenk
tube was sealed and the reaction mixture was stirred in an oil bath at 110 °C for 22 hours.
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2-amino-4-methyl-N-phenylbenzamide(1n). Follow above-mentioned procedure, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 8:1. 1n was obtained as yellow solid (160.5
mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.71 (br, 1H), 7.55 (dd, J = 8.6, 1.0 Hz, 2H), 7.36 (m, 3H), 7.16 – 7.10 (m, 1H),
6.53 (m, 2H), 5.50 (br, 2H), 2.28 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.6, 149.2, 143.4, 138.0, 129.1, 127.1, 124.4,
120.5, 118.1, 117.9, 113.5, 21.5. Melting point(oC): 107.1-108.8. HRMS (ESI) m/z calcd for C14H15N2O+ (M+H)+ 227.1179,
found 227.1177. IR (cm-1): 3462, 3278, 2914, 1525, 1440, 1258, 746, 690.
8
9
2-amino-4-chloro-N-phenylbenzamide (1o). Follow above-mentioned procedure, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 8:1. 1o was obtained as yellow solid (161.1
mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.67 (br, 1H), 7.54 (dd, J = 8.6, 1.0 Hz, 2H), 7.41 – 7.33 (m, 3H), 7.18 – 7.13
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(m, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.66 (dd, J = 8.4, 2.0 Hz, 1H), 5.681 (br, 2H). C{1H} NMR (101 MHz, CDCl3) δ
13
166.9, 150.1, 138.6, 137.6, 129.1, 128.5, 124.7, 120.7, 116.9, 116.8, 114.5. Melting point(oC): 138.2-140.9. HRMS (ESI) m/z
calcd for C13H12ClN2O+ (M+H)+ 247.0633, found 247.0633. IR (cm-1): 3490, 3380, 3282, 1933, 1443, 1255, 1102, 846, 690.
2-amino-5-chloro-N-phenylbenzamide (1p). Follow above-mentioned procedure, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 8:1. 1p was obtained as yellow solid (148.7
mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.68 (br, 1H), 7.56 (dd, J = 8.5, 1.0 Hz, 2H), 7.43 (d, J = 2.4 Hz, 1H), 7.37 (t,
J = 8.0 Hz, 2H), 7.22 – 7.14 (m, 2H), 6.66 (d, J = 8.8 Hz, 1H), 5.48 (br, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.4,
147.5, 137.5, 132.6, 129.1, 126.8, 124.8, 121.2, 120.7, 118.8, 117.2. Melting point(oC): 154.4-160.1. HRMS (ESI) m/z calcd for
C13H11ClN2O+ (M+H)+ 247.0633, found 247.0634. IR (cm-1): 3409, 3282, 1882, 1517, 1331, 821, 691.
According to a literature procedure,4c 1q, 1r and 1s were prepared via decarboxylative amination of
corresponding isatoic anhydrides. A flame-dried 50 mL pear shaped flask were placed with a stirring bar. Isatoic
anhydride (214.5 mg, 1 mmol, 1.0 equiv), aromatic amine (1 mmol, 1.0 equiv), and EtOAc (2.0 mL) were added.
The resulting mixture was stirred vigorously at 70 oC temperature for 12 hours.
2-amino-5-bromo-N-phenylbenzamide (1q). Follow above-mentioned procedure, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 5:1. 1q was obtained as yellow solid (185.6
mg, 64%). 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.56 (dd, J = 8.6, 1.4 Hz, 3H), 7.41 – 7.35 (m, 2H), 7.32 (dd, J =
13
8.8, 2.4 Hz, 1H), 7.20 – 7.13 (m, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.50 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ 166.3,
147.9, 137.5, 135.4, 129.6, 129.1, 124.8, 120.7, 119.1, 117.8, 107.9. Melting point(oC): 159.7-163.2. HRMS (ESI) m/z calcd for
C13H12BrN2O+ (M+H)+ 291.0128, found 291.0130. IR (cm-1): 3467, 3372, 3288, 1637, 1537, 1442, 1252, 818, 752,690.
2-amino-5-nitro-N-phenylbenzamide (1r). Follow above-mentioned procedure, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 3:1. 1r was obtained as yellow solid (138.8
1
mg, 54%). H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H),
7.41 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.49 (s, 2H). 13C{1H} NMR (101 MHz, DMSO)
δ 166.5, 155.7, 139.2, 135.4, 129.1, 128.1, 126.9, 124.4, 121.3, 116.4, 114.0. Melting point(oC): 207.8-209.8. HRMS (ESI) m/z
calcd for C13H12N3O3+ (M+H)+ 258.0873, found 258.0875. IR (cm-1): 3478, 3368, 3341, 2923, 1638, 1321, 1131, 749.
2-amino-5-methoxy-N-phenylbenzamide (1s). Follow above-mentioned procedure, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 4:1. 1s was obtained as yellow solid (121 mg,
50%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.8 Hz, 2H), 7.14 (t, J = 7.4 Hz,
1H), 7.06 (d, J = 2.8 Hz, 1H), 6.91 (dd, J = 8.8, 2.8 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.91 (s, 2H), 3.78 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 167.0, 151.7, 142.0, 137.9, 129.1, 124.5, 120.5, 119.7, 119.4, 118.2, 112.2, 56.1. Melting point(oC):
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127.1-128.3. HRMS (ESI) m/z calcd for C14H15N2O2 (M+H)+ 243.1128, found 243.1125. IR (cm-1): 3422, 3295, 1647, 1502,
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Preparation of N,N'-(1,3-phenylene)bis(2-aminobenzamide)
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A flame-dried 50 mL pear shaped flask were placed with a stirring bar. Isatoic anhydride (800 mg, 4.4 mmol,
2.2 equiv), benzene-1,3-diamine (216.4 mg, 2 mmol, 1.0 equiv), and EtOAc (2.0 mL) were added. The resulting
mixture was stirred in an oil bath at 70 oC for 24 hours.4c Purification by flash chromatography on silica gel using
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petroleum ether : ethyl acetate = 3:1. The product was obtained as white solid (415.2 mg, 60%). H NMR (400
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MHz, CD3CN) δ 8.65 (s, 2H), 8.15 (s, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.44 – 7.31 (m, 3H), 7.26 (t, J = 7.4 Hz, 2H), 6.78
(d, J = 8.2 Hz, 2H), 6.68 (t, J = 7.5 Hz, 2H), 5.78 (s, 4H). 13C{1H} NMR (101 MHz, CD3CN) δ 168.9, 150.6, 140.2, 133.5,
+
129.8, 129.3, 118.3, 117.7, 117.3, 116.7, 114.1. Melting point(oC): 184.8-186.8. HRMS (ESI) m/z calcd for C20H19N4O2
(M+H)+ 347.1503, found 347.1504. IR (cm-1): 3495, 3367, 3266, 1931, 1435, 1248, 1158, 752, 690.
Typical experimental procedures.
General Procedures A:
A flame-dried 50 mL pear shaped flask were placed with a stirring bar. Then, N-Phenyl-2-aminobenzamide (42.4 mg,
0.2 mmol, 1.0 equiv), CuCl (4.0 mg, 0.04 mmol, 20 mol%), Et3N (14.0 μL, 0.1 mmol, 0.5 equiv), arylboronic acid (0.3 mmol,
1.5 equiv), and MeOH (4.0 mL) were added. The resulting mixture was stirred vigorously at ambient temperature for 3
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hours. Then DMSO (1.0 mL) was added and the temperature was raised to 120 C in an oil bath. The mixture was stirred
for 4 hours. MeOH (4.0 mL) was distilled into a beaker. After cooling, the reaction mixture was treated with EtOAc (5.0
mL) and water (5.0 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 5.0 mL).
The combined organic layer was dried over sodium sulfate, and concentrated to afford residue, which was purified by
column chromatography on silica gel to give the target product.
General Procedures B:
A flame-dried 50 mL pear shaped flask were placed with a stirring bar. Isatoic anhydride (32.0 mg, 0.2 mmol, 1.0 equiv),
o
Amine (0.2 mmol, 1.0 equiv), and EtOAc (0.5 mL) were added. The resulting mixture was stirred vigorously at 70 C
temperature for 12 hours. Cooling to room temperature, CuCl (4.0 mg, 0.04 mmol, 20 mol%), Et3N (14.0 L, 0.1 mmol, 0.5
equiv), arylboronic acid (0.3 mmol, 1.5 equiv), and MeOH (4.0 mL) were added. Then DMSO (1.0 mL) was added and the
o
temperature was raised to 120 C in an oil bath. The mixture was stirred for 4 hours. MeOH (4.0 mL) was distilled into a
beaker. After cooling, the reaction mixture was treated with EtOAc (5.0 mL) and water (5.0 mL). The organic layer was
separated, and the aqueous layer was extracted with EtOAc (3 × 5.0 mL). The combined organic layer was dried over
sodium sulfate, and concentrated to afford residue, which was purified by column chromatography on silica gel to give
the target product.
Experimental procedures for large-scale synthesis of N,N’-Diaryl Indazole-3-ones:
A flame-dried 250 mL pear shaped flask were placed with a stirring bar. Then, N-Phenyl-2-aminobenzamide (636 mg, 3
mmol, 1.0 equiv), CuCl (60 mg, 0.6 mmol, 20 mol%), Et3N (210 μL, 1.5 mmol, 0.5 equiv), phenylboronic acid (548 mg, 4.5
mmol, 1.5 equiv), and MeOH (60.0 mL) were added. The resulting mixture was stirred vigorously at ambient temperature
o
for 12 hours. Then DMSO (10.0 mL) was added and the temperature was raised to 120 C in an oil bath. The mixture was
stirred for 12 hours. MeOH (60.0 mL) was distilled into a beaker. After cooling, the reaction mixture was treated with
EtOAc (30 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 ×
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30 mL). The combined organic layer was dried over sodium sulfate, and concentrated to afford residue, which was
purified by column chromatography on silica gel to give the target product as yellow solid (626 mg, 73%).
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A flame-dried 250 mL pear shaped flask were placed with a stirring bar. Isatoic anhydride (489.4 mg, 3 mmol, 1.0 equiv),
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aniline (3 mmol, 1.0 equiv), and EtOAc (5.0 mL) were added. The resulting mixture was stirred vigorously at 70 C
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temperature for 12 hours. Cooling to room temperature，then CuCl (60 mg, 0.6 mmol, 20 mol%), Et3N (210 L, 1.5 mmol,
0.5 equiv), phenylboronic acid (1097 mg, 9 mmol, 3 equiv), and MeOH (60.0 mL) were added. The mixture was stirred
vigorously at ambient temperature for 12 hours. Then DMSO (10.0 mL) was added and the temperature was raised to 120
oC in an oil bath. The mixture was stirred for 12 hours. MeOH (60.0 mL) was distilled into a beaker. The mixture was
stirred for 12 hours. After cooling,the reaction mixture was treated with EtOAc (30 mL) and water (30 mL). The organic
layer was separated, and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layer was dried
over sodium sulfate, and concentrated to afford residue, which was purified by column chromatography on silica gel to
give the target product as yellow solid (558 mg, 65%).
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Preparation and characterization data for isolated products.
Compounds 3a,4c 3b,4c 3c,4c 3d,4c 3e,4c 3g,4c 3h,4c 3n,4c 3o,4c 3p,4c 3q,4c 3r,4c 4a,4c 4b,4c 4f,4c are known compounds and the
characterization data were in accordance with the literature. 1H / 13C NMR data for these compounds are provided here for
completion sake.
1,2-diphenyl-1H-indazol-3(2H)-one (3a). Follow general procedures A, purification by flash chromatography on silica gel
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using petroleum ether : ethyl acetate = 5:1. 3a was obtained as yellow solid (53.7 mg, 94%). H NMR (400 MHz, CDCl3) δ
7.97 (d, J = 7.6 Hz, 1H), 7.60 (dd, J = 8.8, 1.2 Hz, 2H), 7.50 (ddd, J = 8.4, 7.3, 1.2 Hz, 1H), 7.37 – 7.27 (m, 6H), 7.20 (m, 3H),
7.15 – 7.10 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.7, 150.2, 142.3, 135.9, 133.1, 129.7, 128.9, 127.5, 125.9, 124.5, 124.2, 123.5,
123.3, 118.3, 112.4.
2-phenyl-1-(p-tolyl)-1H-indazol-3(2H)-one (3b). Follow general procedures A, purification by flash chromatography on
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silica gel using petroleum ether : ethyl acetate = 5:1. 3b was obtained as yellow solid (46.9 mg, 78%). H NMR (400 MHz,
CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.59 (dd, J = 8.8, 1.2 Hz, 2H), 7.51 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.38 – 7.31 (m, 2H), 7.25 –
13
7.23 (m, 1H), 7.19 – 7.12 (m, 6H), 2.29 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 162.7, 150.5, 139.8, 137.5, 135.9, 133.0, 130.2,
128.8, 125.9, 124.5, 124.3, 123.4, 123.3, 118.3, 112.5, 21.0.
1-(4-methoxyphenyl)-2-phenyl-1H-indazol-3(2H)-one (3c) Follow general procedures A, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 3:1. 3c was obtained as yellow solid (45.5 mg, 72%). 1H
NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 1H), 7.58 (dd, J = 8.8, 1.2 Hz, 2H), 7.50 (m, 1H), 7.34 (t, J = 8.0 Hz, 2H), 7.25
(d, J = 6.0 Hz, 1H), 7.23 – 7.17 (m, 2H), 7.15 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 3.74 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 162.5, 158.9, 150.9, 135.7, 135.0, 133.0, 128.8, 126.2, 126.0, 124.4, 123.7, 123.2, 118.3, 114.8, 112.6,
55.4.
2-phenyl-1-(m-tolyl)-1,2-dihydro-3H-indazol-3-one (3d) Follow general procedures A, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 5:1. 3d was obtained as yellow solid (53.2 mg, 89%).
1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 8.4, 1.2 Hz, 2H), 7.52 (m, 1H), 7.35 (t, J = 8.0 Hz, 2H), 7.25
– 7.13 (m, 4H), 7.12 – 7.07 (m, 2H), 7.04 (d, J = 7.4 Hz, 1H), 2.31 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.8, 150.4, 142.4,
139.8, 136.0, 133.0, 129.4, 128.9, 128.4, 125.9, 124.7, 124.5, 123.4, 123.3, 121.4, 118.3, 112.5, 21.4.
1-(3-methoxyphenyl)-2-phenyl-1H-indazol-3(2H)-one (3e) Follow general procedures A, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 3:1. 3e was obtained as yellow solid (51.2 mg, 81%) 1H
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NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 8.4, 1.2 Hz, 2H), 7.54 – 7.48 (m, 1H), 7.38 – 7.31 (m, 2H), 7.24
(d, J = 7.2 Hz, 3H), 7.17 – 7.12 (m, 1H), 6.91 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 6.80 (t, J = 2.2 Hz, 1H), 6.75 (ddd, J = 8.4, 2.4, 0.4
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Hz, 1H), 3.70 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 162.8, 160.5, 150.1, 143.5, 136.0, 133.1, 130.3, 128.9, 125.9, 124.5, 123.5,
123.2, 118.3, 116.4, 112.9, 112.4, 109.9, 55.4.
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1-(4-(methylthio)phenyl)-2-phenyl-1H-indazol-3(2H)-one (3f) Follow general procedures A, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 3:1. 3f was obtained as yellow solid (54.5 mg, 82%) 1H
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.58 (dd, J = 8.8, 1.2 Hz, 2H), 7.55 – 7.50 (m, 1H), 7.35 (t, J = 8.0 Hz, 2H),
7.28 (d, J = 7.2 Hz, 1H), 7.21 (s, 4H), 7.16 (t, J = 8.0 Hz, 2H), 2.44 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.7, 150.4, 139.4,
138.3, 135.8, 133.1, 128.9, 127.2, 126.0, 124.9, 124.5, 123.5, 123.4, 118.3, 112.4, 15.6. Melting point(oC): 53.9-60.3. HRMS (ESI) m/z
calcd for C20H17N2OS+ (M+H)+ 333.1056, found 333.1060. IR (cm-1): 2919, 2366, 1676, 1457, 1272, 715, 694.
1-(4-fluorophenyl)-2-phenyl-1H-indazol-3(2H)-one (3g) Follow general procedures A, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 5:1. 3g was obtained as yellow solid (51.9 mg, 85%) 1H
NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.60 – 7.51 (m, 3H), 7.39 – 7.32 (m, 2H), 7.29 (m, 3H), 7.20 – 7.15 (m, 1H),
7.12 (d, J = 8.4 Hz, 1H), 7.08 – 7.01 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.6, 161.5 (d, J = 247), 160.3, 150.5, 138.4 (d, J =
3 Hz), 135.6, 133.2, 129.0, 126.4 (d, J = 9 Hz), 126.2, 124.6, 123.6, 123.5, 118.4, 116.7 (d, J = 23 Hz), 112.4. 19F NMR (376 MHz,
CDCl3) δ -113.18.
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1-(4-chlorophenyl)-2-phenyl-1,2-dihydro-3H-indazol-3-one (3h) Follow general procedures A, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 5:1. 3h was obtained as yellow solid (51.6 mg, 81%) 1H
NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.60 – 7.51 (m, 3H), 7.39 – 7.28 (m, 5H), 7.26 – 7.22 (m, 2H), 7.18 (t, J =
7.9 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.7, 150.1, 141.0, 135.7, 133.3, 133.2, 129.9, 129.0, 126.2, 125.6, 124.7, 123.8, 123.3,
118.4, 112.3.
1-(4-bromophenyl)-2-phenyl-1,2-dihydro-3H-indazol-3-one (3i) Follow general procedures A, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 5:1. 3i was obtained as yellow solid (64.2 mg, 88%) 1H
NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.56 (m, 3H), 7.48 (d, J = 8.8 Hz, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.29 (t, J =
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7.6 Hz, 1H), 7.21 – 7.15 (m, 4H). C{1H} NMR (101 MHz, CDCl3) δ 162.7, 159.0, 141.6, 135.7, 133.3, 132.9, 129.0, 126.2, 125.8,
124.7, 123.8, 123.3, 121.0, 118.4, 112.3. Melting point(oC): 130.3-132.1. HRMS (ESI) m/z calcd for C19H14BrN2O+ (M+H)+ 365.0284,
found 365.0288. IR (cm-1): 3051, 2343, 1686, 1476, 1272, 927, 749.
2-phenyl-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-indazol-3-one (3j) Follow general procedures A, purification by
flash chromatography on silica gel using petroleum ether : ethyl acetate = 5:1. 3j was obtained as yellow solid (58.9 mg,
83%) 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.60 – 7.55 (m, 3H), 7.43 (d, J = 8.4 Hz,
13
2H), 7.37 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.28 (s, 1H), 7.19 (t, J = 7.6 Hz, 1H). C{1H} NMR (101 MHz, CDCl3) δ
162.9, 149.4, 145.6, 135.8 133.5, 129.1, 129.1 (q, J = 33 Hz), 127.0 (q, J = 3 Hz), 126.2, 125.6 (d, J = 371 Hz), 124.8, 124.1, 123.9, 123.0,
118.4, 112.0. 19F NMR (376 MHz, CDCl3) δ -62.49. Melting point(oC): 52.9-54.9. HRMS (ESI) m/z calcd for C20H14F3N2O+
(M+H)+ 355.1053, found 355.1054. IR (cm-1): 3066, 2360, 1694, 1607, 1324, 1065, 929, 782, 609.
2-phenyl-1-(4-vinylphenyl)-1,2-dihydro-3H-indazol-3-one (3k) Follow general procedures A, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 4:1. 3k was obtained as yellow solid (43.0 mg, 69%)
1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.56 – 7.49 (m, 1H), 7.41 – 7.31 (m, 4H), 7.27 (d,
J = 7.3 Hz, 1H), 7.26 – 7.23 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 7.15 (m, 1H), 6.64 (dd, J = 17.6, 10.8 Hz, 1H), 5.69 (d, J = 17.6 Hz,
1H), 5.25 (d, J = 11.2 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.7, 150.1, 141.7, 136.8, 135.9, 135.6, 133.1, 128.9, 127.4, 126.0,
124.6, 124.3, 123.5, 123.3, 118.3, 114.9, 112.3. Melting point(oC): 53.8-55.5. HRMS (ESI) m/z calcd for C21H17N2O+ (M+H)+
313.1335, found 313.1333. IR (cm-1): 3440, 2970, 1693, 1463, 1309, 754.
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2-phenyl-1-(4-(trimethylsilyl)phenyl)-1,2-dihydro-3H-indazol-3-one (3l) Follow general procedures A, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 4:1. 3l was obtained as yellow solid (55.4 mg, 87%) 1H
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.62 (dd, J = 8.4, 1.2 Hz, 2H), 7.55 – 7.47 (m, 3H), 7.36 (t, J = 8.0 Hz, 2H),
7.28 (s, 2H), 7.24 (m, 2H), 7.16 (t, J = 7.4 Hz, 1H), 0.22 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.1, 151.3, 144.0, 141.1, 137.2,
135.8, 134.3, 130.1, 127.1, 125.7, 124.6, 124.4, 124.3, 119.4, 113.6. Melting point(oC): 213.6-215.4. HRMS (ESI) m/z calcd for
C22H23N2OSi+ (M+H)+ 359.1574, found 359.1578. IR (cm-1): 2952, 2343, 1698, 1458, 1105, 836, 749.
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Methyl 4-(3-oxo-2-phenyl-2,3-dihydro-1H-indazol-1-yl)benzoate (3m) Follow general procedures A, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 3:1. 3m was obtained as yellow solid (42.4 mg, 62%)
1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 7.2 Hz, 1H), 7.56 (m, 3H), 7.34 (m, 6H), 7.16 (t, J = 7.4 Hz,
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1H), 3.88 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 166.1, 162.8, 149.2, 146.3, 135.8, 133.4, 131.2, 129.1, 128.8, 126.1, 124.8, 123.9,
123.4, 123.0, 118.4, 111.9, 52.3. Melting point(oC): 178.9-182.1. HRMS (ESI) m/z calcd for C21H17N2O3+ (M+H)+ 345.1234, found
345.1231. IR (cm-1): 3044, 2949, 2342, 1686, 1475, 1262, 1105, 926, 746.
6-methyl-1,2-diphenyl-1H-indazol-3(2H)-one (3n) Follow general procedures A, purification by flash chromatography on
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silica gel using petroleum ether : ethyl acetate = 5:1. 3n was obtained as yellow solid (55.1 mg, 92%) H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H), 7.58 (m, 2H), 7.40 – 7.27 (m, 6H), 7.23 (m, 1H), 7.16 – 7.11 (m, 1H), 7.08 (dd, J = 8.0, 0.4 Hz,
1H), 6.98 (s, 1H), 2.41 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.9, 150.7, 144.3, 142.5, 136.1, 129.6, 128.8, 127.4, 125.8, 125.1,
124.3, 124.2, 123.2, 115.9, 112.2, 22.3.
6-chloro-1,2-diphenyl-1H-indazol-3(2H)-one (3o) Follow general procedures A, purification by flash chromatography on
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silica gel using petroleum ether : ethyl acetate = 5:1. 3o was obtained as yellow solid (58.3 mg, 91%) H NMR (400 MHz,
CDCl3) δ 7.89 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 8.4, 1.2 Hz, 2H), 7.36 (m, 4H), 7.30 – 7.26 (m, 3H), 7.23 (dd, J = 8.3, 1.6 Hz,
1H), 7.17 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.9, 150.5, 141.5, 139.5, 135.6, 129.9, 120.0, 127.9, 126.2, 125.7, 124.3, 124.3,
123.4, 116.7, 112.5.
5-chloro-1,2-diphenyl-1H-indazol-3(2H)-one (3p) Follow general procedures A, purification by flash chromatography on
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silica gel using petroleum ether : ethyl acetate = 5:1. 3p was obtained as yellow solid (55.7 mg, 87%) H NMR (400 MHz,
CDCl3) δ 7.94 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.6, 1.0 Hz, 2H), 7.46 (dd, J = 8.8, 2.0 Hz, 1H), 7.39 – 7.32 (m, 4H), 7.28 (d, J =
2.4 Hz, 2H), 7.25 – 7.22 (m, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.4, 148.5,
141.8, 135.5, 133.4, 129.8, 129.1, 129.0, 127.9, 126.3, 124.3, 124.0, 123.4, 119.6, 113.8.
5-bromo-1,2-diphenyl-1H-indazol-3(2H)-one (3q) Follow general procedures A, purification by flash chromatography on
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silica gel using petroleum ether : ethyl acetate = 5:1. 3q was obtained as yellow solid (57.7 mg, 79%) H NMR (400 MHz,
CDCl3) δ 8.10 (d, J = 1.7 Hz, 1H), 7.58 (ddd, J = 9.7, 8.6, 1.5 Hz, 3H), 7.35 (dt, J = 10.7, 7.7 Hz, 4H), 7.27 (d, J = 2.0 Hz, 1H), 7.16
(t, J = 7.4 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.2, 148.8, 141.7, 136.0, 135.5, 129.8, 129.0, 127.9,
127.1, 126.3, 124.3, 123.4, 120.0, 116.3, 114.1.
5-nitro-1,2-diphenyl-1H-indazol-3(2H)-one (3r) Follow general procedures A, purification by flash chromatography on
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silica gel using petroleum ether : ethyl acetate = 3:1. 3r was obtained as yellow solid (45.4 mg, 69%) H NMR (400 MHz,
CDCl3) δ 8.89 (d, J = 2.0 Hz, 1H), 8.38 (dd, J = 9.1, 2.3 Hz, 1H), 7.50 (dd, J = 8.6, 1.1 Hz, 2H), 7.45 – 7.40 (m, 2H), 7.34 (dt, J =
14.2, 8.0 Hz, 5H), 7.26 (d, J = 9.0 Hz, 1H), 7.24 – 7.19 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.0, 151.3, 143.7, 134.7, 130.10,
129.2, 128.6, 128.2, 127.1, 124.8, 124.0, 121.9, 117.8, 112.3.
5-methoxy-1,2-diphenyl-1H-indazol-3(2H)-one (3s) Follow general procedures A, purification by flash chromatography on
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silica gel using petroleum ether : ethyl acetate = 4:1. 3s was obtained as yellow solid (54.9 mg, 87%) H NMR (400 MHz,
CDCl3) δ 7.62 (d, J = 7.6 Hz, 2H), 7.38 – 7.35 (m, 2H), 7.33 (d, J = 8.0 Hz, 3H), 7.27 (d, J = 6.8 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H),
13
7.17 – 7.08 (m, 3H), 3.86 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 162.8, 156.6, 145.4, 143.0, 136.0, 129.6, 128.9, 127.4, 125.9,
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124.0, 123.5, 123.2, 118.9, 113.9, 104.6, 55.9. Melting point(oC): 91.6-94.2. HRMS (ESI) m/z calcd for C20H17N2O2 (M+H)+
+
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317.1285, found 317.1288. IR (cm-1): 3442, 2833, 1684, 1489, 1250, 1025, 824, 739.
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1,2-diphenyl-1H-indazol-3(2H)-one (3a) Follow general procedures B, purification by flash chromatography on silica gel
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using petroleum ether : ethyl acetate = 5:1. 3a was obtained as white solid (38.8 mg, 68%) H NMR (400 MHz, CDCl3) δ
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7.97 (d, J = 7.6 Hz, 1H), 7.60 (dd, J = 8.8, 1.2 Hz, 2H), 7.50 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.37 – 7.27 (m, 6H), 7.20 (m, 3H),
7.15 – 7.10 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.7, 150.2, 142.3, 135.9, 133.1, 129.7, 128.9, 127.5, 125.9, 124.5, 124.2, 123.5,
123.3, 118.3, 112.4.
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1-phenyl-2-(p-tolyl)-1H-indazol-3(2H)-one (4a) Follow general procedures B, purification by flash chromatography on
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silica gel using petroleum ether : ethyl acetate = 5:1. 4a was obtained as white solid (38.8 mg, 68%) H NMR (400 MHz,
CDCl3) δ 7.96 (d, J = 8.0 Hz, 1H), 7.55 – 7.42 (m, 3H), 7.35 (t, J = 7.6 Hz, 2H), 7.26 (m, 4H), 7.18 (d, J = 8.4 Hz, 1H), 7.13 (d, J
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= 8.0 Hz, 2H), 2.27 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 162.7, 150.1, 142.3, 135.9, 133.3, 132.9, 129.6, 129.5, 127.5, 124.5,
124.4, 123.4, 123.3, 118.3, 112.3, 21.0.
1-phenyl-2-(m-tolyl)-1H-indazol-3(2H)-one (4b) Follow general procedures B, purification by flash chromatography on
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silica gel using petroleum ether : ethyl acetate = 5:1. 4b was obtained as white solid (34.6 mg, 58%) H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.51 (m, 1H), 7.47 (s, 1H), 7.39 – 7.27 (m, 6H), 7.24 – 7.17 (m, 3H), 6.96 (d, J = 7.6 Hz, 1H),
2.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.8, 150.2, 142.4, 138.8, 135.8, 133.0, 129.6, 128.6, 127.5, 126.9, 124.5, 124.3, 124.2,
123.4, 120.5, 118.3, 112.4, 21.5.
1-(4-bromophenyl)-2-phenyl-1H-indazol-3(2H)-one (4c) Follow general procedures B, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 4:1. 4c was obtained as yellow solid (38.0 mg, 52%) 1H
NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.56 (m, 3H), 7.48 (d, J = 8.8 Hz, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.29 (t, J =
13
7.6 Hz, 1H), 7.21 – 7.15 (m, 4H). C{1H} NMR (101 MHz, CDCl3) δ 162.7, 150.0, 141.6, 135.7, 133.3, 132.9, 129.0, 126.2, 125.8,
124.7, 123.8, 123.3, 121.0, 118.4, 112.3. Melting point(oC): 130.3-132.1. HRMS (ESI) m/z calcd for C19H14BrN2O+ (M+H)+ 365.0284,
found 365.0288. IR (cm-1): 3051, 2343, 1686, 1476, 1272, 927, 749.
1-(4-chlorophenyl)-2-(4-methoxyphenyl)-1H-indazol-3(2H)-one (4d) Follow general procedures B, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 3:1. 4d was obtained as yellow solid (45.4 mg, 65%) 1H
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.53 (m, 1H), 7.46 – 7.41 (m, 2H), 7.35 – 7.31 (m, 2H), 7.30 – 7.27 (m, 1H),
7.23 – 7.19 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.90 – 6.86 (m, 2H), 3.77 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.7, 158.0,
149.8, 140.8, 133.2, 133.0, 129.9, 128.5, 125.9, 125.4, 124.6, 123.6, 118.4, 114.4, 112.2, 55.4. Melting point(oC): 152.5-157.3. HRMS
(ESI) m/z calcd for C20H16ClN2O2+ (M+H)+ 351.0895, found 351.0893 IR (cm-1): 3365, 3271, 1680, 1506, 1464, 1245, 1089, 1020,
817.
1-(4-chlorophenyl)-2-(2-methoxyphenyl)-1H-indazol-3(2H)-one (4e) Follow general procedures B, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 3:1. 4e was obtained as yellow solid (28.8 mg, 41%) 1H
NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.6 Hz, 1H), 7.51 (m, 1H), 7.32 – 7.27 (m, 3H), 7.25 (s, 1H), 7.21 (m, 3H), 7.06 (d, J = 8.4
Hz, 1H), 6.98 (dd, J = 8.4, 0.8 Hz, 1H), 6.91 (td, J = 7.7, 1.2 Hz, 1H), 3.85 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.9, 155.8,
149.6, 140.0, 133.4, 132.7, 130.3, 129.6, 129.5, 126.8, 124.5, 124.1, 122.9, 120.8, 118.0, 112.7, 111.8, 56.1. Melting point(oC): 73.1-78.5.
+
HRMS (ESI) m/z calcd for C20H16ClN2O2 (M+H)+ 351.0895, found 351.0899. IR (cm-1): 3435, 3065, 2838, 2360, 1694, 1461,
1285, 751.
2-(4-chlorophenyl)-1-phenyl-1H-indazol-3(2H)-one (4f) Follow general procedures B, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 5:1. 4f was obtained as yellow solid (29.2 mg, 46%) 1H
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 1H), 7.58 – 7.51 (m, 3H), 7.38 (m, 2H), 7.29 (ddd, J = 6.9, 5.0, 3.8 Hz, 6H), 7.19
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(d, J = 8.4 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.8, 150.4, 142.2, 134.5, 133.4, 131.4, 129.8, 129.1, 127.7, 124.6, 124.2, 124.2,
123.7, 118.1, 112.5.
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2-(4-chlorophenyl)-1-(3-methoxyphenyl)-1H-indazol-3(2H)-one (4g) Follow general procedures B, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 3:1. 4g was obtained as yellow solid (28.3 mg, 40%) 1H
NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 1H), 7.60 – 7.51 (m, 3H), 7.34 – 7.27 (m, 4H), 7.24 (d, J = 8.3 Hz, 1H), 6.93 –
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6.87 (m, 1H), 6.81 – 6.75 (m, 2H), 3.74 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 162.8, 160.6, 150.3, 143.4, 134.6, 133.4, 131.3,
130.5, 129.1, 124.6, 124.1, 123.7, 118.1, 116.3, 113.0, 112.5, 110.0, 55.4. Melting point(oC): 63.3-71.5. HRMS (ESI) m/z calcd for
C20H16ClN2O2+ (M+H)+ 351.0895, found 351.0891. IR (cm-1): 3435, 2934, 1694, 1489, 1090, 754.
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2-(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-indazol-3(2H)-one (4h) Follow general procedures B, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 3:1. 4h was obtained as yellow solid (20.0 mg, 30%) 1H
NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 1H), 7.57 – 7.49 (m, 3H), 7.28 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.05 (m, 3H),
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6.86 (m, 2H), 3.77 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 162.6, 160.6 (d J = 245), 159.1, 150.9, 134.7, 133.1, 131.7 (d, J = 3 Hz),
126.4, 125.6 (d, J = 9 Hz), 124.4, 123.3, 118.1, 115.8 (d, J = 22 Hz), 114.8, 112.6, 55.5. 19F NMR (376 MHz, CDCl3) δ -115.51. Melting
point(oC): 97.5-99.4. HRMS (ESI) m/z calcd for C20H16FN2O2+ (M+H)+ 335.1190, found 335.1197. IR (cm-1): 3435, 3070, 1686,
1503, 1219, 835.
1-(4-chlorophenyl)-2-(p-tolyl)-1H-indazol-3(2H)-one (4i) Follow general procedures B, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 5:1. 4i was obtained as yellow solid (46.6 mg, 70%) 1H
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 1H), 7.53 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.31 (m, 3H), 7.25 – 7.21 (dt, J = 8.8
Hz, 2.8H), 7.15 (dd, J = 8.3, 2.4 Hz, 3H), 2.30 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.6, 149.9, 141.0, 136.2, 133.1, 133.1,
133.1, 129.9, 129.6, 125.7, 124.6, 123.7, 123.5, 118.4, 112.2, 21.0. Melting point(oC): 156.3-157.8. HRMS (ESI) m/z calcd for
C20H16ClN2O+ (M+H)+ 335.0946, found 335.0950. IR (cm-1): 3043, 2344, 1689, 1506, 1307, 1151, 1087, 802.
2-benzyl-1-phenyl-1,2-dihydro-3H-indazol-3-one (4j) Follow general procedures B, purification by flash chromatography
on silica gel using petroleum ether : ethyl acetate = 3:1. 4j was obtained as yellow solid (12.1 mg, 20%) 1H NMR (400 MHz,
CDCl3) δ 7.93 (d, J = 7.6 Hz, 1H), 7.49 – 7.36 (m, 4H), 7.23 – 7.15 (m, 6H), 7.09 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 4.95 (s, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 163.9, 149.8, 140.5, 136.3, 132.4, 129.8, 128.4, 128.4, 128.2, 127.7, 125.9, 124.1, 122.6, 118.0, 111.9,
46.2. Melting point(oC): 58.4-60.1. HRMS (ESI) m/z calcd for C20H17N2O+ (M+H)+ 301.1335, found 301.1336. IR (cm-1): 3431,
2924, 1682, 1445, 1305, 753, 700.
2-phenethyl-1-phenyl-1,2-dihydro-3H-indazol-3-one (4k) Follow general procedures B, purification by flash
chromatography on silica gel using petroleum ether : ethyl acetate = 2:1. 4k was obtained as yellow solid (26.2 mg, 42%) 1H
NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.6 Hz, 1H), 7.51 – 7.36 (m, 4H), 7.24 – 7.15 (m, 6H), 7.05 (dd, J = 7.8, 1.4 Hz, 2H), 6.99
(d, J = 8.4 Hz, 1H), 4.04 – 3.94 (m, 2H), 2.96 – 2.85 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.8, 149.8, 140.6, 138.2, 132.4,
129.9, 128.8, 128.5, 128.3, 126.5, 125.5, 123.9, 122.7, 118.3, 111.8, 44.2, 34.3. Melting point(oC): 94.1-98.7. HRMS (ESI) m/z calcd
for C21H19N2O+ (M+H)+ 315.1492, found 315.1494. IR (cm-1): 3432, 2936, 1678, 1454, 1307, 929, 748, 703.
2,2'-(1,3-phenylene)bis(1-phenyl-1,2-dihydro-3H-indazol-3-one) Follow general procedures A, and arylboronic acid (3.o
equiv), CuCl (40 mol%), Et3N (1.o equiv). purification by flash chromatography on silica gel using petroleum ether : ethyl
acetate = 1.5:1. target product was obtained as yellow solid (33.6 mg, 68%) 1H NMR (400 MHz, CDCl3) δ 7.94 (m, 3H), 7.52
(m, 2H), 7.41 (dd, J = 2.0, 1.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.35 – 7.27 (m, 6H), 7.26 – 7.21 (m, 7H), 7.18 (d, J = 8.3 Hz,
13
2H). C{1H} NMR (101 MHz, CDCl3) δ 162.7, 150.4, 142.3, 136.3, 133.2, 129.7, 129.2, 127.5, 124.5, 124.3, 123.5, 120.6, 118.3, 118.2,
+
112.6. Melting point(oC): 217.7-222.8. HRMS (ESI) m/z calcd for C32H23N4O2 (M+H)+ 495.1816, found 495.1817. IR (cm-1):
3448, 3054, 1679, 1490, 1285, 769, 697.
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ASSOCIATED CONTENT
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Supporting Information
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Additional H and 13C spectra and spectral data for all compounds. This material is available free of charge via the Internet at
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http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
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*Yu Wei, E-mail: yuweichem@shzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the financial support by the National Natural Science Foundation of China (No. 21602141), Shihezi University
(CXRC201602 and CXRC201601).
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Synthesis 2017, 49, 3835-3847; (b) Chen, C.-Y.; Tang, G.; He, F.; Wang, Z.; Jing, H.; Faessler, R., A Synthesis of 1H-Indazoles via a
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