A General One-Pot Synthesis of 2H-Indazoles Using an Organophosphorus–Silane System

Article abstract of DOI:10.1002/chem.201800763

A simple and direct approach for the regioselective construction of the privileged 2H-indazole scaffold is described. The developed one-pot strategy involves phospholene-mediated N?N bond formation to access 2H-indazoles. The amount of organophosphorus reagent was minimized by recycling the phospholene oxide with organosilane reductants. Starting from functionalized 2-nitrobenzaldehydes and primary amines, a mild reductive cyclization, involving the use of commercially available phospholene oxide and silanes, delivered a wide variety of substituted 2H-indazoles in good to excellent yields.

Full text of DOI:10.1002/chem.201800763

A Journal of
Accepted Article
Title: A General One-Pot Synthesis of 2H-Indazoles Using an
Organophosphorus-Silane System
Authors: Jens Schoene, Hassane Bel Abed, Peter Schmieder, Mathias
Christmann, and Marc Nazaré
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10.1002/chem.201800763
Chemistry - A European Journal
A General One-Pot Synthesis of 2H-Indazoles Using an
Organophosphorus-Silane System
Jens Schoene[a], Hassen Bel Abed[a], Peter Schmieder[a], Mathias Christmann[b] and Marc
[a],[c]
Nazaré*
[a] Dipl. Chem. J. Schoene, Dr. H. Bel Abed, Dr. P. Schmieder, Dr. M. Nazaré
Departments of Chemical Biology and Structural Biology, Leibniz-Forschungsinstitut fϋr
Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Roessle-Str. 10, 13125
Berlin, Germany.
E-mail: nazare@fmp-berlin.de
[b] Prof. Dr. M. Christmann
Institut für Chemie und Biochemie, Organische Chemie, Freie Universität Berlin,
Takustrasse. 3, 14195 Berlin, Germany.
[c] Dr. M. Nazaré
Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Str. 2, 10178 Kapelle-Ufer 2, 10117
Berlin, Germany
1
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FULL PAPER
A simple mix & heat procedure
enables rapid access to 2H-indazoles
Jens Schoene, Hassen Bel Abed, Peter
Schmieder, Mathias Christmann and
Marc Nazaré
from
primary amines using a commercially
available organophosphorus/silane
2-nitrobenzaldehydes
and
Page No. – Page No.
system. Using this methodology, a
library of 65 2H-indazole derivatives
carrying a broad range of substitution
patterns could be synthesized.
A General One-Pot Synthesis of 2H-
Indazoles using an
Organophosphorus-Silane System
2
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Abstract: A simple and direct approach for the regioselective construction of the privileged
2H-indazole scaffold is described. The developed one-pot strategy employs a phospholene
mediated N-N bond formation to access 2H-indazoles. The amount of organophosphorus
reagent was minimized by recycling the phospholene oxide with organosilanes as reductant.
Starting from functionalized 2-nitrobenzaldehydes and primary amines a mild reductive
cyclisation, using commercially available phospholene oxide and silanes, delivered a wide
variety of substituted 2H-indazoles in good to excellent yields.
Introduction
Among the plethora of nitrogen-containing heterocycles, indazoles have emerged as a novel
class of privileged structures which continue to inspire the development of new synthetic
methodologies[1]. In addition to non-natural indazole framework being an effective isostere for
indoles and benzimidazoles in biological systems, these scaffolds also play an increasingly
important role due to their ability to distinctly interact with a wide variety of targets[1b]. Despite
these striking features, only a few methods provide direct regioselective access to N-
2]
substituted 2H-indazoles[1c-g,
with a broad substitution pattern. Unimpressed by the
shortcomings of current synthetic methodologies, this framework is of well documented
relevance as a pharmacophore with in drugs like Niraparib[3] or Pazopanib[4] (Figure 1). In
addition, recently the attractive fluorophoric properties of 2H-indazoles were described in a
systematic study that illustrated their diagnostic value as tools for cellular imaging in
chemical biology investigations[2r, 5]
.
Figure 1. a) Biologically active molecules with 2H-indazole motif. b) 2H-indazole
fluorophore[2r, 3-4, 6]
Most N-alkylating or N-arylating approaches of 1H-indazoles either lead to mixtures of N-
substituted 1H- and 2H- indazoles, with the 1H-indazole being the thermodynamically
favored product[1c, 7], or are based on not readily accessible starting materials requiring
several additional synthetic transformations. Therefore, considerable effort has been devoted
to the development of regioselective cyclization reactions for the direct construction of the
2H-indazole backbone.[2l, 2o, 2r, 8] Unfortunately, these routes often suffer from a narrow
substrate scope due to restricted availability of starting materials, harsh reaction conditions
3
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and incompatibility with other functional groups. One of the most effective and general
methods for the regioselective construction of 2H-indazoles is the Cadogan-type[9] N-N bond
formation via a reductive cyclization of 2-nitrobenzaldimine derivatives by organophosphorus
reagents at elevated temperatures. Until the very recent reports by Genung et al.[2s] and
Radosevich et al.[10] however, preformed 2-nitrobenzaldimines, neat conditions, or at least a
large excess of the phosphines or phosphites were required. Despite these advances, a
direct one-step conversion of 2-nitrobenzaldehydes and amines in a domino imine
condensation/reductive cyclization reaction to the corresponding 2H-indazoles would be
highly desirable. A sequential stop-and-go procedure either with intermediate isolation of the
2-nitrobenzaldimine precursor or with individual reaction monitoring is necessary to ensure
conversion and to determine the best subsequent time-point for phosphine addition to access
the desired 2H-indazoles. In addition, excessive use of over-stochiometric amounts of
organophosphorus reagents hampers purification and the complete removal of the
phosphine oxide byproducts is tedious. These characteristics are in stark contrast to the
requirements of any library synthesis and structure-activity-relationship study where brevity
and efficiency i.e. pot economy of the applied synthetic methodology[11] is of utmost
importance to generate a broad range of substitution patterns and a diverse spectrum of
compounds based on the 2H-indazole backbone.
Our investigation was therefore aiming at an efficient and operationally simple one-step, one-
pot procedure which would give direct access to a very diverse range of 2H-indazoles based
on readily available 2-nitrobenzaldehydes and amines as starting materials. Moreover, a
reducing system consisting of a combination of commercially available reagents was sought
that avoids excessive use of phosphines and tedious purifications.
Scheme 1. Proposed direct organophosphorus mediated 2H-indazole formation.
Herein we report a general robust strategy for the synthesis of substituted polyfunctionalized
2H-indazoles and its aza derivatives, minimizing the amount of necessary phosphine by
silane mediated in-situ regeneration.[10, 12]
Results and Discussion
We started our investigation for a one-pot domino reaction towards 2H-indazoles by
screening for suitable phosphine oxides at a sub-stoichiometric ratio using only one
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equivalent of the phosphine oxide for the reductive cyclization which corresponded to 0.5
redox equivalents. All reaction components 2-nitrobenzaldehyde (1, 1 eq.), aniline (2, 1.1
eq.), phosphine oxide (1 eq.) and diphenylsilane (2 eq.) as a phosphine regenerating agent
were added at once in toluene and heated to 110°C for 24h. The acyclic triphenylphosphine
oxide resulted in no conversion of the in situ formed imine intermediate (Table 1, entry 1) and
triethylphosphine oxide gave the desired 2-phenyl-2H-indazole (3) in only 15% yield (Table 1,
entry 2) whereas methyl diphenylphosphine oxide increased the yield to 38% (Table 1, entry
3). When using the commercially available cyclic 3-methyl-1-phenyl-2-phospholene-1-oxide
(4) under the same conditions, 82% yield of the desired 2H-indazole 3 was obtained (Table
1, entry 4). Based on this finding, we started the further refinement of the reaction conditions
with respect to the stoichiometric ratio, the silane reagent and the solvent. Reducing the
amount of phospholene oxide 4 to 0.8 equivalents resulted in a lower yield (76%, Table 1,
entry 5) but by simultaneously increasing the quantity of diphenylsilane to 2.6 eq. 2H-
indazole 3 was isolated in 87% yield. A sub-stoichiometric amount of 0.4 equivalents of 4 led
to a significantly reduced yield of 43% (Table 1, entry 7). Next, we examined the influence of
the nature of the silane reagent on the efficiency of the reaction. Balancing the required
reactivity versus the desired reaction selectivity of the intermediate was considered crucial to
avoid undesired side-reactions i.e. non-productive reduction of the nitro group, the aldehyde
or imine functionality. Surprisingly, phenylsilane which is a well-established reagent for the
reduction of tertiary phosphine oxides[10, 12c, 13], was less efficient (55% yield, Table 1, entry 8)
while triphenylsilane and methyldiethoxysilane led to the desired product only in trace
amounts or very low yields (Table 1, entries 9-10). To our surprise, the easily separable and
inexpensive 2,4,6,8-tetramethylcyclotetrasiloxane (TMCTS) was comparably effective to
diphenylsilane and afforded 3 in 73% yield (Table 1, entry 11). This could be improved further
to 83% yield by a slight increase of the siloxane to 1.8 equivalents (Table 1, entry 12). These
results indicated that TMCTS is a nearly equivalent substitute for the regenerative
organophosphorus indazole synthesis. To the best of our knowledge this is the first
successful application of this siloxane in an organophosphorus recycling reaction.
Interestingly, in control experiments using classical Cadogan-type conditions with 3 eq.
P(nBu)3 or P(OEt)3 in toluene instead of the phospholene oxide/silane system, only the
formation of traces of the desired 2H-indazole 3 could be observed under these one-pot
conditions. (see supporting information Table S1). A further investigation on the impact of the
solvent confirmed that toluene was optimal for the domino reaction, and protic or more polar
aprotic solvents such as i-PrOH or dioxane were inferior but did however generate the
desired product in acceptable yields. (Table 1, entries 6, 13-14). It should be noted that for
this operationally simple reaction set-up no dried glassware or particular handling
precautions such as e.g. glovebox or special glassware were necessary.
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Table 1. Optimization of reaction conditions.[a]
Entry R3PO (eq.)
Silane (eq.)
Ph2SiH2 (2)
Ph2SiH2 (2)
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Yield [%]b
1
Ph3PO (1)
Et3PO (1)
0
2
15
38
82
76
87
43c
55c
16
44c
73
83
56
78
3
Ph2MePO (1) Ph2SiH2 (2)
4
4 (1)
Ph2SiH2 (2)
5
4 (0.8)
4 (0.8)
4 (0.4)
4 (0.8)
4 (0.8)
4 (0.8)
4 (0.8)
4 (0.8)
4 (0.8)
4 (0.8)
Ph2SiH2 (2)
6
Ph2SiH2 (2.6)
Ph2SiH2 (2.6)
PhSiH3 (1.73)
Ph3SiH (5.2)
7
8
9
10
11
12
13
14
MeSi(OEt2)H (5.2) Toluene
TMCTS (1.3)
TMCTS (1.8)
Ph2SiH2 (2.6)
Ph2SiH2 (2.6)
Toluene
Toluene
i-PrOH
Dioxane
[a] See supporting information table S1 for further details. [b] Yield of
the isolated product after flash chromatography on silica gel. The
isolated yields are averages of more than one experiment. [c]
Formation of side products observed.
With these optimized reaction conditions in hand we investigated the flexibility and scope of
the reaction towards different functional groups (Figure 2-4). Several anilines bearing a
variety of electron-donating or –withdrawing groups at different positions were examined. The
reaction cascade proved to be robust toward steric demand. Moreover, substituents adjacent
to the reacting amine centre with an electronic influence such as halogens, methoxy or
nitriles in ortho, meta and para substituted anilines were well tolerated and afforded the
respective 2H-indazoles in moderate to excellent yields (5-16). Even highly electron deficient
aminopyridines or aminothiazoles can undergo this cyclization in acceptable to good yields
(17-19). Interestingly, 4-carboxyaniline and its corresponding methyl ester were effective
substrates for the conversion to 20 and 21 (77% and 76%) without any interference of this
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bystander functionality with these reductive conditions. In addition, also phenylhydrazine
could be converted into the corresponding N-2-amino-2H-indazoles (22) in 54% yield using
the same one-pot procedure. The methodology proved to be very mild and robust towards
other functionalities and a variety of anilines were compatible with the reaction conditions,
e.g. a boronic ester (23), amide (24), ketone (25), sulfonamide (26), phenol (27) and
protected amine (28) were obtained in moderate to excellent isolated yields (30-77%).
Additional nitro groups either on the 2-nitrobenzaldehyde or the aniline component were not
reduced under these conditions and stayed intact even under prolonged reactions times and
revealed that the reduction and subsequent cyclization preferentially takes place at the ortho-
position (29: 40% and 30: 50% yield). We next turned our attention to the scope of the 2-
nitrobenzaldehyde component. Variation with halides at the 4-, 5- or 6-position of the
benzaldehyde led to the desired product in moderate to excellent yield (31-37, 44-90%).
Interestingly, in case of the 4-chloro substituted indazole 37, we could only obtain the product
after preforming the corresponding 2-nitrobenzaldimine and then subjecting it to our standard
cyclisation conditions due to a sluggish imine formation. A tosyl group was also tolerated and
afforded the tosylated products 38 and 39 in 86% and 73% yield, respectively. Strong
electron-withdrawing groups like methylsulfonyl (41) or trifluoromethyl (42) attached to the 2-
nitrobenzaldehyde component did not inhibit the reaction and resulted in 74% and 56% yield.
Even the pyrazolo[3,4-c]pyridine derivative (43) bearing an electron-donating methoxy group
was obtained in good yields starting from the corresponding 2-methoxy-5-
nitroisonicotinaldehyde. In stark contrast, substituents at the 7-position of the 2-
nitrobenzaldehydes in vicinity to the reacting centre were apparently detrimental for an
efficient conversion, as 44 was obtained in only low yields. This finding is in line with all
described reductive cyclizations of 3-substituted 2-nitrobenzaldimines to 2H-indazoles[2s, 10]
and shows that proximal substituents severely affect this Cadogan-type organophosphorus
mediated cyclizations[2s, 9-10, 14]. Nonetheless, our procedure also reliably generated more
complex 2H-indazoles bearing base or acid-sensitive substitutions at the benzene ring, such
as the N2-(1H-indol-1-yl)-2H-indazole heterocycle with two acetoxy groups as well as an
ester (45-46) in moderate yield (44-46%) or terminal alkynes in 47 (51%). Here, the siloxane
TMCTS is an effective replacement of diphenylsilane for all examined cases (7, 9, 34, 40)
and results in similar or only slightly lower yields which confirmed our initial results.
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Figure 2. Substrate scope of aromatic amines. See experimental section for further details.
The reported isolated yields are averages of at least two experiments. [a] Using 1.8 eq.
TMCTS instead of 2.6 eq. Ph2SiH2. [b] Gram-scale. [c] 2-Nitrobenzaldimine preformed (see
experimental section).
Surprisingly, albeit the high utility and significance of N-alkyl 2H-indazoles, the reductive
cyclization of 2-nitrobenzaldimines with aliphatic amines is rarely reported. We therefore
investigated a broad variety of aliphatic amines (Figure 3). Here, linear, branched as well as
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cyclic alkyl amines are effective substrates and provided the corresponding 2H-indazoles 48-
51 in moderates to excellent yields. Primary aliphatic amines bearing functional groups like a
free hydroxy group and protected amine (52: 62% and 53: 66% yield) and even glycine
methyl ester 54 (25%) is tolerated. Chlorine substituted 2-nitrobenzaldehydes combined with
a protected aminomethylpiperidine (55) as well as diethoxyacetal (56) were obtained in
excellent yields. Allylamine and sterically hindered unprotected 2-aminoindanol can be used
as substrates in combination with the methyl ester substituted 2-nitrobenzaldehydes and 57
(38%) as well as 58 (36%) were isolated in moderate yields. The fluorine substituted
aldehyde undergoes the cyclization to 59 in good yields (82%). Here TMCTS again was
interchangeable with diphenylsilane as a reducing agent for the phospholene oxide when
using aliphatic amines 55 and 59 and the products were isolated in similar yields. Even
pyrazolo[3,4-c]pyridine (60) was obtained in good yields starting from the corresponding 3-
nitroisonicotinaldehyde. Substituents like electron-donating methoxy or dimethylamine
groups were tolerated and gave rise to the desired 2H-indazoles 61-62 in moderate to good
yields (43-71%). The obtained chiral 2H-indazoles 51 and 58 retained full stereochemical
integrity and no racemization could be detected.
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Figure 3. Substrate scope of aliphatic amines. See experimental section for further details.
The reported isolated yields are averages of at least two experiments. [a] Using 1.8 eq.
TMCTS instead of 2.6 eq. Ph2SiH2. [b] 2-Nitrobenzaldimine preformed (see experimental
section).
To explore the flexibility and robustness of our one-pot methodology and to further expand
the substrate scope we applied our method towards the synthesis of 3-amino-2H-indazoles
(64) (Figure 4) via the reductive cyclization of N-substituted 2-nitrobenzamidines (63).[2b]
While previously a high excess of 5 eq. of tributylphosphine as organophosphorus reagent
was required for an effective reaction, we could again decrease this by applying our standard
reaction conditions using 0.8 equivalents of phospholene oxide. The nature of the
substituents on both phenyl rings of substrate 63 did not hamper the formation of the desired
products 65-70. Several substituted derivatives bearing a methyl, halide, methoxy, protected
amine, trifluoromethoxy and methylsulfonyl group were tolerated and could be obtained in
moderate to excellent yields.
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Figure 4. Substrate scope of 3-amino-2H-indazoles. See experimental section for further
details. The reported isolated yields are averages of at least two experiments. [a] Using 1.8
eq. TMCTS instead of 2.6 eq. Ph2SiH2.
On the basis of the generally accepted mechanisms of the Cadogan reaction[2s, 9, 14-15] and the
12e, 16]
reduction of phosphine oxides by silanes[12b,
we suggest two interconnected
mechanistic cycles for this one-pot reaction involving the in-situ regeneration of the
phospholene species by the respective silane in each cycle (Figure 5). This reduction
process is facilitated by the lower energetic barrier of the cyclic backbone of the phospholene
to undergo the geometrical transformation involving the reduction process of the phosphorus
atom.[12c, 12e, 17] The formation of the 2-phenyl-2H-indazole (3) in the complex mixture could be
monitored by an online NMR-experiment at 110°C. The online measurements suggested a
rapid, almost instantaneous formation of the 2-nitrobenzaldimine (71) with no residual 2-
nitrobenzaldehyde present (see supporting information Figure S3). Once formed, the
phospholene 73 generated by the silane reduction performs the first deoxygenation of 71 to a
putative nitroso compound 74 and subsequent deoxygenation to the nitrene intermediate
76[9] which undergoes the decisive reductive cyclization and N-N bond formation to generate
the 2H-indazole 3.
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Figure 5. Plausible mechanism for the recycled one-pot domino Cadogan reaction.
Conclusions
In conclusion, we have developed a one-step, one-pot domino reaction for polyfunctionalized
2H-indazoles from readily available starting materials using mild conditions for the reductive
cyclization, minimizing the required phosphine to sub-stoichiometric quantities by using
silanes as in-situ organophosphorus regenerating agents. Moreover, we established the first
successful use of the low-cost siloxane TMCTS for the regeneration of phosphines in
organophosphorus chemistry. The procedure is simple to carry out, efficient and broadly
applicable and does not require reaction monitoring or the sequential addition of reagents.
The mild reaction conditions are compatible with a wide variety of functional groups such as
carboxylic acids, boronic esters, protected amines, phenols, etc. This new robust procedure
described herein, enables to rapidly synthesize highly versatile intermediates or “drug-like”
compound libraries based on the 2H-indazole scaffold and is thus enabling a systematic
investigation of this privileged motif.
Experimental Section
I. General Information
All amines, silanes, 3-methyl-1-phenyl-2-phospholene 1-oxide and solvents were
commercially available and used as received without further purification. 2-
Nitrobenzaldehydes were commercially available except 2-methoxy-5-nitroisonicotinaldehyde
(77) and 4,5-dichloro-2-nitrobenzaldehyde (78) which were synthesized by using a known
13
procedure (see supporting information).[18] 1H NMR and C NMR spectra were recorded on
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AV 300MHz, AV 600 MHz or AV 750 MHz from Bruker using CDCl3 or DMSO-d6 as internal
standard. Used abbreviations are: s = singlet, d = doubled, t = triplet, q = quartet, hept =
heptet, br. s = broad signal, m = multiplet. Coupling constant (J) are expressed in Hz.
MestreNova software was used to analyze NMR data. Mass and UV spectra were obtained
with two different spectrometers using the same column. LCMS (method 1): instrument:
Agilent Technologies 6220 Accurate Mass TOF LC/MS linked to Agilent Technologies HPLC
1200 Series; column: Thermo Accuore RP-MS; particle size: 2.6 µM dimension: 30 ×
2.1 mm; Eluent A: H2O with 0.1% TFA Eluent B: MeCN with 0.1% TFA; gradient: 0.00 min
95% A, 0.2 min 95% A, 1.1 min 1% A, 2.5 min stop time, 1.3 min post time; flow rate: 0.8 ml
min−1; UV-detection: 220 nm, 254 nm, 300 nm. LCMS (method 2): instrument: Agilent
Technologies 6120 Quadrupole LC/MS linked to Agilent Technologies HPLC 1290 Infinity;
column: Thermo Accuore RP-MS; particle size: 2.6 µM dimension: 30 × 2.1 mm; Eluent A:
H2O with 0.1% TFA Eluent B: MeCN with 0.1% TFA; gradient: 0.00 min 95% A, 0.2 min 95%
A, 1.1 min 1% A, 2.5 min stop time, 1.3 min post time; flow rate: 0.8 ml min−1; UV-detection:
220 nm, 254 nm, 300 nm. LCMS (method 3): instrument: Agilent Technologies HPLC 1200
Series linked to Agilent Technologies 1260 Infinity ELSD; column: Lux® 5 µm Cellulose-1;
particle size: 5.0 µM dimension: 250 × 4.6 mm; Eluent A: H2O with 0.1% Eluent B: MeCN
with 0.1% FA; gradient I: 0.00 min 95% A, 1.5 min 95% A, 7.5 min 1% A, 13 min stop time,
5.0 min post time; flow rate: 1 ml min−1; UV-detection: 250 nm, 254 nm; ELSD. Gradient II:
0.00 min 40% A, 15 min 20% A, 18 min 1% A, 25 min stop time, 5.0 min post time; flow rate:
1 ml min−1; UV-detection: 210 nm, 250 nm, 254 nm; ELSD. Gradient III: 25 min 50% A, 25
min stop time, 0.3 min post time; flow rate: 1 ml min−1; UV-detection: 250 nm, 254 nm; ELSD.
Gradient IV: 20 min 20% A, 20 min stop time, 0.3 min post time; flow rate: 1 ml min−1; UV-
detection: 250 nm, 254 nm; ELSD. Gradient V: 8 min 50% A, 8 min stop time, 0.3 min post
time; flow rate: 1 ml min−1; UV-detection: 250 nm, 254 nm; ELSD. Precoated aluminum
sheets (Fluka Silica gel/TLC-cards, 254 nm) were used for TLC. Purification of the
compounds was performed by flash chromatography using a CombiFlash Rf UV/Vis System
from Axel Semrau®. Melting Points ware determined with a Büchi® Melting Point B-545.
Optical Rotation was recorded on a Jasco® P-2000 polarimeter and samples were inserted
into a quartz cell with a path length of 1 dm.
II. General procedure for the 2H-indazole synthesis
To a solution of 2-nitrobenzaldehyde derivative (0.66 mmol) and 3-methyl-1-phenyl-2-
phospholene 1-oxide (101.8 mg, 0.53 mmol) in dry toluene (4 mL) in a sealed tube was
added amine (0.73 mmol) followed by diphenylsilane (317.1 µL, 1.72 mmol) at room
temperature. The reaction mixture was heated at 110°C for 24 h. After completion of the
reaction as monitored by LCMS, the mixture was cooled down to room temperature and
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transferred into a round bottom flask using DCM as a solvent. The solvents were removed
under reduced pressure and the crude product was purified by flash chromatography on
silica gel using a EtOAc/cyclohexane gradient as eluent.
2-Phenyl-2H-indazole (3): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66 mmol) and
aniline (66.3 µL, 0.73 mmol). The product was purified by flash chromatography on silica gel
(0-5% EtOAc/cyclohexane) to afford 112 mg (87% yield) of 3 as a light yellow solid. m.p. 77-
79°C. 1H NMR (600 MHz, CDCl3): δ 8.35 (s, 1H), 7.90-7.89 (m, 2H), 7.83 (d, J = 8.8 Hz, 1H),
7.69 (d, J = 8.5 Hz, 1H), 7.52-7.47 (m, 2H), 7.40-7.32 (m, 2H), 7.12 (dd, J = 8.2, 6.9 Hz, 1H).
13C NMR (151 MHz, CDCl3): δ 149.8, 140.5, 129.6, 127.9, 126.9, 122.8, 122.5, 120.9, 120.5,
120.4, 118.0. HRMS calcd. for C13H10N2 [M + H+] 195.0917, found 195.0932.
2-(2-Chlorophenyl)-2H-indazole (5): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and o-chloroaniline (77.0 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 77 mg (51% yield) of 5 as
a brown oil. 1H NMR (600 MHz, CDCl3): δ 8.34 (d, J = 0.9 Hz, 1H), 7.81 (dd, J = 8.8, 0.9 Hz,
1H), 7.76-7.73 (m, 1H), 7.71-7.68 (m, 1H), 7.59-7.56 (m, 1H), 7.45-7.39 (m, 2H), 7.34-7.37
(m, 1H), 7.16-7.13 (m, 1H). 13C NMR (151 MHz, CDCl3): δ 149.5, 138.7, 130.7, 130.0, 129.0,
128.6, 127.8, 127.0, 125.3, 122.5, 122.1, 120.6, 118.0. HRMS calcd. for C13H10ClN2 [M + H+]
229.0527, found 229.0522.
2-(2-Fluorophenyl)-2H-indazole (6): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and o-fluoroaniline (70.5 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 69 mg (49% yield) of 6 as
1
a brown oil. H NMR (600 MHz, Chloroform-d) δ 8.49 (dd, J = 2.8, 1.0 Hz, 1H), 8.09 (td, J =
7.8, 1.8 Hz, 1H), 7.81 (dq, J = 8.8, 0.9 Hz, 1H), 7.72 (dt, J = 8.5, 1.0 Hz, 1H), 7.38-7.26 (m,
4H), 7.12 (ddd, J = 8.5, 6.6, 0.8 Hz, 1H). 13C NMR (151 MHz, CDCl3): δ 155.1, 153.4, 149.3,
134.4, 129.2, 129.1, 127.2, 125.9, 125.2, 125.1, 124.8, 124.7, 122.7, 122.5, 120.6, 117.8,
117.1, 117.0. HRMS calcd. for C13H10FN2 [M + H+] 213.0823, found 213.0813.
2-(3-Chlorophenyl)-2H-indazole (7): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and m-chloroaniline (76.3 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 107 mg (71% yield) of 7 as
1
a light yellow solid. m.p. 106-108°C. H NMR (600 MHz, CDCl3): δ 8.40 (d, J = 0.7 Hz, 1H),
7.98 (t, J = 2.0 Hz, 1H), 7.80 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 7.79-7.77 (m, 1H), 7.70 (d, J =
8.5 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.38 (ddd, J = 8.0, 1.9, 0.9 Hz, 1H), 7.34 (ddd, J = 8.8,
6.6, 1.0 Hz, 1H), 7.14-7.11 (m, 1H). 13C NMR (151 MHz, CDCl3): δ 150.1, 141.6, 135.6,
130.7, 128.1, 127.4, 123.0, 123.0, 121.4, 120.6, 119.0, 118.2. HRMS calcd. for C13H10ClN2
[M + H+] 229.0527, found 229.0541.
14
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10.1002/chem.201800763
Chemistry - A European Journal
2-(4-Chlorophenyl)-2H-indazole (8): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and p-chloroaniline (93.1 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 107 mg (71% yield) of 8 as
1
a light brown solid. m.p. 137-139°C. H NMR (600 MHz, CDCl3): δ 8.34 (s, 1H), 7.83 (d, J =
8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.32-
13
7.34 (m, 1H), 7.14-7.09 (m, 1H). C NMR (151 MHz, CDCl3): δ 150.0, 139.1, 133.7, 129.8,
127.2, 123.0, 122.8, 122.1, 120.5, 120.4, 118.0. HRMS calcd. for C13H10ClN2 [M + H+]
229.0527, found 229.0533.
2-(2-Methylphenyl)-2H-indazole (9): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and o-toluidine (78.4 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 117 mg (85% yield) of 9 as
1
a yellow oil. H NMR (600 MHz, CDCl3): δ 8.09 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.75 (d, J =
8.5 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.41-7.31 (m, 4H), 7.18-7.14 (m, 1H), 2.26 (s, 3H). 13C
NMR (151 MHz, CDCl3); δ 149.3, 140.3, 133.9, 131.3, 129.1, 126.6, 126.4, 124.3, 122.1,
122.0, 120.3, 117.9, 17.9. HRMS calcd. for C14H12N2 [M + H+] 209.1073, found 209.1092.
2-(3-Methylphenyl)-2H-indazole (10): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and m-toluidine (79.1 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 84 mg (61% yield) of 10 as
a light brown solid. m.p. 69-71°C. 1H NMR (600 MHz, CDCl3): δ 8.37 (d, J = 1.0 Hz, 1H), 7.82
(dq, J = 8.8, 0.9 Hz, 1H), 7.78-7.75 (m, 1H), 7.70 (dt, J = 8.5, 1.0 Hz, 1H), 7.67-7.64 (m, 1H),
7.38 (t, J = 7.8 Hz, 1H), 7.33 (ddd, J = 8.8, 6.6, 1.1 Hz, 1H), 7.22-7.18 (m, 1H), 7.12 (ddd, J =
8.4, 6.6, 0.8 Hz, 1H), 2.46 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 149.8, 140.5, 139.8, 129.4,
128.73, 126.8, 122.8, 122.4, 121.8, 120.5, 120.5, 118.0, 118.0, 21.5. HRMS calcd. for
C14H12N2 [M + H+] 209.1073, found 209.1067.
2-(4-Methylphenyl)-2H-indazole (11): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and p-toluidine (78.2 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 103 mg (75% yield) of 11
as a light brown solid. m.p. 100-102C. 1H NMR (600 MHz, CDCl3): δ 8.34 (d, J = 0.9 Hz, 1H),
7.82-7.81 (m, 1H), 7.79-7.75 (m, 2H), 7.69 (dt, J = 8.4, 1.0 Hz, 1H), 7.34-7.31 (m, 1H), 7.31-
7.29 (m, 2H), 7.11 (ddd, J = 8.4, 6.6, 0.7 Hz, 1H), 2.42 (s, 3H). 13C NMR (151 MHz, CDCl3): δ
149.7, 138.3, 138.0, 130.2, 126.7, 122.8, 122.4, 120.9, 120.4, 120.4, 118.0, 21.1. HRMS
calcd. for C14H12N2 [M + H+] 209.1073, found 209.1060.
2-(2-Methoxyphenyl)-2H-indazole (12): Synthesized from 2-nitrobenzaldehyde (100 mg,
0.66 mmol) and o-anisidine (82.5 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 80 mg (54% yield) of 12 as
15
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10.1002/chem.201800763
Chemistry - A European Journal
a brown oil. 1H NMR (600 MHz, CDCl3): δ 8.52-8.51 (d, J = 0.9 Hz, 1H), 7.89 (dd, J = 7.9, 1.7
Hz, 1H), 7.81-7.79 (m, 1H), 7.74-7.72 (m, 1H), 7.41-7.38 (m, 1H), 7.32 (ddd, J = 8.7, 6.6, 1.0
Hz, 1H), 7.14-7.09 (m, 3H), 3.89 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 152.0, 148.9, 130.1,
129.4, 126.7, 126.6, 125.6, 122.1, 122.0, 121.3, 120.6, 117.8, 112.5, 56.1. HRMS calcd. for
C14H12N2O [M + H+] 225.1022, found 225.1020.
2-(3-Methoxyphenyl)-2H-indazole (13): Synthesized from 2-nitrobenzaldehyde (100 mg,
0.66 mmol) and m-anisidine (81.7 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 112 mg (79% yield) of 13
as a brown solid. m.p. 46-48°C. 1H NMR (600 MHz, CDCl3): δ 8.37 (d, J = 0.8 Hz, 1H), 7.83-
7.79 (m, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.53 (t, J = 2.3 Hz, 1H), 7.44-7.42 (m, 1H), 7.39 (t, J =
8.0 Hz, 1H), 7.33 (ddd, J = 8.7, 6.6, 1.0 Hz, 1H), 7.13-7.09 (m, 1H), 6.93 (ddd, J = 8.1, 2.5,
13
0.9 Hz, 1H), 3.88 (s, 3H). C NMR (151 MHz, CDCl3): δ 160.6, 149.8, 141.7, 130.32, 126.9,
122.8, 122.5, 120.6, 120.5, 118.0, 114.0, 112.9, 106.9, 55.6. HRMS calcd. for C14H12N2O [M
+ H+] 225.1022, found 225.1015.
2-(4-Methoxyphenyl)-2H-indazole (14): Synthesized from 2-nitrobenzaldehyde (100 mg,
0.66 mmol) and p-anisidine (89.9 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 115 mg (78% yield) of 14
1
as a colorless solid. m.p. 131-133°C. H NMR (600 MHz, CDCl3): δ 8.32 (s, 1H), 7.82-7.78
(m, 3H), 7.71-7.69 (m, 1H), 7.34-7.30 (m, 1H), 7.13-7.09 (m, 1H), 7.03 (d, J = 9.0 Hz, 2H),
3.87 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 159.4, 149.7, 134.2, 126.7, 122.8, 122.6, 122.4,
120.5, 120.4, 117.9, 114.8, 55.7. HRMS calcd. for C14H12N2O [M + H+] 225.1022, found
225.1042.
2-(2-Cyanophenyl)-2H-indazole (15): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and 2-aminobenzonitrile (86.2 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 68 mg (47% yield) of 15
as alight yellow solid. m.p. 124-126°C. 1H NMR (600 MHz, CDCl3): δ 8.60 (s, 1H), 7.98 (d, J =
8.2 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.82-7.76 (m, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.54 (t, J =
13
7.6 Hz, 1H), 7.39-7.34 (m, 1H), 7.18-7.13 (m, 1H). C NMR (151 MHz, CDCl3): δ 150.4,
142.5, 134.7, 134.2, 128.6, 127.8, 126.1, 123.6, 123.2, 123.0, 120.8, 118.2, 116.7, 107.0.
HRMS calcd. for C14H9N3 [M + H+] 220.0869, found 220.0873.
2-(3-Cyanophenyl)-2H-indazole (16): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and 4-aminobenzonitrile (86.2 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 94 mg (65% yield) of 16
1
as a colorless solid. m.p. 112-113°C. H NMR (600 MHz, CDCl3): δ 8.44 (s, 1H), 8.29-8.24
(m, 1H), 8.21-8.15 (m, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.69-7.64 (m,
16
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10.1002/chem.201800763
Chemistry - A European Journal
2H), 7.37-7.33 (m, 1H), 7.16-7.13 (m, 1H). 13C NMR (151 MHz, CDCl3): δ 150.4, 141.2,
131.2, 130.7, 127.8, 124.8, 124.2, 123.4, 123.2, 120.6, 120.4, 118.2, 117.9, 114.1. HRMS
calcd. for C14H9N3 [M + H+] 220.0869, found 220.0857.
2-(Pyridin-2-yl)-2H-indazole (17): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and 2-aminopyridin (68.7 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 40 mg (31% yield) of 17
as a light yellow solid. m.p. 109-111°C. 1H NMR (600 MHz, CDCl3): δ 9.11 (s, 1H), 8.57-8.45
(m, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.93-7.86 (m, 1H), 7.76-7.72 (m, 2H), 7.36-7.28 (m, 2H),
7.13-7.06 (m, 1H). 13C NMR (151 MHz, CDCl3): δ 152.0, 150.5, 148.5, 139.0, 127.7, 122.9,
122.9, 122.5, 121.4, 120.8, 118.2, 114.3. HRMS calcd. for C12H9N3 [M + H+] 196.0869, found
196.0854.
2-(Pyridin-3-yl)-2H-indazole (18): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and 3-aminopyridin (68.7 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-20% EtOAc/cyclohexane) to afford 89 mg (69% yield) of 18
as a colorless solid. m.p. 115-117°C. 1H NMR (600 MHz, CDCl3): δ 9.18 (d, J = 2.5 Hz, 1H),
8.65 (dd, J = 4.7, 1.1 Hz, 1H), 8.45 (s, 1H), 8.29 (ddd, J = 8.3, 2.5, 1.5 Hz, 1H), 7.79-7.77 (m,
1H), 7.72-7.71 (m, 1H), 7.49 (dd, J = 8.2, 4.7 Hz, 1H), 7.38-7.31 (m, 1H), 7.14 (dd, J = 8.3,
6.7 Hz, 1H). 13C NMR (151 MHz, CDCl3): δ 150.4, 149.0, 142.1, 137.2, 128.6, 127.6, 124.3,
123.2, 120.6, 118.1. HRMS calcd. for C12H9N3 [M + H+] 196.0869, found 196.0883.
2-(2H-Indazol-2-yl)thiazole (19): Synthesized from 2-nitrobenzaldehyde (100.0 mg,
0.66 mmol) and 2-aminothiazole (73.1 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 24 mg (18% yield) of 19 as
a light yellow solid. m.p. 119-121°C. 1H NMR (600 MHz, CDCl3): δ 8.86 (s, 1H), 7.71 (dd, J =
15.5, 8.7 Hz, 2H), 7.66 (d, J = 3.4 Hz, 1H), 7.37-7.31 (m, 1H), 7.25 (d, J = 3.4 Hz, 1H), 7.16-
7.09 (m, 1H). 13C NMR (151 MHz, CDCl3): δ 162.2, 150.6, 140.9, 128.5, 123.7, 122.7, 121.2,
120.8, 118.1, 117.9. HRMS calcd. for C10H7N3S [M + H+] 202.0433, found 202.0406.
4-(2H-Indazol-2-yl)benzoic acid (20): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and 4-aminobenzoic acid (100.1 mg, 0.73 mmol). The product was purified by filtration
and the solids were washed with DCM (3x) to afford 121 mg (77% yield) of 20 as a pale grey
solid. For the 1 g scale experiment the reaction time was increased to 48 h to achieve full
1
conversion (930 mg, 59% yield) m.p. 270-272°C. H NMR (600 MHz, DMSO-d6): δ 9.19 (s,
1H), 8.22 (d, J = 8.1 Hz, 2H), 8.14 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.4 Hz, 1H), 7.72 (d, J =
13
8.7 Hz, 1H), 7.37-7.31 (m, 1H), 7.15-7.08 (m, 1H). C NMR (151 MHz, DMSO): δ 166.7,
149.3, 142.7, 130.8, 130.7, 127.3, 122.6, 122.5, 122.1, 121.1, 119.9, 117.6. HRMS calcd. for
C14H10N2O2 [M + H+] 239.0815, found 239.0804.
17
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Chemistry - A European Journal
Methyl 4-(2H-indazol-2-yl)benzoate (21): Synthesized from 2-nitrobenzaldehyde (100 mg,
0.66 mmol) and methyl 4-aminobenzoate (110.3 mg, 0.73 mmol). The product was purified
by flash chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 127 mg (76%
yield) of 21 as a colorless solid. m.p. 180-182°C. 1H NMR (600 MHz, CDCl3): δ 8.48 (s, 1H),
8.20 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.5 Hz,
1H), 7.36-7.31 (m, 1H), 7.16-7.10 (m, 1H), 3.96 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 166.3,
150.3, 143.8, 134.5, 131.3, 129.4, 127.6, 123.1, 120.6, 120.6, 120.4, 118.2, 52.5. HRMS
calcd. for C15H12N2O2 [M + H+] 253.0972, found 253.0976.
N-Phenyl-2H-indazol-2-amine (22): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and phenylhydrazine (71.9 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 75 mg (54% yield) of 22
1
as a colorless solid. m.p. 165-167°C. H NMR (600 MHz, CDCl3): δ 8.13 (s, 1H), 7.72-7.69
(m, 2H), 7.37-7.34 (m, 1H), 7.19-7.15 (m, 3H), 6.97-6.94 (m, 1H), 6.52-6.50 (m, 2H).
13C NMR (151 MHz, CDCl3): δ 147.4, 146.9, 129.4, 127.0, 124.3, 122.8, 122.5, 120.6, 120.4,
117.7, 114.3. HRMS calcd. for C13H11N3 [M + H+] 210.1026, found 210.1021.
2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-2H-indazole (23): Synthesized
from 2-nitrobenzaldehyde (100 mg, 0.66 mmol) and 4-(4,4,5,5-Tetramethyl-1,3,2-
dioxaborolan-2-yl)aniline (160.0 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 89 mg (42% yield) of 23 as
a colorless solid. m.p. 157-159°C. 1H NMR (600 MHz, CDCl3): δ 8.45 (s, 1H), 7.98 (d, J = 8.4
Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.34-7.30
(m, 1H), 7.13-7.08 (m, 1H), 1.38 (s, 12H). 13C NMR (151 MHz, CDCl3): δ 150.0, 142.6, 136.3,
134.5, 127.2, 122.9, 122.7, 120.5, 120.5, 119.9, 118.1, 84.2, 25.0. HRMS calcd. for
C19H21BN2O2 [M + H+] 321.1769, found 321.1787.
4-(2H-Indazol-2-yl)benzamide (24): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and 4-aminobenzamide (99.4 mg, 0.73 mmol). The product was purified by filtration
and the solids were washed with DCM (3x) and MeOH (3x) to afford 55 mg (35% yield) of 24
as a light yellow solid. m.p. 252-254°C. 1H NMR (600 MHz, DMSO-d6): δ 9.20 (d, J = 0.7 Hz,
1H), 8.22-8.17 (m, 2H), 8.12-8.11 (m, 1H), 8.10-8.07 (m, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.74-
7.70 (m, 1H), 7.48 (s, 1H), 7.35-7.32 (m, 1H), 7.15-7.09 (m, 1H). 13C NMR (151 MHz,
DMSO): δ 166.9, 149.2, 141.8, 133.2, 129.1, 127.2, 122.6, 122.4, 122.0, 121.0, 119.7, 117.5.
HRMS calcd. for C14H11N3O [M + H+] 238.0975, found 238.0968.
1-(4-(2H-Indazol-2-yl)phenyl)ethan-1-one (25): Synthesized from 2-nitrobenzaldehyde (100
mg, 0.66 mmol) and 4'-Aminoacetophenone (98.7 mg, 0.73 mmol). The product was purified
by flash chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 80 mg (50%
18
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10.1002/chem.201800763
Chemistry - A European Journal
yield) of 25 as a colorless solid. m.p. 175-177°C. 1H NMR (600 MHz, CDCl3) δ 8.49 (s, 1H),
8.15-8.08 (m, 2H), 8.08-8.00 (m, 2H), 7.78 (dd, J = 9.5, 2.0 Hz, 1H), 7.73-7.68 (m, 1H), 7.36-
7.33 (m, 1H), 7.15-7.11 (m, 1H), 2.66 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 196.9, 150.3,
143.7, 136.2, 134.5, 130.1, 127.7, 123.2, 123.2, 120.6, 120.5, 118.2, 26.8. HRMS calcd. for
C15H12N2O [M + H+] 237.1022, found 237.1014.
4-(2H-Indazol-2-yl)benzenesulfonamide (26): Synthesized from 2-nitrobenzaldehyde (100
mg, 0.66 mmol) and sulfanilamide (125.7 mg, 0.73 mmol). The product was purified by
filtration and the solids were washed with MeOH (3x) to afford 54 mg (30% yield) of 26 as a
light yellow solid. m.p. 230-232°C. 1H NMR (600 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.31 (d, J =
8.7 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.49
13
(s, 2H), 7.37-7.33 (m, 1H), 7.15-7.11 (m, 1H). C NMR (151 MHz, DMSO): δ 149.3, 143.0,
142.0, 127.5, 127.3, 122.6, 122.6, 122.3, 121.1, 120.4, 117.6. HRMS calcd. for C13H11N3O2S
[M + H+] 274.0645, found 274.0629.
4-(2H-Indazol-2-yl)phenol (27): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66 mmol)
and methyl 4-aminophenol (79.7 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-20% EtOAc/cyclohexane) to afford 83 mg (60% yield) of 27
as a colorless solid. m.p. 195-197°C. 1H NMR (600 MHz, DMSO-d6): δ 9.83 (br. s, 1H), 8.90
(s, 1H), 7.86 (d, J = 8.9 Hz, 2H), 7.75-7.73 (m, 1H), 7.68-7,67 (m, 1H), 7.28 (ddd, J = 8.7,
6.6, 1.0 Hz, 1H), 7.08 (ddd, J = 8.3, 6.6, 0.7 Hz, 1H), 6.93 (d, J = 8.9 Hz, 2H). 13C NMR (151
MHz, DMSO): δ 157.2, 148.6, 132.2, 126.2, 122.3, 121.8, 121.7, 120.9, 120.7, 117.2, 115.9.
HRMS calcd. for C13H10N2O [M + H+] 211.0866, found 220.0867.
Tert-butyl
(4-(2H-indazol-2-yl)phenyl)carbamate
(28):
Synthesized
from
2-
nitrobenzaldehyde (100 mg, 0.66 mmol) and N-Boc-p-phenylenediamine (152.0 mg, 0.73
mmol). The product was purified by flash chromatography on silica gel (0-10%
EtOAc/cyclohexane) to afford 157 mg (77% yield) of 28 as a colorless solid. m.p. 196-198°C.
1H NMR (600 MHz, CDCl3): δ 8.35 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 1H),
7.70 (d, J = 8.4 Hz, 1H), 7.54-7.52 (m, 2H), 7.33-7.30 (m, 1H), 7.12-7.10 (m, 1H), 6.66 (s,
1H), 1.54 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 152.7, 149.7, 138.4, 135.8, 126.9, 122.8,
122.5, 121.9, 121.8, 120.5, 120.4, 119.3, 117.9, 117.9, 81.2, 28.4. HRMS calcd. for
C18H19N3O2 [M + H+] 310.1550, found 310.1553.
2-(3-Nitrophenyl)-2H-indazole (29): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and 3-nitroaniline (100.8 mg, 0.73 mmol). The product was purified by flash chro-
matography on silica gel (0-5% EtOAc/cyclohexane) to afford 63 mg (40% yield) of 29 as a
1
colorless solid. m.p. 141-143°C. H NMR (600 MHz, CDCl3): δ 8.80 (t, J = 2.2 Hz, 1H), 8.52
(d, J = 0.5 Hz, 1H), 8.36-8.31 (m, 1H), 8.27-8.23 (m, 1H), 7.81-7.77 (m, 1H), 7.73 (t, J = 8.3
19
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Hz, 2H), 7.38-7.35 (m, 1H), 7.17-7.14 (m, 1H). 13C NMR (151 MHz, CDCl3): δ 150.4, 149.2,
141.5, 130.8, 127.9, 126.4, 123.5, 123.3, 122.4, 120.7, 120.6, 118.2, 115.7. HRMS calcd. for
C13H9N3O2 [M + H+] 240.0768, found 240.0786.
6-Nitro-2-phenyl-2H-indazole (30): Synthesized from 2,4-dinitrobenzaldehyde (129.4 mg,
0.66 mmol) and aniline (66.3 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 78 mg (50% yield) of 30
as a yellow solid. m.p. 133-135 °C. 1H NMR (600 MHz, CDCl3): δ 8.80 (s, 1H), 8.54 (s, 1H),
7.96-7.93 (m, 3H), 7.84 (d, J = 9.2 Hz, 1H), 7.60-7.57 (m, 2H), 7.51-7.48 (m, 1H). 13C NMR
(151 MHz, CDCl3): δ 147.9, 147.3, 130.0, 129.2, 127.9, 125.2, 121.9, 121.5, 121.4, 116.7,
116.3. For C13H9N3O2 [M + H+] 240.0768, found 240.0776.
5-Chloro-2-phenyl-2H-indazole (31): Synthesized from 5-chloro-2-nitrobenzaldehyde
(122.5 mg, 0.66 mmol) and aniline (66.3 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 121 mg (80% yield) of 31
as a colorless solid. m.p. 148-150 °C. 1H NMR (600 MHz, CDCl3): δ 8.34 (s, 1H), 7.88 (d, J =
7.8 Hz, 2H), 7.73 (d, J = 9.1 Hz, 1H), 7.68 (s, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.42 (t, J = 7.4 Hz,
1H), 7.27-7.24 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 148.2, 140.4, 129.8, 128.4, 128.4,
128.2, 123.2, 121.1, 120.1, 119.7, 119.2. For C13H9ClN2 [M + H+] 229.0527, found 229.0542.
5-Bromo-2-phenyl-2H-indazole (32): Synthesized from 5-bromo-2-nitrobenzaldehyde
(151.8 mg, 0.66 mmol) and aniline (66.3 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 135 mg (75% yield) of 32
1
as a colorless solid. m.p. 142-143°C. H NMR (600 MHz, CDCl3): δ 8.35 (s, 1H), 7.89-7.87
(m, 3H), 7.67 (d, J = 9.1 Hz, 1H), 7.54-7.52 (m, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.37 (dd, J =
9.1, 1.7 Hz, 1H). 13C NMR (151 MHz, CDCl3): δ 148.3, 140.4, 130.6, 129.8, 128.4, 124.1,
122.6, 121.1, 120.0, 120.0, 116.1. HRMS calcd. for C13H9BrN2 [M + H+] 273.0022, found
273.0027.
6-Chloro-2-phenyl-2H-indazole (33): Synthesized from 4-chloro-2-nitrobenzaldehyde
(122.5 mg, 0.66 mmol) and aniline (66.3 µL, 0.73 mmol). The reaction time was 48 h. The
product was purified by flash chromatography on silica gel (0-10% EtOAc/cyclohexane) to
afford 88 mg (58% yield) of 33 as a colorless solid. MP: 128-130 °C. 1H NMR (600 MHz,
CDCl3): δ 8.39 (s, 1H), 7.89-7.87 (m, 2H), 7.78 (s, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.55-7.52
(m, 2H), 7.43-7.41 (m, 1H), 7.07 (dd, J = 8.9, 1.6 Hz, 1H). 13C NMR (151 MHz, CDCl3): δ
150.0, 140.4, 132.9, 129.8, 128.4, 124.2, 121.8, 121.3, 121.1, 121.0, 117.1. For C13H9ClN2
[M + H+] 229.0527, found 229.0528.
5-Chloro-2-(4-methoxyphenyl)-2H-indazole (34): Synthesized from 5-chloro-2-nitrobenzal-
dehyde (122.5 mg, 0.66 mmol) and p-anisidine (89.9 mg, 0.73 mmol). The product was
20
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purified by flash chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 154 mg
(90% yield) of 34 as a colorless solid. m.p. 160-162°C. 1H NMR (600 MHz, CDCl3): δ 8.27 (s,
1H), 7.80-7.77 (m, 2H), 7.72 (d, J = 9.1 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.26-7.24 (m, 1H),
7.06-7.02 (m, 2H), 3.88 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 159.7, 147.9, 134.57, 133.86,
128.18, 123.16, 122.59, 120.13, 119.40, 119.06, 114.89, 55.79. HRMS calcd. for
C14H11ClN2O [M + H+] 259.0633, found 259.0653.
5-Bromo-2-(4-methoxyphenyl)-2H-indazole (35): Synthesized from 5-bromo-2-nitrobenzal-
dehyde (151.8 mg, 0.66 mmol) and p-anisidine (89.9 mg, 0.73 mmol). The product was
purified by flash chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 142 mg
(71% yield) of 35 as a colorless solid. m.p. 168-169°C. 1H NMR (600 MHz, CDCl3): δ 8.26 (s,
1H), 7.86 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 9.0 Hz, 2H), 7.66 (d, J = 9.1 Hz, 1H), 7.36 (dd, J =
9.1, 1.8 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 159.7,
148.1, 133.9, 130.3, 124.0, 122.6, 122.5, 119.9, 119.7, 115.8, 114.9, 55.8. HRMS calcd. for
C14H11BrN2O [M + H+] 303.0128, found 303.0154.
6-Chloro-2-(4-methoxyphenyl)-2H-indazole
(36):
Synthesized
from
4-chloro-2-
nitrobenzaldehyde (122.5 mg, 0.66 mmol) and p-anisidine (89.9 mg, 0.73 mmol). The product
was purified by flash chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 108
mg (63% yield) of 36 as a light yellow solid. m.p. 142-144°C. 1H NMR (600 MHz, CDCl3): δ
8.30 (s, 1H), 7.79-7.77 (m, 3H), 7.64 (d, J = 8.9 Hz, 1H), 7.07 (dd, J = 8.8, 1.6 Hz, 1H), 7.05-
7.02 (m, 2H), 3.88 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 159.7, 149.7, 133.9, 132.7, 124.0,
122.6, 121.7, 121.2, 121.0, 116.9, 114.9, 55.8. HRMS calcd. for C14H11ClN2O [M + H+]
259.0633, found 259.0655.
4-Chloro-2-(4-methoxyphenyl)-2H-indazole
(37):
Synthesized
from
6-chloro-2-
nitrobenzaldehyde (122.5 mg, 0.66 mmol) and p-anisidine (89.9 mg, 0.73 mmol). 6-chloro-2-
nitrobenzaldehyde and p-anisidine in dry toluene (4 mL) was heated at 110°C for 2h. After
cooling to RT 3-methyl-1-phenyl-2-phospholene 1-oxide (101.8 mg, 0.53 mmol) and
diphenylsilane (317.1 µL, 1.72 mmol) were added and heated to 110°C for 22h. The product
was purified by flash chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 75
mg (44% yield) of 37 as a light colorless solid. m.p. 87-89°C. 1H NMR (600 MHz, CDCl3): δ
8.40 (s, 1H), 7.82 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 8.7 Hz, 1H), 7.23 (dd, J = 8.6, 7.3 Hz, 1H),
7.10 (d, J = 7.2 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H). 13C NMR (151 MHz, CDCl3): δ
159.8, 150.1, 133.9, 127.0, 125.5, 123.2, 122.6, 121.5, 120.2, 116.6, 114.9, 55.8. HRMS
calcd. for C14H11ClN2O [M + H+] 259.0633, found 259.0653.
21
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2-(4-((Tert-butoxycarbonyl)amino)phenyl)-2H-indazol-5-yl
4-methylbenzenesulfonate
(38): 5-Hydroxy-2-nitrobenzaldehyde (110.3 mg, 0.66 mmol) was solved in dry DCM (5 mL).
p-toluenesulfonyl chloride (125.8 mg, 0.66 mmol) and dry triethylamine (91.5 µL, 0.66 mmol)
were added sequentially at room temperature. The reaction mixture was heated for 45 min at
45°C under nitrogen. After completion of the reaction as monitored by LCMS, the mixture
was cooled down to room temperature and 2M HCl (10 mL) was added. The layers ware
separated and the water phase was washed once with DCM (10 mL). The combined organic
layers were dried with MgSO4 and the solvent was removed under reduced pressure. The
resulting 3-formyl-4-nitrophenyl-4-methylbenzenesulfonate (used without further purification)
and 3-methyl-1-phenyl-2-phospholene 1-oxide (101.5 mg, 0.53 mmol) were solved in dry
toluene in dry toluene (4 mL) in a sealed tube. N-Boc-p-phenylenediamine (152.0 mg,
0.73 mmol) and diphenylsilane (316.3 µL, 1.72 mmol) were added sequentially at room
temperature. The reaction mixture was heated at 110°C for 24 h. After completion of the
reaction as monitored by LCMS, the mixture was cooled down to room temperature and
transferred into a round bottom flask using DCM as a solvent. The solvents were removed
under reduced pressure and the crude product was purified by flash chromatography on
silica gel (0-20% EtOAc/cyclohexane) to afford 275 mg (86% yield) over two steps of 38 as a
beige solid. m.p. 191-193°C. 1H NMR (300 MHz, Methylene Chloride-d2): δ 8.37 (s, 1H), 7.79
(d, J = 9.0 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 9.3 Hz, 1H), 7.54 (d, J = 8.9 Hz, 2H),
7.35 – 7.31 (m, 3H), 6.86 (dd, J = 9.3, 2.2 Hz, 1H), 6.82 (s, 1H), 2.44 (s, 3H), 1.52 (s, 9H).
13C NMR (75 MHz, CD2Cl2): δ 153.0, 148.3, 146.3, 145.2, 139.4, 135.7, 132.7, 130.4, 129.0,
123.1, 122.3, 122.0, 121.7, 119.8, 119.5, 113.5, 81.3, 28.6, 22.0. HRMS calcd. for
C25H25N3O5S [M + H+] 480.1588, found 480.1593.
2-(4-Methoxyphenyl)-2H-indazol-5-yl 4-methylbenzene-sulfonate (39): 5-Hydroxy-2-
nitrobenzaldehyde (110.3 mg, 0.66 mmol) was solved in dry DCM (5 mL). p-Toluenesulfonyl
chloride (125.8 mg, 0.66 mmol) and dry triethylamine (91.5 mg, 0.66 mmol) were added
sequentially at room temperature. The reaction mixture was heated for 45 min at 45°C under
nitrogen. After completion of the reaction as monitored by LCMS, the mixture was cooled
down to room temperature and 2M HCl (10 mL) was added. The layers were separated and
the water phase was washed once with DCM (10 mL). The combined organic layers were
dried with MgSO4 and the solvent was removed under reduced pressure. The resulting 3-
formyl-4-nitrophenyl-4-methylbenzenesulfonate (used without further purification) and 3-
methyl-1-phenyl-2-phospholene 1-oxide (101.5 mg, 0.53 mmol) were dissolved in dry toluene
(4 mL) in a sealed tube. p-Anisidine (89.9 mg, 0.73 mmol) and diphenylsilane (316.3 µL,
1.72 mmol) were added sequentially at room temperature. The reaction mixture was heated
at 110°C for 24 h. After completion of the reaction as monitored by LCMS, the mixture was
cooled down to room temperature and transferred into a round bottom flask using DCM as a
22
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solvent. The solvents were removed under reduced pressure and the crude product was
purified by flash chromatography on silica gel (0-20% EtOAc/cyclohexane) to afford 190 mg
(73% yield) over two steps of 39 as a pale brown solid. m.p. 150-152°C. 1H NMR (600 MHz,
CDCl3): δ 8.29 (s, 1H), 7.76 (dd, J = 9.6, 2.6 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 9.3
Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.05-7.01 (m, 2H), 6.85 (dd, J =
13
9.3, 2.2 Hz, 1H), 3.88 (s, 3H), 2.45 (s, 3H). C NMR (151 MHz, CDCl3): δ 159.8, 147.9,
145.4, 144.9, 133.9, 132.6, 129.9, 128.8, 122.7, 122.6, 122.0, 121.4, 119.4, 114.9, 113.1,
55.8, 21.9. HRMS calcd. for C21H18N2O4S [M + H+] 395.1060, found 395.1093.
6-Nitro-2-(4-methoxyphenyl)-2H-indazole (40): Synthesized from 2,4-dinitrobenzaldehyde
(129.4 mg, 0.66 mmol) and p-anisidine (89.9 mg, 0.73 mmol). The product was purified by
flash chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 101 mg (57% yield)
of 40 as a yellow solid. m.p. 142-143°C. 1H NMR (600 MHz, CDCl3): δ 8.78 (s, 1H), 8.45 (s,
1H), 7.94 (dd, J = 9.1, 1.9 Hz, 1H), 7.86-7.81 (m, 3H), 7.09-7.06 (m, 2H), 3.90 (s, 3H). 13C
NMR (151 MHz, CDCl3): δ 160.3, 147.7, 147.0, 133.6, 125.2, 122.8, 121.7, 121.3, 116.5,
116.0, 115.0, 55.8. HRMS calcd. for C14H1118N3O3 [M + H+] 270.0873, found 270.0892.
2-(4-Bromophenyl)-6-(methylsulfonyl)-2H-indazole
(41):
Synthesized
from
4-
(methylsulfonyl)-2-nitrobenzaldehyde (151.3 mg, 0.66 mmol) and p-bromoaniline (125.6 mg,
0.73 mmol). The product was purified by filtration and washing with DCM to afford 132.1 mg
(57% yield) of 41 as pale brown solid. The combined organic layers were removed under
reduced pressure and purified by flash chromatography on silica gel (0-5% DCM/MeOH) to
1
afford 40 mg (17% yield) of 37 as a pale brown solid. m.p. 224-226°C. H NMR (600 MHz,
Chloroform-d) δ 8.52 (s, 1H), 8.50 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H),
7.70 (d, J = 8.8 Hz, 2H), 7.58 (dd, J = 8.8, 1.3 Hz, 1H), 3.12 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 148.2, 139.3, 139.2, 133.1, 124.7, 122.9, 122.7, 122.7, 121.3, 120.5, 119.2, 44.5.
HRMS calcd. for C14H11BrN2O2S [M + H+] 350.9797, found 350.9799.
2-(3,5-Dichlorophenyl)-6-(trifluoromethyl)-2H-indazole (42): Synthesized from 2-nitro-4-
(trifluoromethyl)benzaldehyde (118.3 mg, 0.66 mmol) and 3,5-dichloroaniline (125.6 mg, 0.73
mmol). The product was purified by flash chromatography on silica gel (0-5%
EtOAc/cyclohexane) to afford 122 mg (56% yield) of 42 as a colorless solid. m.p. 131-132°C.
1H NMR (600 MHz, Chloroform-d) δ 8.46 (s, 1H), 8.10 (s, 1H), 7.88 (t, J = 1.6 Hz, 2H), 7.82
(d, J = 8.9 Hz, 1H), 7.43 (dd, J = 2.2, 1.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H). 13C NMR (151
MHz, CDCl3) δ 148.6, 141.7, 136.34, 130.1, 129.9, 129.7, 129.5, 128.5, 125.3, 123.9, 123.5,
122.0, 121.1, 119.6, 119.1, 116.9. HRMS calcd. for C14H7Cl2F3N2 [M + H+] 331.0011, found
331.0015.
23
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Chemistry - A European Journal
Tert-butyl
(4-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)phenyl)carbamate
(43):
Synthesized from 2-methoxy-5-nitroisonicotinaldehyde (120.2 mg, 0.66 mmol) and N-Boc-p-
phenylenediamine (152.0 mg, 0.73 mmol). The product was purified by flash chromatography
on silica gel (0-20% EtOAc/cyclohexane) to afford 153 mg (68% yield) of 43 as a pale brown
solid. m.p. 175-177°C. 1H NMR (600 MHz, Chloroform-d) δ 9.05 (s, 1H), 8.23 (s, 1H), 7.79 (d,
J = 8.9 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 6.93 (s, 1H), 6.78 (s, 1H), 3.96 (s, 3H), 1.52 (s, 9H).
13C NMR (151 MHz, CDCl3) δ 158.8, 152.7, 144.4, 142.8, 139.2, 135.3, 127.9, 122.0, 119.2,
118.8, 91.8, 81.2, 54.9, 28.4. HRMS calcd. for C18H20N4O3 [M + H+] 341.1608, found
341.1602.
7-Methoxy-2-phenyl-2H-indazole (44): Synthesized from 3-methoxy-2-nitrobenzaldehyde
(122.5 mg, 0.66 mmol) and aniline (66.3 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 22 mg (15% yield) of 44 as
1
a brown oil. H NMR (600 MHz, CDCl3): δ 8.37 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.51 (t, J =
7.9 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.60 (d,
13
J = 7.3 Hz, 1H), 4.04 (s, 3H). C NMR (151 MHz, CDCl3): δ 150.5, 143.4, 140.4, 129.6,
128.1, 124.5, 123.4, 121.4, 121.1, 112.4, 103.5, 55.6. HRMS calcd. for C14H11N2O [M + H+]
225.1022, found 225.1033.
Methyl 2-(1H-indol-1-yl)-2H-indazole-5-carboxylate (45): Synthesized from methyl 3-
formyl-4-nitrobenzoate (138.0 mg, 0.66 mmol) and 1H-indol-1-amine (96.5 mg, 0.73 mmol).
The product was purified by flash chromatography on silica gel (0-5% EtOAc/cyclohexane) to
1
afford 88 mg (46% yield) of 45 as a pale yellow solid. m.p. 141-143°C. H NMR (600 MHz,
Chloroform-d) δ 8.60 (s, 1H), 8.43 (s, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.78 (d, J = 9.1 Hz, 1H),
7.70 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 3.3 Hz, 1H), 7.27-7.24 (m, 2H), 7.11-7.03 (m, 1H), 6.73
(d, J = 3.3 Hz, 1H), 3.98 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 167.2, 148.3, 137.0, 127.3,
127.3, 126.7, 125.6, 125.6, 125.0, 124.2, 122.3, 121.7, 120.0, 118.1, 108.9, 104.2, 52.4.
HRMS calcd. for C17H13N3O2 [M + H+] 292.1081, found 292.1079.
2-(1H-Indol-1-yl)-2H-indazole-5,6-diyl diacetate (46): Synthesized from 4-formyl-5-nitro-
1,2-phenylene diacetate (176.3 mg, 0.66 mmol) and 1H-indol-1-amine (96.5 mg, 0.73 mmol).
The product was purified by flash chromatography on silica gel (0-25% EtOAc/cyclohexane)
1
to afford 101 mg (44% yield) of 46 as a pale brown solid. m.p. 168-169°C. H NMR (600
MHz, Chloroform-d) δ 8.26 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 4.5 Hz, 2H), 7.41 (d,
J = 3.5 Hz, 1H), 7.29-7.22 (m, 2H), 7.05 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 3.4 Hz, 1H), 2.35 (s,
6H). 13C NMR (151 MHz, CDCl3) δ 168.9, 168.6, 144.8, 143.5, 140.1, 137.1, 127.4, 126.6,
124.2, 124.0, 122.1, 121.6, 118.2, 113.2, 111.5, 109.0, 103.9, 20.8, 20.8. HRMS calcd. for
C19H15N3O4 [M + H+] 350.1135, found 350.1156.
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5,6-Dichloro-2-(4-ethynylphenyl)-2H-indazole (47): Synthesized from 4,5-dichloro-2-
nitrobenzaldehyde (145.2 mg, 0.66 mmol) and 4-ethynylaniline (85.5 mg, 0.73 mmol). The
product was purified by flash chromatography on silica gel (0-20% EtOAc/cyclohexane) to
1
afford 97 mg (51% yield) of 47 as a pale yellow solid. m.p. 179-180°C. H NMR (600 MHz,
Chloroform-d) δ 8.35 (s, 1H), 7.91 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.82 (s, 1H), 7.65 (d, J =
8.1 Hz, 2H), 3.19 (s, 1H). 13C NMR (151 MHz, CDCl3) δ 148.5, 140.0, 133.7, 131.9, 127.5,
122.5, 122.0, 121.2, 120.7, 120.2, 119.23, 82.6, 79.2. HRMS calcd. for C15H8Cl2N2 [M + H+]
287.014, found 287.0142.
2-Isopropyl-2H-indazole (48): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66 mmol)
and isopropylamine (62.5 µL, 0.73 mmol). The product was purified by flash chromatography
on silica gel (0-5% EtOAc/cyclohexane) to afford 42 mg (40% yield) of 48 as a yellow oil.
1H NMR (600 MHz, CDCl3): δ 7.95 (s, 1H), 7.74-7.72 (m, 1H), 7.66-7.64 (m, 1H), 7.29-7.27
(m, 1H), 7.07 (ddd, J = 8.2, 6.6, 0.8 Hz, 1H), 4.80 (hept, J = 6.7 Hz, 1H), 1.66 (d, J = 6.7 Hz,
13
6H). C NMR (151 MHz, CDCl3) δ 148.5, 125.8, 121.6, 121.6, 120.2, 120.1, 117.6, 55.5,
23.4. HRMS calcd. for C10H12N2 [M + H+] 161.1073, found 161.1075.
2-Cyclohexyl-2H-indazole (49): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and cyclohexylamine (84.5 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 79 mg (60% yield) of 49 as
a colorless solid. m.p. 82-84°C. 1H NMR (600 MHz, CDCl3): δ 7.95 (s, 1H), 7.72 (d, J = 8.7
Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 12.6, 3.8 Hz, 1H), 7.09-7.04 (m, 1H), 4.42 (tt,
J = 11.6, 3.7 Hz, 1H), 2.32-2.24 (m, 2H), 1.99-1.87 (m, 4H), 1.82-1.75 (m, 1H), 1.50 (qt, J =
12.8, 3.4 Hz, 2H), 1.33 (qt, J = 13.1, 3.6 Hz, 1H). 13C NMR (151 MHz, CDCl3): δ 148.2, 125.9,
121.6, 121.5, 120.4, 120.2, 117.5, 63.0, 34.1, 25.6, 25.5. HRMS calcd. for C13H16N2 [M + H+]
201.1386, found 201.1381.
2-Benzyl-2H-indazole (50): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66 mmol) and
benzylamine (79.6 µL, 0.73 mmol). The product was purified by flash chromatography on
silica gel (0-5% EtOAc/cyclohexane) to afford 114 mg (83% yield) of 50 as a brown solid.
m.p. 70-72°C. 1H NMR (600 MHz, CDCl3): δ 7.88 (s, 1H), 7.78-7.74 (m, 1H), 7.63 (d, J = 8.4
Hz, 1H), 7.38-7.28 (m, 6H), 7.12-7.06 (m, 1H), 5.60 (s, 2H). 13C NMR (151 MHz, CDCl3): δ
148.9, 135.7, 129.0, 128.5, 128.1, 126.2, 123.1, 122.1, 121.9, 120.3, 117.5, 57.5. HRMS
calcd. for C14H12N2 [M + H+] 209.1073, found 209.1072.
(S)-2-(1-Phenylethyl)-2H-indazole (51): Synthesized from 2-nitrobenzaldehyde (100 mg,
0.66 mmol) and (S)-(-)-1-phenylethylamine (93.1 µL, 0.73 mmol). The product was purified by
flash chromatography on silica gel (0-5% EtOAc/cyclohexane) to afford 117 mg (83% yield)
[ ]23
of 51 as a colorless oil. ∝
+34.4° (β 0.009 g.mL-1, MeOH).[2s] 1H NMR (600 MHz, CDCl3): δ
D
25
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10.1002/chem.201800763
Chemistry - A European Journal
7.91 (s, 1H), 7.80-7.76 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.36-7.34 (m, 2H), 7.33-7.27 (m,
4H), 7.11-7.07 (m, 1H), 5.84 (q, J = 7.1 Hz, 1H), 2.06 (d, J = 7.1 Hz, 3H). 13C NMR (189 MHz,
CDCl3): δ 148.6, 141.1, 128.9, 128.2, 126.6, 125.9, 121.8, 121.7, 121.5, 120.3, 117.7, 62.7,
21.7. HRMS calcd. for C15H14N2 [M + H+] 223.1230, found 223.1247.
2-(2H-Indazol-2-yl)ethan-1-ol (52): Synthesized from 2-nitrobenzaldehyde (100 mg, 0.66
mmol) and 2-aminoethanol (44.1 µL, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-50% EtOAc/cyclohexane) to afford 66 mg (62% yield) of 52
as a light brown solid. m.p. 101-103°C. 1H NMR (600 MHz, CDCl3): δ 7.95 (s, 1H), 7.67-7.64
(m, 2H), 7.32-7.27 (m, 1H), 7.12-7.06 (m, 1H), 4.53-4.46 (m, 2H), 4.11-4.05 (m, 2H), 3.39 (s,
1H). 13C NMR (151 MHz, CDCl3): δ 149.1, 126.5, 124.0, 122.0, 121.7, 120.3, 117.3, 61.8,
55.4. HRMS calcd. for C9H10N2O [M + H+] 163.0866, found 163.0853.
Tert-butyl (2-(2H-indazol-2-yl)ethyl)carbamate (53): Synthesized from 2-nitrobenzaldehyde
(100 mg, 0.66 mmol) and tert-butyl (2-aminoethyl)carbamate (115.6 µL, 0.73 mmol). The
product was purified by flash chromatography on silica gel (0-25% EtOAc/cyclohexane) to
1
afford 114 mg (66% yield) of 53 as a pale yellow solid. m.p. 97-98°C. H NMR (600 MHz,
Chloroform-d) δ 7.90 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.32-7.27 (m,
1H), 7.11-7.06 (m, 1H), 4.95 (s, 1H), 4.61-4.39 (m, 2H), 3.82-3.52 (m, 2H), 1.42 (s, 9H).
13C NMR (151 MHz, CDCl3) δ 156.0, 149.3, 126.3, 123.9, 121.9, 121.8, 120.3, 117.4, 79.9,
53.2, 41.0, 28.5. HRMS calcd. for C14H19N3O2 [M + H+] 262.1550, found 262.1554.
Methyl 2-(2H-indazol-2-yl)acetate (54): Glycine methyl ester hydrochloride (82.9.3 mg, 0.66
mmol) was stirred with dry trimethylamine (91.5 µL, 0.66 mmol) in dry toluene (4 mL) in a
sealed tube for 1 h. Then the 2-nitrobenzaldehyde (100 mg, 0.66 mmol) was added, followed
by the 3-methyl-1-phenyl-2-phospholene 1-oxide (101.5 mg, 0.53 mmol) and diphenylsilane
(316.3 µL, 1.72 mmol) at room temperature. The reaction mixture was heated at 110°C for
24 h. After completion of the reaction as monitored by LCMS, the mixture was cooled down
to room temperature and transferred into a round bottom flask using DCM as a solvent. The
solvents were removed under reduced pressure and the crude product was purified by flash
chromatography on silica gel (0-20% EtOAc/cyclohexane) to afford 31 mg (25% yield) of 54
as a brown oil. 1H NMR (600 MHz, CDCl3): δ 8.00 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.66 (d, J
= 8.5 Hz, 1H), 7.31-7.28 (m, 1H), 7.11-7.08 (m, 1H), 5.22 (s, 2H), 3.79 (s, 3H). 13C NMR (151
MHz, CDCl3): δ 167.7, 149.3, 134.5, 126.7, 124.6, 122.3, 120.4, 117.7, 54.5, 53.0. HRMS
calcd. for C10H10N2O2 [M + H+] 191.0815, found 191.0817.
Tert-butyl
4-((5,6-dichloro-2H-indazol-2-yl)methyl)piperidine-1-carboxylate
(55):
Synthesized from 4,5-dichloro-2-nitrobenzaldehyde (145.2 mg, 0.66 mmol) and tert-butyl 4-
(aminomethyl)piperidine-1-carboxylate (154. 4 µL, 0.73 mmol). The product was purified by
26
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10.1002/chem.201800763
Chemistry - A European Journal
flash chromatography on silica gel (0-20% EtOAc/cyclohexane) to afford 241 mg (95% yield)
1
of 55 as a pale yellow solid. m.p. 116-118°C. H NMR (600 MHz, Chloroform-d) δ 7.82 (s,
2H), 7.76 (s, 1H), 4.25 (d, J = 7.3 Hz, 2H), 4.11 (dd, J = 12.4, 4.8 Hz, 2H), 2.66 (t, J = 12.5
Hz, 2H), 2.27-2.20 (m, 1H), 1.53 (d, J = 12.7 Hz, 2H), 1.44 (s, 9H), 1.21 (qd, J = 12.7, 4.6 Hz,
2H). 13C NMR (151 MHz, CDCl3) δ 154.8, 147.6, 130.8, 126.5, 123.5, 121.0, 120.7, 118.7,
79.7, 59.5, 43.5, 37.6, 29.8, 28.6. HRMS calcd. for C18H23Cl2N3O2 [M + H+] 384.1240, found
384.1239.
5,6-Dichloro-2-(3,3-diethoxypropyl)-2H-indazole (56): Synthesized from 4,5-dichloro-2-
nitrobenzaldehyde (145.2 mg, 0.66 mmol) and 3,3-diethoxypropan-1-amine (118.1 µL, 0.73
mmol). The product was purified by flash chromatography on silica gel (0-20%
EtOAc/cyclohexane) to afford 188 mg (90% yield) of 56 as a pale yellow solid. m.p. 42-49°C.
1H NMR (600 MHz, Chloroform-d): δ 7.87 (s, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 4.48 (t, J = 7.1
Hz, 2H), 4.42 (t, J = 5.4 Hz, 1H), 3.63 (p, J = 7.2 Hz, 2H), 3.46 (p, J = 7.2 Hz, 2H), 2.31 (q, J
= 6.5 Hz, 2H), 1.18 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 147.5, 130.5, 126.2,
123.2, 121.0, 120.8, 118.7, 100.4, 62.1, 49.9, 34.5, 15.4. HRMS calcd. for C14H18Cl2N2O2
[M + H+] 317.0818, found 317.0820.
Methyl 2-allyl-2H-indazole-5-carboxylate (57): Synthesized from methyl 3-formyl-4-
nitrobenzoate (138.0 mg, 0.66 mmol) and allylamine (54.6 µL, 0.73 mmol). The product was
purified by flash chromatography on silica gel (0-10% EtOAc/cyclohexane) to afford 54 mg
1
(38% yield) of 57 as a brown solid. m.p. 47-49°C. H NMR (600 MHz, Chloroform-d) δ 8.49
(s, 1H), 8.07 (s, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 9.1 Hz, 1H), 6.13 (ddt, J = 16.6,
9.9, 6.2 Hz, 1H), 5.39-5.31 (m, 2H), 5.05 (d, J = 6.1 Hz, 2H), 3.92 (s, 3H). 13C NMR (151
MHz, CDCl3) δ 167.6, 150.3, 131.9, 126.0, 125.1, 125.0, 124.0, 121. 5, 120.2, 117.4, 56.5,
52.1. HRMS calcd. for C12H12N2O2 [M + H+] 217.0972, found 217.0970.
Methyl 2-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2H-indazole-5-carboxylate (58):
Synthesized from methyl 3-formyl-4-nitrobenzoate (138.0 mg, 0.66 mmol) and (1R,2S)-1-
amino-2,3-dihydro-1H-inden-2-ol (108.9 mg, 0.73 mmol). The product was purified by flash
chromatography on silica gel (0-20% EtOAc/cyclohexane) to afford 73 mg (36% yield) of 58
[ ]23
as a colorless solid. m.p. 160-161°C. ∝
1
+69.9° (β: 0.003 g.mL-1, MeOH). H NMR (600
D
MHz, Chloroform-d) δ 8.47 (s, 1H), 7.98 (s, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 9.1 Hz,
1H), 7.40 (d, J = 6.5 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.04 (d, J =
5.8 Hz, 1H), 4.97 (q, J = 5.8 Hz, 1H), 3.93 (s, 3H), 3.35 (dd, J = 16.1, 6.3 Hz, 1H), 3.15 (dd, J
= 16.1, 5.2 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 167.5, 150.5, 141.7, 137.4, 130.1, 127.8,
126.6, 126.4, 126.0, 125.7, 125.2, 124.2, 120.9, 117.3, 74.3, 69.9, 52.2, 39.7. HRMS calcd.
for C18H16N2O3 [M + H+] 309.1234, found 309.1230.
27
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10.1002/chem.201800763
Chemistry - A European Journal
2-(2-(1H-Indol-3-yl)ethyl)-6-fluoro-2H-indazole (59): Synthesized from 4-fluoro-2-
nitrobenzaldehyde (111.6 mg, 0.66 mmol) and tryptamine (117.0 mg, 0.73 mmol). The
product was purified by flash chromatography on silica gel (0-20% EtOAc/cyclohexane) to
1
afford 151 mg (82% yield) of 59 as a beige solid. m.p. 178-180°C. H NMR (600 MHz,
Chloroform-d): δ 8.12 (s, 1H), 7.63 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 9.0, 5.3 Hz,
1H), 7.35 (t, J = 10.3 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.87 (td, J =
9.1, 1.7 Hz, 1H), 6.74 (s, 1H), 4.67 (t, J = 7.0 Hz, 2H), 3.47 (t, J = 7.0 Hz, 2H). 13C NMR
(151 MHz, CDCl3): δ 162.7, 161.1, 148.8, 148.7, 136.4, 127.0, 124.0, 122.7, 122.4, 122.1,
122.0, 119.7, 118.7, 118.5, 113.3, 113.1, 111.7, 111.5, 100.7, 100.5, 54.4, 26.8. HRMS
calcd. for C17H14FN3 [M + H+] 280.1245, found 280.1241.
2-(2-(1H-Indol-3-yl)ethyl)-2H-pyrazolo[3,4-c]pyridine
(60):
Synthesized
from
3-
nitroisonicotinaldehyde (100.4 mg, 0.66 mmol) and tryptamine (117.0 mg, 0.73 mmol). The
product was purified by flash chromatography on silica gel (0-60% EtOAc/cyclohexane) to
1
afford 111 mg (64% yield) of 60 as a brown solid. m.p. 149-151°C. H NMR (600 MHz,
Chloroform-d) δ 9.29 (s, 1H), 8.13 (d, J = 5.9 Hz, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 7.56 (d, J =
7.9 Hz, 1H), 7.42 (d, J = 5.9 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.13 (t,
J = 7.4 Hz, 1H), 6.75 (s, 1H), 4.78 (t, J = 7.0 Hz, 2H), 3.51 (t, J = 7.0 Hz, 2H). 13C NMR (151
MHz, CDCl3) δ 145.8, 144.1, 137.6, 136.4, 127.0, 123.9, 123.3, 122.7, 122.5, 119.9, 118.4,
113.9, 111.5, 111.5, 55.0, 27.0. HRMS calcd. for C16H14N4 [M + H+] 263.1291, found
263.1293.
6-Methoxy-2-((tetrahydrofuran-2-yl)methyl)-2H-indazole (61): Synthesized from 4-
methoxy-2-nitrobenzaldehyde (120 mg, 0.66 mmol) and (tetrahydrofuran-2-yl)methanamine
(75.2 µL, 0.73 mmol). The product was purified by flash chromatography on silica gel (0-30%
1
EtOAc/cyclohexane) to afford 109 mg (71% yield) of 61 as a yellow oil. H NMR (600 MHz,
Chloroform-d) δ 7.89 (s, 1H), 7.47 (d, J = 9.1 Hz, 1H), 6.93 (s, 1H), 6.74 (dd, J = 9.1, 2.1 Hz,
1H), 4.47-4.42 (m, 1H), 4.37-4.30 (m, 2H), 3.82 (s, 4H), 3.76-3.71 (m, 1H), 2.03-1.97 (m, 1H),
1.87-1.79 (m, 1H), 1.77-1.69 (m, 1H), 1.66-1.61 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 158.8,
149.6, 124.0, 121.1, 117.5, 116.5, 94.6, 77.8, 68.5, 57.2, 55.2, 28.8, 25.7. HRMS calcd. for
C13H16N2O2 [M + H+] 233.1285, found 233.1284.
2-(Benzo[d][1,3]dioxol-5-ylmethyl)-N,N-dimethyl-2H-indazol-6-amine (62): Synthesized
from 4-(dimethylamino)-2-nitrobenzaldehyde (128.2 mg, 0.66 mmol) and benzo[d][1,3]dioxol-
5-ylmethanamine (90.9 µL, 0.73 mmol). The product was purified by flash chromatography
on silica gel (0-20% EtOAc/cyclohexane) to afford 84 mg (43% yield) of 62 as a brown oil.
1H NMR (600 MHz, Chloroform-d) δ 7.70 (s, 1H), 7.46 (d, J = 9.1 Hz, 1H), 6.92-6.85 (m, 1H),
13
6.82-6.73 (m, 4H), 5.92 (s, 2H), 5.38 (s, 2H), 2.97 (s, 6H). C NMR (151 MHz, CDCl3) δ
28
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10.1002/chem.201800763
Chemistry - A European Journal
150.9, 149.9, 148.2, 147.7, 130.1, 122.5, 121.7, 120.4, 116.4, 115.3, 108.6, 108.5, 101.3,
95.9, 57.0, 41.5. HRMS calcd. for C17H17N3O2 [M + H+] 296.1394, found 296.1393.
III. General procedure for the 3-amino-2H-indazole synthesis
The benzamidine derivative 63 were synthesized according to a known procedure.[2b] To a
solution of benzamidine derivative 63 (0.33 mmol) and 3-methyl-1-phenyl-2-phospholene 1-
oxide (101.8 mg, 0.53 mmol) in dry toluene (4 mL) in a sealed tube was added diphenylsilane
(317.1 µL, 1.72 mmol) at room temperature. The reaction mixture was heated at 110°C for 24
h. After completion of the reaction as monitored by LCMS, the mixture was cooled down to
room temperature and transferred into a round bottom flask using DCM as a solvent. The
solvents were removed under reduced pressure and the crude product was purified by flash
chromatography on silica gel using EtOAc/cyclohexane as eluent.
2-(4-Bromophenyl)-6-methyl-2H-indazol-3-amine
(65):
Synthesized
from
N'-(4-
bromophenyl)-4-methyl-2-nitrobenzimidamide (110.3 mg, 0.33 mmol). The product was
purified by flash chromatography on silica gel (0-15% EtOAc/cyclohexane) to afford 65 mg
(65% yield) of 65 as a pale yellow solid. m.p. 249-251°C. 1H NMR (600 MHz, Chloroform-d) δ
7.66 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 1H), 7.25 (s, 1H), 6.74
(d, J = 8.6 Hz, 1H), 4.24 (s, 2H), 2.41 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 149.4, 138.1,
137.9, 137.9, 132.9, 126.3, 122.1, 122.1, 118.8, 115.3, 108.4, 22.5. HRMS calcd. for
C14H12BrN3 [M + H+] 302.0287, found 302.0295.
6-Methoxy-2-(4-(methylsulfonyl)phenyl)-2H-indazol-3-amine (66): Synthesized from 4-
methoxy-N'-(4-(methylsulfonyl)phenyl)-2-nitrobenzimidamide (115.3 mg, 0.33 mmol). The
product was purified by flash chromatography on silica gel (0-5% MeOH/DCM) to afford
71 mg (68% yield) of 66 as a yellow solid. m.p. 228-230°C. 1H NMR (600 MHz, DMSO-d6) δ
8.07 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 9.1 Hz, 1H), 6.58 (d, J = 2.0 Hz,
1H), 6.47 (s, 2H), 6.38 (dd, J = 9.1, 2.1 Hz, 1H), 3.76 (s, 3H), 3.28 (s, 3H). 13C NMR (151
MHz, DMSO) δ 159.9, 149.7, 143.5, 141.8, 138.2, 128.2, 123.5, 122.4, 111.7, 105.0, 92.7,
54.9, 43.6. HRMS calcd. for C15H15N3O3S [M + H+] 318.0907, found 318.0916.
2-(4-(Dibenzylamino)phenyl)-5-fluoro-2H-indazol-3-amine (67): Synthesized from N'-(4-
(dibenzylamino)phenyl)-5-fluoro-2-nitrobenzimidamide (150.0 mg, 0.33 mmol). The product
was purified by flash chromatography on silica gel (0-15% EtOAc/cyclohexane) to afford
48 mg (34% yield) of 67 as a yellow solid. m.p. 220-221°C. 1H NMR (600 MHz, DMSO-d6) δ
7.41 (dd, J = 9.7, 2.4 Hz, 1H), 7.39-7.29 (m, 10H), 7.28-7.23 (m, 3H), 6.98 (td, J = 9.3, 2.5
Hz, 1H), 6.80 (d, J = 9.0 Hz, 2H), 5.87 (s, 2H), 4.79 (s, 4H). 13C NMR (151 MHz, DMSO) δ
155.1, 153.6, 147.6, 144.7, 140.6, 140.6, 138.6, 128.6, 128.0, 126.8, 126.6, 125.3, 117.6,
29
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