A simple synthesis of 2-{2-[(arylmethylidene)amino]-indazol-3-yl}malonate esters

Article abstract of DOI:10.1007/s10593-020-02699-0

[Figure not available: see fulltext.] A method was developed for the synthesis of dimethyl {2-[(arylmethylidene)amino]-2H-indazol-3-yl}malonates on the basis of a Knoevenagel condensation between 2-azidobenzaldehyde and dimethyl malonate, followed by treatment of the obtained adduct with aromatic aldehydes in the presence of polymer-supported triphenylphosphine. It was shown that the interaction of the synthesized Schiff bases with Corey ylide provided a route for the synthesis of 2-(aziridin-1-yl)indazoles.

Full text of DOI:10.1007/s10593-020-02699-0

DOI 10.1007/s10593-020-02699-0
Chemistry of Heterocyclic Compounds 2020, 56(5), 555–561
A simple synthesis of 2-{2-[(arylmethylidene)amino]-
indazol-3-yl}malonate esters
1
1,2
3
Lyubov I. Kuznetsova , Alexey O. Chagarovskiy , Irina I. Levina ,
4
1,4
1,2
Victor B. Rybakov , Olga A. Ivanova *, Igor V. Trushkov *
1
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky Ave., Moscow 119991, Russia; e-mail: trush@ioc.ac.ru
2
3
4
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology,
Samory Mashela St., Moscow 117997, Russia
M. N. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences,
Kosygina St., Moscow 119334, Russia
Lomonosov Moscow State University,
Build. 3 Leninskie Gory, Moscow 119991, Russia;
e-mail: iv@kinet.chem.msu.ru
1
4
1
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
020, 56(5), 555–561
Submitted November 28, 2019
Accepted after revision April 24, 2020
2
A method was developed for the synthesis of dimethyl {2-[(arylmethylidene)amino]-2H-indazol-3-yl}malonates on the basis of a Knoevenagel
condensation between 2-azidobenzaldehyde and dimethyl malonate, followed by treatment of the obtained adduct with aromatic
aldehydes in the presence of polymer-supported triphenylphosphine. It was shown that the interaction of the synthesized Schiff bases
with Corey ylide provided a route for the synthesis of 2-(aziridin-1-yl)indazoles.
Keywords: aldehydes, alkenes, aziridines, indazoles, organic azides.
Polyfunctional reagents continue to attract significant
interest of synthetic organic chemists, since the presence of
several functional groups with a relative arrangement
enables a wide range of chemical transformations in such
compounds, making them convenient building blocks for
the assembly of natural compounds, synthetic
pharmaceutical substances, and other products with useful
properties.
the СН acid and reaction conditions. Thus, suitable nitriles
reacted with 2-azidobenzaldehyde (1), leading to the
2–4
formation of either tetrazolo[1,5-a]quinolines (Scheme 1a)
4,5
or triazolo[1,5-a]quinazolines (Scheme 1b). However, the
reaction of 2-azidobenzaldehyde (1) with dialkyl malonates,
keto esters, or 1,3-diketones produced the "classic"
Knoevenagel adducts 2, which upon irradiation were
6
,7
converted into either 2,3-substituted indoles (Scheme 1с)
7
One of such polyfunctional reagents is 2-azidobenz-
aldehyde (1), the azide and formyl groups of which may
participate in a wide range of transformations leading to
or quinolines (Scheme 1d). The latter were also formed by
treatment with sodium sulfide, triethyl phosphite,8 and
triphenylphosphine9 (Scheme 1d). At the same time,
Molina et al. reported that diethyl (2-azidobenzylidene)-
malonate in the presence of triphenylphosphine was
converted into an indazole derivative (Scheme 1e). The
formation of this compound was recognized to be of great
practical significance, since such iminophosphoranes can
be efficiently transformed not only into various
3
1
a signifacant increase of structural complexity. Among
such transformations, diverse condensations of the
aldehyde group with СН acids, followed by the
involvement of the azide group in the formation of a new
ring form one of the most important groups. The chemo-
selectivity of these reactions depends both on the nature of
10
0
009-3122/20/56(5)-0555©2020 Springer Science+Business Media, LLC
555

Chemistry of Heterocyclic Compounds 2020, 56(5), 555–561
Scheme 1
2
-aminoindazole derivatives having
a
significant
Scheme 2
1
1
pharmacological potential,
but also into certain
polyheterocyclic compounds that may find applications
1
2
both as biologically active agents and in the field of
materials science. Unfortunately, Molina et al. provided
only a single example for the given transformation. As
recently demonstrated by the Ding research group,13
pyrazolo[1,5-b]indazoles were formed from the cor-
responding 1,3-diketones, β-keto esters, and β-ketoamides
under similar conditions (Scheme 1f). For these reasons,
there has been a significant interest in detailed study of this
remarkable transformation, including the factors directing
reaction of (2-azidobenzylidene)malonates with triphenyl-
phosphine, and in the synthesis of new 2-aminoindazole
derivatives.
We also found that during the synthesis of indazole 4a, it is
advantageous to use polymer-supported triphenylphosphine.
Even though this approach required a longer time for
achieving a complete conversion of azidoalkene, the
immobilized phosphine and its transformation products
could be easily removed by filtration after the completion
of the reaction, not only providing for an easier
experimental procedure, but also substantially improving
the yield of compound 4a, compared to the use of
triphenylphosphine itself. The structure of product 4а was
confirmed on the basis of X-ray structural analysis results
(Fig. 1).
In the current work, we studied the interaction of
dimethyl 2-(2-azidobenzylidene)malonate (2) with aromatic
aldehydes 3a–i in the presence of polymer-supported
triphenylphosphine at room temperature. It was shown that
the products were ({2-[(het)arylmethylidene]amino}-
indazol-3-yl)malonates 4a–i – a previously unknown
subtype of indazole derivatives.
The most efficient method for the preparation of the
starting material – 2-azidobenzaldehyde (1) is the reaction
of 2-nitrobenzaldehyde with NaN
3
in hexamethyl-
1
4
phosphoramide (HMPA), but this solvent has been
categorized as undesirable due to its carcinogenic proper-
ties. Another study published by Gribble in 1997 proposed
15
to perform this reaction via moderate heating in DMF.
Indeed, 2-azidobenzaldehyde (1) was formed under those
conditions in a quite high yield. A subsequent step
involving the Knoevenagel reaction of 2-azidobenz-
aldehyde (1) and dimethyl malonate allowed to obtain
dimethyl 2-(2-azidobenzylidene)malonate (2) (Scheme 2).
It is important to note that this reaction must be performed
using PhH as solvent, since refluxing the mixture in PhMe
resulted in a spontaneous decomposition, associated with a
significant heating of the reaction mixture and dangerous
gas evolution.
After the synthesis of azidoalkene 2, we studied its
reaction with triphenylphosphine and benzaldehyde (3a),
finding that the sole product of this reaction was 2-(benzyl-
idenamino)indazole 4а (Scheme 2), the formation of which
was in agreement with the mechanism of interrupted
1
0
Staudinger reaction (Scheme 1e), but not with direct
formation of iminophosphorane, which would be the
reaction intermediate giving rise to quinolines (Scheme 1d).9
Figure 1. The molecular structure of compound 4a with atoms
represented by thermal vibration ellipsoids of 30% probability.
5
56

Chemistry of Heterocyclic Compounds 2020, 56(5), 555–561
We studied the scope of applicability for this reaction
or at 0°С10,13 led to the formation of indazole derivatives
via an interrupted Staudinger reaction. On the other hand, if
the reaction with triphenylphosphine was performed under
and demonstrated that various aromatic aldehydes 3b–i
containing either electron-donating or electron-withdrawing
groups afforded (2-{[(het)arylmethylidene]amino}indazol-
9
heating, rapid elimination of a molecular dinitrogen was
3
-yl)malonates 4b–i in good yields (Scheme 3, Table 1).
Aldehydes with heteroaromatic substituents also can be
efficiently involved into the given process.
observed, with the formation of iminophosphoranes
according to the typical course of the Staudinger reaction.
We demonstrated the significant synthetic potential of
the synthesized Schiff bases by using the example of imine
Scheme 3
16
4
а as a model compound in a Corey–Chaykovsky reaction.
MeO2C
As a result of this interaction, aziridine 5 was obtained in a
7% yield (Scheme 5). The respective aziridines are
CO Me
2
1
2
. Polymer-bound TPP
CH2Cl)2, 20°C, 2 h
6
CO2Me
CO2Me
(
polyfunctional compounds that could be subjected to
further structural modifications for the purpose of
assembling important biologically active molecules.
N N
. RCHO 3b–i, (CH Cl)
2
N
R
N3
2
90°C, 5–8 h
2
4b–i
Scheme 5
Table 1. The reaction conditions and isolated yields in the
synthesis of iminoindazoles 4b–i
Com-
pound
Reaction time,
h
R
Yield, %
4
b
3-BrC
6
H
4
6
6
6
5
5
8
5
5
75*
48*
4
c
4-MeOC
6
H
4
4
d
Thiophen-2-yl
4-MeC
4-FC
4-O NC
77*
4
e
6
H
4
77**
71**
48**
59**
63**
The structure of product 5 was established on the basis
1
13
of the data obtained from H– C HMBC experiment. Thus,
signals of the methylеne group protons of the small ring
appeared as double doublets at 2.70 and 3.78 ppm and
exhibited cross peaks with the quaternary carbon atom of
the phenyl substituent at 136.6 ppm. The signal of the
methine proton of the malonate residue at 5.76 ppm
correlated with the quaternary carbon atom signals of the
indazole system at 120.2 and 124.6 ppm (Fig. 2).
4
f
6 4
H
4
g
2
6 4
H
4
h
5-Me-furan-2-yl
4
i
5-Me-thiophen-2-yl
*
*
Yield after chromatographic purification.
2 2
* Yield after recrystallization from 1:1 mixture of CH Cl – petroleum
ether.
The reaction leading to the preparation of indazoles 4
can be viewed as a domino process: the initial formation of
phosphazene intermediate
I
was followed by its
cyclization, leading to iminophosphorane II. As a result of
the reaction between iminophosphorane II and (hetero)-
aromatic aldehydes 3, the target imines 4 were obtained
(
Scheme 4).
Scheme 4
MeO C
CO Me
MeO C
2
CO Me
2
2
2
1
13
Figure 2. The characteristic correlations in H– C HMBC spect-
rum of compound 5.
Ph3P
N
PPh3
Thus, we have developed a simple method for the
preparation of substituted 2-{2-[(arylmethylidene)amino]-
indazol-3-yl}malonate esters on the basis of a reaction
between 2-azidobenzylidenemalonate and aromatic alde-
hydes in the presence of polymer-supported triphenyl-
phosphine. The results of this work provide a contribution
to understanding the effects of the reagent type and
reaction conditions on the chemoselectivity in the reactions
between 2-azidobenzylidene derivatives of a СН acid and
phosphines.
N N N
N
N
2
I
MeO2C
MeO2C
RCHO
3
CO2Me
CO2Me
N N
N N
N
PPh3
N
R
II
4
Comparison of the reaction conditions that resulted in
the formation of either indazoles or quinolines from
-azidobenzylidene derivatives of malonic acid, β-keto
esters, and 1,3-diketones showed that the temperature regime
and the nature of phosphorus(III) reagent were the key
factors determining the reaction chemoselectivity. The use
of triphenylphosphine at room temperature (in this study)
2
Experimental
IR spectra were recorded on a Thermo Scientific Nicolet
IR 200 FT-IR spectrometer with the spectral resolution of
–1
4 cm , the number of scans was 20, using a ZnSe ATR
5
57

Chemistry of Heterocyclic Compounds 2020, 56(5), 555–561
1
13
accessory with an incidence angle of 45°. Н and С NMR
mixture was stirred at room temperature for 2 h, followed
by the addition of the appropriate aldehyde 3a–d and
refluxing at 90°С for 6 h. The solid polymer was removed
by filtration and washed with 1,2-dichloroethane (2×5 ml).
The filtrate was concentrated at reduced pressure, the
residue was purified by chromatography on alumina
(petroleum ether – EtOAc eluent system, gradient from
20:1 to 4:1).
Dimethyl {2-[(phenylmethylidene)amino]-2H-indazol-
3-yl}malonate (4a) was obtained from a solution of com-
pound 2 (1.0 g, 3.83 mmol) in 1,2-dichloroethane (20 ml),
using polymer-supported triphenylphosphine (2.55 g,
7.65 mmol) and benzaldehyde (3a) (0.71 ml, 7.67 mmol).
Yield 0.95 g (71%), colorless crystals, mp 126.4–127.7°С
spectra (500 and 126 MHz, respectively), as well as the two-
1
13
1
13
1
15
dimensional H– C HMBC, Н– С HSQC, and Н– N
HMBC experiments were acquired on a Bruker Avance-
5
00 instrument, using the residual solvent signals as
1
internal standard (CDCl : 7.26 ppm for Н nuclei, 77.2 ppm
3
1
3
1
for С nuclei; DMSO-d
6
: 2.50 ppm for Н nuclei, 39.5 ppm
1
3
1
for С nuclei; CD
3
OD: 3.31 ppm for Н nuclei, 49.0 ppm
13
for
С
nuclei). High-resolution mass spectra with
electrospray ionization were recorded on an LTQ Orbitrap
Elite instrument for samples in MeCN–H O solutions,
2
using HCO
2
Na–HCO H for calibration. Elemental analysis
2
was performed on a Fisons EA-1108 instrument.
The starting materials used in this study were commerci-
ally available reagents. The polymer-supported triphenyl-
phosphine was a diphenylphosphinylated copolymer of
styrene and divinylbenzene (CAS 39319-11-4), with the
triphenylphosphine content of the polymer equivalent to
(CH
2
Cl
2
), R
f
0.51 (petroleum ether – EtOAc, 4:1).
–1
IR spectrum, ν, cm : 3066, 3037, 3018, 2954, 1751, 1739,
1598, 1574, 1477, 1448, 1436, 1319, 1309, 1273, 1198,
1
1153, 1016. H NMR spectrum (CDCl
3
), δ, ppm: 3.82 (6H,
3
mmol/g.
2
s, 2ОCH ); 5.94 (1H, s, CH); 7.15–7.18 (1H, m, H Ar);
3
1
5
-Azidobenzaldehyde (1). A solution of o-nitrobenz-
7.38–7.42 (1H, m, H Ar); 7.51–7.57 (3H, m, H Ar); 7.72–
7.76 (2H, m, H Ar); 7.97–8.00 (2H, m, H Ar); 9.54 (1H, s,
aldehyde (8.0 g, 53 mmol) in anhydrous DMF (106 ml)
was stirred under argon atmosphere and treated by the
CH=N). 13C NMR spectrum (CDCl
), δ, ppm: 48.7 (CH);
3
addition of NaN
3
(6.89 g, 1.06 mmol). The reaction
53.2 (2OCH ); 117.4 (CH Ar); 120.5 (CH Ar); 120.9
3
mixture was heated on an oil bath at 60°C for 20 h, then
cooled, and poured into ice water (70 ml). The aqueous
phase was extracted with EtOAc (5×30 ml), then washed
(C Ar); 122.6 (CH Ar); 122.5 (C Ar); 127.9 (CH Ar); 129.0
(4CH Ar); 132.0 (CH Ar); 132.6 (C Ar); 145.9 (C Ar);
153.6 (CH=N); 166.8 (2CO
2
СH ). Found, m/z: 352.1298
3
+
with brine (5×20 ml) and H
(
2
O (2×20 ml). Yield 4.36 g
[M+H] . С19
Н
18
N
3
O . Calculated, m/z: 352.1292. Found,
4
56%). The physicochemical characteristics of the obtained
%: С 64.69; Н 4.87; N 11.56. С19
Н
17
N
3
O . Calculated, %:
4
15,17
azide 1 were in agreement with those described earlier.
Dimethyl 2-(2-azidobenzylidene)malonate (2).
C 64.95; H 4.88; N 11.96.
A
Dimethyl (2-{[(3-bromophenyl)methylidene]amino}-
2H-indazol-3-yl)malonate (4b) was obtained from a
solution of compound 2 (0.50 g, 1.92 mmol) in 1,2-dichloro-
ethane (29 ml), using polymer-supported triphenyl-
phosphine (1.28 g, 3.84 mmol) and 3-bromobenzaldehyde
(3b) (0.69 ml, 5.89 mmol). Yield 0.62 g (75%), colorless
solution of 2-azidobenzaldehyde (1) (4.75 g, 32.3 mmol)
and dimethyl malonate (3.69 ml, 32.3 mmol) in PhH (10 ml)
was treated by the addition of glacial AcOH (0.37 ml,
6
.5 mmol) and piperidine (0.13 ml, 1.3 mmol). The
reaction mixture was refluxed in a flask equipped with a
Dean–Stark trap until the evolution of H O ceased. The
organic layer was washed with brine (4×10 ml) and dried
with anhydrous Na SO . PhH was evaporated at reduced
crystals, mp 112–113°С, R 0.54 (petroleum ether – EtOAc,
f
2
–1
4:1). IR spectrum, ν, cm : 3019, 2959, 1757, 1739, 1603,
2
4
1557, 1520, 1430, 1383, 1350, 1294, 1280, 1215, 1199,
1
pressure, the residue was purified by column
chromatography on silica gel using a petroleum ether –
EtOAc eluent system with a gradient from 20:1 to 4:1.
1178, 1070. H NMR spectrum (CDCl
3
), δ, ppm (J, Hz):
3.83 (6H, s, 2ОCH
3
); 5.89 (1H, s, CH); 7.14 (1H, ddd,
3
3
4
J = 8.5, J = 6.7, J = 0.5, H Ar); 7.36–7.41 (2H, m, H Ar);
3
4
4
Yield 4.26 g (61%), yellow solid, mp 85–86°C, R
f
0.58
7.66 (1H, ddd, J = 8.1, J = 1.8, J = 1.1, H Ar); 7.69 (1H,
3 3
–
1
(
petroleum ether – EtOAc, 4:1). IR spectrum, ν, cm :
br. d, J = 8.9, H Ar); 7.72 (1H, br. d, J = 8.5, H Ar); 7.84
3 4 4
2
954, 2451, 2139, 2106, 1735, 1693, 1626, 1595, 1481,
(1H, br. d, J = 7.6, H Ar); 8.12 (1H, dd, J = 1.8, J = 1.2,
H Ar); 9.46 (1H, s, CH=N). 13C NMR spectrum (CDCl
),
); 117.5 (CH Ar); 120.6
1
456, 1392, 1315, 1267, 1221, 1093, 1063, 976, 933.
3
1
H NMR spectrum (CDCl
3
), δ, ppm (J, Hz): 3.75 (3H, s,
δ, ppm: 48.7 (CH); 53.2 (2ОCH
3
3
OCH
3
); 3.82 (3H, s, OCH
3
); 7.08 (1H, ddd, J = 8.4,
(CH Ar); 121.0 (C Ar); 122.8 (CH Ar); 123.2 (C Ar); 125.5
(C); 127.9 (CH Ar); 128.1 (CH Ar); 130.5 (CH Ar); 131.2
3
4
3
4
J = 8.0, J = 0.6, H Ar); 7.16 (1H, dd, J = 8.1, J = 0.6,
3
4
H Ar); 7.33 (1H, dd, J = 8.0, J = 1.5, H Ar); 7.40 (1H,
(CH Ar); 134.7 (C Ar); 134.8 (CH Ar); 146.0 (C Ar); 152.1
3
3
4
+
ddd, J = 8.4, J = 8.1, J = 1.5, H Ar); 7.95 (1H, s, CH=).
(CH=N); 166.6 (2CO
2
СH
3
). Found, m/z: 430.0397 [M+H] .
1
3
C NMR spectrum (CDCl
3
), δ, ppm: 52.5; 52.7; 118.5;
C
19
H
17BrN
3
O . Calculated, m/z: 430.0397. Found, %:
4
1
24.7; 124.8; 126.6; 128.9; 131.7; 138.1; 139.6; 164.2; 166.6.
C 53.20; Н 3.75; N 9.77. C19
H
16BrN
3
O . Calculated, %:
4
+
Found, m/z: 262.0823 [M+H] . С12
m/z: 262.0822. Found, %: С 55.16; Н 4.23; N 16.08.
. Calculated, %: C 55.17; H 4.24; N 16.09.
Synthesis of compounds 4a–d (General method). A
Н
12
N
3
O
4
. Calculated,
C 53.04; H 3.75; N 9.77.
Dimethyl (2-{[(4-methoxyphenyl)methylidene]amino}-
2H-indazol-3-yl)malonate (4c) was obtained from a solu-
tion of compound 2 (0.20 g, 0.77 mmol), using polymer-
supported triphenylphosphine (0.51 g, 1.53 mmol) in
1,2-dichloroethane (4 ml) and 4-methoxybenzaldehyde (3с)
(0.17 ml, 1.53 mmol). Yield 141 mg (48%), yellowish
12
C H
11
N
3
O
4
solution of azidoalkene 2 in 1,2-dichloroethane was stirred
under argon atmosphere and treated with 2 equiv of
polymer-supported triphenylphosphine. The obtained
5
58

Chemistry of Heterocyclic Compounds 2020, 56(5), 555–561
crystals, mp 157–159°С, R
f
0.56 (petroleum ether – EtOAc,
H Ar); 7.31–7.33 (2H, m, H Ar); 7.36–7.39 (1H, m, H Ar);
7.70–7.74 (2H, m, H Ar); 7.85–7.87 (2H, m, H Ar); 9.50
–
1
4
1
1
:1). IR spectrum, ν, cm : 3036, 3009, 2922, 2900, 2807,
13
734, 1717, 1583, 1550, 1499, 1419, 1364, 1293, 1266,
(1H, s, CH=N). C NMR spectrum (CDCl
3
), δ, ppm: 21.8
); 117.4 (CH Ar); 120.6
1
236, 1198, 1155, 1143, 1021, 1007, 971. H NMR
(CH ); 48.8 (CH); 53.2 (2OCH
3
3
spectrum (CDCl
3
), δ, ppm (J, Hz): 3.77 (6H, s, 2ОCH
3
3
);
(CH Ar); 121.0 (C Ar); 122.6 (CH Ar); 125.1 (C Ar); 127.8
(CH Ar); 129.1 (2CH Ar); 129.8 (2CH Ar); 130.0 (C Ar);
3
.86 (3H, s, ОCH ); 5.87 (1H, s, CH); 6.98 (2H, br. d,
3
J = 8.8, H Ar); 7.08–7.11 (1H, m, H Ar); 7.31–7.35 (1H,
142.9 (C Ar); 145.8 (C Ar); 153.8 (CH=N); 166.9
+
m, H Ar); 7.65–7.68 (2H, m, H Ar); 7.87 (2H, br. d,
(2CO
2
СH
3
). Found, m/z: 366.1449 [M+H] . С20
Н
20
N
3
O .
4
3
13
J = 8.8, H Ar); 9.42 (1H, s, CH=N). C NMR spectrum
Calculated, m/z: 366.1448.
(
CDCl
3
), δ, ppm: 48.7 (CH); 53.1 (2ОCH
3
); 55.4 (ОCH
3
);
Dimethyl (2-{[(4-fluorophenyl)methylidene]amino}-
1
14.5 (2CH Ar); 117.3 (CH Ar); 120.4 (CH Ar); 120.8
2H-indazol-3-yl)malonate (4f). Yield 141 mg (71%),
(
(
C Ar); 122.4 (CH Ar); 124.6 (C); 125.3 (C Ar); 127.5
CH Ar); 130.9 (2CH Ar); 145.6 (C Ar); 153.2 (CH=N);
beige crystals, mp 162–163°С, R 0.47 (petroleum ether –
f
–1
EtOAc, 4:1). IR spectrum, ν, cm : 3075, 3005, 2955, 1760,
1
62.8 (C Ar); 166.8 (2CO
2
СH
. Calculated, m/z: 382.1397. Found,
: 62.62; Н 5.08; N 10.90. C20 . Calculated, %:
3
). Found, m/z: 382.1391
1745, 1600, 1585, 1510, 1480, 1435, 1380, 1305, 1230,
+
1
[
M+H] . C20
H
20
N
3
O
5
1155, 1015, 880, 830, 750. H NMR spectrum (CDCl
3
),
%
H
19
N
3
O
5
δ, ppm: 3.81 (6H, s, 2OCH ); 5.90 (1H, s, CH); 7.12–7.20
3
C 62.99; H 5.02; N 11.02.
(3H, m, H Ar); 7.35–7.38 (1H, m, H Ar); 7.68–7.73 (2H,
Dimethyl 2-(2-{[(thien-2-yl)methylidene]amino}-2H-
indazol-3-yl)malonate (4d) was obtained from a solution
of compound 2 (0.30 g, 1.15 mmol) in 1,2-dichloroethane
m, H Ar); 7.93–7.96 (2H, m, H Ar); 9.48 (1H, s, CH=N).
13
C NMR spectrum (CDCl ), δ, ppm (J, Hz): 48.8 (CH);
3
2
53.3 (2OCH ); 116.4 (d, JCF = 22, 2CH Ar); 117.5 (CH
3
(
6 ml), using polymer-supported triphenylphosphine (0.76 g,
Ar); 120.6 (CH Ar); 121.0 (C Ar); 122.7 (CH Ar); 125.3
4
2
2
9
.3 mmol) and 2-thienylcarbaldehyde (3d) (0.21 ml,
(C Ar); 128.0 (CH Ar); 128.9 (d, JCF = 3, C Ar); 131.2
3
.3 mmol). Yield 0.32 g (77%), yellowish crystals, mp 93–
(d, JCF = 9, 2СH Ar); 145.9 (C Ar); 152.5 (CH=N); 165.1
4°С, R
f
0.58 (petroleum ether – EtOAc, 4:1). IR spectrum,
(d, 1
J
CF = 254, C Ar); 166.8 (2CO
2
СH
3
). Found, m/z:
–
1
+
ν, cm : 3080, 3019, 2959, 1748, 1735, 1587, 1438, 1323,
370.1195 [M+H]
370.1198.
С
19
Н
17FN
3
O . Calculated, m/z:
4
1
1
269, 1157, 1018. H NMR spectrum (CDCl
δ, ppm (J, Hz): 3.81 (6H, s, 2ОCH ); 5.84 (1H, s, CH);
.10–7.14 (1H, m, H Ar); 7.17 (1H, dd, J = 5.0, J = 3.6,
3
+ CD OD),
3
3
Dimethyl
(2-{[(4-nitrophenyl)methylidene]amino}-
3
3
7
2H-indazol-3-yl)malonate (4g). Reaction time 8 h. Yield
H thiophene); 7.33–7.37 (1H, m, H Ar); 7.58 (1H, br. d,
102 mg (48%), bright-yellow crystals, mp 201–202°С,
3
3
–1
J = 5.0, H thiophene); 7.60 (1H, br. d, J = 3.6,
R
f
0.28 (petroleum ether – EtOAc, 2:1). IR spectrum, ν, cm :
H thiophene); 7.65–7.69 (2H, m, H Ar); 9.63 (1H, s,
CH=N). C NMR spectrum (CDCl
3065, 2950, 2850, 1755, 1740, 1520, 1440, 1340, 1305,
13
1
3
+ CD
3
OD), δ, ppm:
1280, 1220, 1155, 845, 755. H NMR spectrum (DMSO-d
6
),
4
1
1
8.5 (CH); 53.1 (2ОCH
3
); 117.1 (CH Ar); 120.3 (CH Ar);
δ, ppm: 3.74 (6H, s, 2OCH
3
); 6.23 (1H, s, CH); 7.15–7.18
20.8 (C Ar); 122.5 (C Ar); 124.7 (C Ar); 127.7 (CH Ar);
28.0 (CH Ar); 131.3 (CH Ar); 134.2 (CH Ar); 137.3 (CH
(1H, m, H Ar); 7.40–7.43 (1H, m, H Ar); 7.67–7.75 (2H,
m, H Ar); 8.28–8.30 (2H, m, H Ar); 8.41–8.42 (2H, m,
Ar); 145.7 (C Ar); 147.6 (CH=N); 166.7 (2CO
2
СH
3
).
H Ar); 9.68 (1H, s, CH=N). 13C NMR spectrum (DMSO-d
6
),
); 117.3 (CH Ar); 120.6
+
Found, m/z: 358.0860 [M+H] . C17
m/z: 358.0856.
H
16
N
3
O
4
S. Calculated,
δ, ppm: 47.9 (CH); 53.1 (2OCH
3
(CH Ar); 120.8 (C Ar); 122.7 (CH Ar); 124.2 (2CH Ar);
126.6 (C Ar); 128.5 (CH Ar); 130.3 (2CH Ar); 138.3
Synthesis of compounds 4e–i (General method). A 10-ml
screw cap vial was charged with a solution of azide 2
(C Ar); 145.4 (C Ar); 149.3 (C Ar); 152.0 (CH=N); 166.5
+
(
140 mg, 0.54 mmol) in 1,2-dichloroethane (5.4 ml), then
(2CO
2
СH
3
). Found, m/z: 397.1139 [M+H] . С19
Н
17
N
4
O .
6
polymer-supported triphenylphosphine (355 mg, 1.07 mmol)
was added and the mixture was stirred until complete
conversion of the starting azide (control by TLC) at room
temperature (1–2 h), followed by the addition of the
appropriate aldehyde 3e–i (1.62 mmol). The reaction
mixture was stirred in a sealed vial at 90°С for 5 h, after
which the precipitate was removed by filtration and washed
Calculated, m/z: 397.1143. Found, %: С 57.48; Н 4.11;
N 14.25. С19
N 14.14.
Н
16
N
4
O . Calculated, %: С 57.58; Н 4.07;
6
Dimethyl 2-(2-{[(5-methylfuran-2-yl)methylidene]-
amino}-2H-indazol-3-yl)malonate (4h). Yield 112 mg
(59%), yellow-brown crystals, mp 126–127°С, R 0.55
f
–1
(petroleum ether – EtOAc, 4:1). IR spectrum, ν, cm :
once with CH
2
Cl
2
(10 ml). The filtrate was evaporated at
3000, 2950, 1745, 1620, 1570, 1520, 1440, 1310, 1285,
1
reduced pressure and precipitated with petroleum ether.
The obtained solid precipitate was dried and recrystallized
1210, 1160, 1020, 750. H NMR spectrum (CDCl
3
), δ, ppm
4
(J, Hz): 2.46 (3Н, d, J = 0.9, CH
3
); 3.80 (6H, s, 2OCH );
3
3
4
as necessary from 1:1 mixture of CH
2
Cl
2
– petroleum ether.
6.00 (1H, s, CH); 6.22 (1H, dd, J = 3.6, J = 0.9, H furan);
3
Dimethyl (2-{[(4-methylphenyl)methylidene]amino}-
6.98 (1H, d, J = 3.6, H furan); 7.10–7.13 (1H, m, H Ar);
2
H-indazol-3-yl)malonate (4e). Yield 150 mg (77%),
7.33–7.36 (1H, m, H Ar); 7.65–7.67 (1H, m, H Ar); 7.72–
13
beige crystals, mp 159–160°С, R
f
0.50 (petroleum ether –
7.73 (1H, m, H Ar); 9.28 (1Н, s, CH=N). C NMR
–
1
EtOAc, 4:1). IR spectrum, ν, cm : 3030, 2960, 1755, 1740,
600, 1435, 1310, 1280, 1155, 1020, 1000, 815, 750.
spectrum (CDCl
3
), δ, ppm: 14.2 (CH ); 48.7 (CH); 53.2
3
1
(2OCH ); 108.9 (CH Ar); 116.7 (CH Ar); 120.3 (CH Ar);
3
1
H NMR spectrum (CDCl
3
), δ, ppm: 2.44 (3H, s, CH
3
);
120.4 (CH Ar); 120.6 (C Ar); 121.9 (CH Ar); 124.2 (C Ar);
127.1 (CH Ar); 141.6 (CH=N); 145.0 (C Ar); 146.6 (C Ar);
3
.81 (6H, s, 2OCH ); 5.94 (1H, s, CH); 7.13–7.16 (1H, m,
3
5
59

Chemistry of Heterocyclic Compounds 2020, 56(5), 555–561
1
57.3 (C Ar); 166.9 (2CO
2
СH
. Calculated, m/z: 356.1241. Found,
: С 60.80; Н 4.84; N 11.73. С18 . Calculated, %:
3
). Found, m/z: 356.1241
rature. The X-ray structural analysis was performed on a
+
[
M+H] . С18
Н
18
N
3
O
5
STOE STADIVARI PILATUS 100K single crystal diffracto-
meter. The structure was solved by direct methods. All
calculations were performed by using the SHELXT and
SHELXL-15 program sets.18 The tables of atomic
coordinates, bond lengths, valence and torsion angles, and
the anisotropic temperature parameters for compound 4а
were deposited at the Cambridge Crystallographic Data
Center (deposit CCDC 1585803).
%
Н
17
N
3
O
5
С 60.84; Н 4.82; N 11.83.
Dimethyl 2-(2-{[(5-methylthiophen-2-yl)methylidene]-
amino}-2H-indazol-3-yl)malonate (4i). Yield 126 mg
(
63%), beige crystals, mp 138–139°С, R 0.52 (petroleum
f
–1
ether – EtOAc, 4:1). IR spectrum, ν, cm : 3040, 2950,
1
1
750, 1730, 1580, 1490, 1440, 1380, 1295, 1270, 1155,
1
015, 805, 750. H NMR spectrum (CDCl
3
), δ, ppm
4
Supplementary information file containing Н and 13С
1
(
J, Hz): 2.57 (3H, d, J = 0.9, CH
3
); 3.81 (6H, s, 2OCH );
3
3
4
5
.84 (1H, s, CH); 6.83 (1H, dd, J = 3.5, J = 0.9,
NMR spectra of all synthesized compounds, as well as
1
13
1
13
H thiophene); 7.11–7.14 (1H, m, H Ar); 7.34–7.37 (1H, m,
Н– С HSQC and Н– С HMBC spectra of compounds
1 15
3
H Ar); 7.41 (1H, d, J = 3.5, H thiophene); 7.66–7.70 (2H,
4а and 5 and Н– N HMBC spectrum of compound 5 is
available at the journal website at http://link.springer.com/
journal/10593.
1
3
m, H Ar); 9.54 (1H, s, CH=N). C NMR spectrum
(
CDCl
3
), δ, ppm: 16.1 (CH
3
); 48.7 (CH); 53.3 (2OCH
3
);
1
17.3 (CH, Ar); 120.5 (CH Ar); 121.0 (C Ar); 122.6 (CH
Ar); 124.7 (C Ar); 126.8 (CH Ar); 127.7 (CH Ar); 135.2
This work received financial support from the Russian
Science Foundation (grant 18-13-00449).
The X-ray structural analysis of compound 4а was
performed on a STOE STADIVARI PILATUS 100K single
crystal X-ray diffractometer, purchased within the
framework of Moscow State University modernization
program.
(
(
С
CH Ar); 135.4 (C Ar); 145.7 (C Ar); 147.5 (C Ar); 147.9
CH=N); 166.8 (2CO
+
2
СH
3
). Found, m/z: 372.1015 [M+H] .
18
Н
18
N
3
O
4
S. Calculated, m/z: 372.1013. Found, %:
С 58.10; Н 4.66; N 10.94. С18
С 58.21; Н 4.61; N 11.31
Н
17
N
3
4
O S. Calculated, %:
Dimethyl 2-[2-(2-phenylaziridin-1-yl)-2H-indazol-3-yl]-
malonate (5). NaH (60% suspension in mineral oil, 114 mg,
References
2
2
.85 mmol) and trimethylsulfoxonium iodide (626 mg,
.85 mmol) were added successively to anhydrous DMSO
1
. (a) Ansari, A. J.; Wani, A. A.; Maurya, A. K.; Verma, S.;
Agnihotri, V. K.; Sharon, A.; Bharatam, P. V.; Sawant, D. M.
Chem. Commun. 2019, 55, 14825. (b) Murugan, A.; Babu, V. N.;
Polu, A.; Sabarinathan, N.; Bakthadoss, M.; Sharada, D. S. J.
Org. Chem. 2019, 84, 7796. (c) Muthengi, A.; Erickson, J.;
Muriph, R. E.; Zhang, W. J. Org. Chem. 2019, 84, 5927.
(d) Ma, X.; Zhang, X.; Awad, J. M.; Xie, G.; Qiu, W.; Zhang, W.
Green Chem. 2019, 21, 4489. (e) Ansari, A. J.; Joshi, G.;
Sharma, P.; Maurya, A. K.; Metre, R. K.; Agnihotri, V. K.;
Chandaluri, C. G.; Kumar, R.; Singh, S.; Sawant, D. M. J.
Org. Chem. 2019, 84, 3817. (f) Xiong, J.; Min, Q.; Yao, G.;
Zhang, J.-A.; Yu, H.-F.; Ding, M.-W. Synlett 2019, 1053.
(
2.6 ml). The reaction mixture was stirred under argon
atmosphere at room temperature for 40 min, followed by
the addition of compound 4a (400 mg, 1.24 mmol). The
reaction mixture was further stirred at 60°C for 3 h, then
poured into cold saturated NH
extracted with EtOAc (5×2 ml). The combined organic
layer was washed with H O (7×2 ml) and dried with
anhydrous Na SO . The solvent was evaporated at reduced
pressure, the residue was purified by column
chromatography on silica gel (eluent petroleum ether –
EtOAc, 4:1). Yield 279 mg (67%), white foam, mp 126–
4
Cl solution (2.5 ml) and
2
2
4
(
g) Zou, F.; Pei, F.; Wang, L. Ren, Z.; Cheng, X.; Sun, Y.; Wu, J.;
He, P. Synlett 2019, 717. (h) da Silva, V. D.; de Faria, B. M.;
Colombo, E.; Ascari, L.; Freitas, G. P. A.; Flores, L. S.;
Cordeiro, Y.; Romao, L.; Buarque, C. D. Bioorg. Chem. 2019,
83, 87.
1
27°С, R
f
0.45 (petroleum ether – EtOAc, 4:1). IR spect-
–1
rum, ν, cm : 2952, 1756, 1743, 1435, 1381, 1313, 1275,
1
1
255, 1220, 1197, 1154, 1029, 988. H NMR spectrum
3
(CDCl
3
+ CD
J = 1.5, CH
.78 (1H, dd, J = 8.1, J = 1.5, CH
3
OD), δ, ppm (J, Hz): 2.70 (1H, dd, J = 5.6,
); 3.65 (3H, s, OCH ); 3.68 (3H, s, OCH );
); 3.98 (1H, dd,
J = 8.1, J = 5.6, CH); 5.76 (1H, s, CH); 7.14 (1H, ddd,
2. Filimonov, V. O.; Abaev, V. T.; Beryozkina, T. V.; Galata, K. A.;
Slepukhin, P. A.; Kostenko, M. A.; Berseneva, V. S. Chem.
Heterocycl. Compd. 2016, 52, 721. [Khim. Geterotsikl.
Soedin. 2016, 52, 721.]
2
2
3
3
3
2
3
2
3
3
3
. Ghosh, S.; Roy, B.; Bandyopadhyay, S. J. Org. Chem. 2019,
3
3
4
J = 7.6, J = 6.7, J = 0.9, H-5); 7.32–7.42 (6H, m, H-6,
H Ph); 7.60–7.63 (1H, m, H-4); 7.65–7.67 (1H, m, H-7).
C NMR spectrum (CDCl
CH ); 45.8 (CH); 48.7 (CH(CO
2.94 (OCH ); 117.2 (7-CH Ar); 119.6 (4-CH Ar); 120.2
C-3a Ar); 122.1 (5-CH Ar); 124.6 (C-3 Ar); 126.2 (6-CH);
8
4, 12031.
5
4
. Porter, T. C.; Smalley, R. K.; Teguiche, M.; Purwono, B.
Synthesis 1997, 773.
1
3
3
+ CD
3
OD), δ, ppm: 40.1
(
2
2
СН
3
)
2
); 52.92 (OCH );
3
5. Shen, H. C.; Ding, F.-X., Deng, Q.; Wilsie, L. C.;
Krsmanovic, M. L.; Taggart, A. K.; Carballo-Jane, E.; Ren, N.;
Cai, T.-Q.; Wu, T.-J.; Wu, K. K.; Cheng, K.; Chen, Q.;
Wolff, M. S.; Tong, X.; Holt, T. G.; Waters, M. G.;
Hammond, M. L.; Tata, J. R.; Colletti, S. L. J. Med. Chem.
2009, 52, 2587.
5
3
(
1
1
26.4 (3,5-CH Ph); 127.9 (4-CH Ph); 128.5 (2,6-CH Ph);
36.6 (C Ph); 144.4 (C-7a Ar); 166.6 (CO СH ); 166.7
). Found, m/z: 388.1277 [M+Na] . С20 NaO
2
3
+
(CO
2
СH
3
Н
19
N
3
4
.
6
. Gairns, R. S.; Moody, C. J.; Rees, C. W. J. Chem. Soc.,
Perkin Trans. 1 1986, 501.
Calculated, m/z: 388.1268.
X-ray structural analysis of compound 4а. Crystals of
compound 4а, suitable for X-ray structural analysis, were
obtained from a solution in petroleum ether – EtOAc
mixture by slow evaporation of solvents at room tempe-
7
. Chaabouni, S.; Pinkerton, N. M.; Abid, S.; Galaup. C.;
Chassaing, S. Synlett 2017, 2614.
8. Luheshi, A.-B. N.; Salem, S. M.; Smalley, R. K., Kennewell, P. D.;
Westwood, R. Tetrahedron Lett. 1990, 31, 6561.
5
60

Chemistry of Heterocyclic Compounds 2020, 56(5), 555–561
9
1
1
. (a) Qu, F.; He, P.; Hu, R.-F.; Cheng, X.-H.; Wang, S.; Wu, J.
Elguero, J.; Atienza, J.; Gomez Barrio, A.; Escario, J. A.
Chem. Pharm. Bull. 1991, 39, 1990.
Synth. Commun. 2015, 45, 2802. (b) Zhang, X.; Ma, X.; Qiu, W.;
Evans, J.; Zhang, W. Green Chem. 2019, 21, 349.
12. (a) Fernandez, P.; Guillen, M. I.; Gomar, F.; Aller, E.;
Molina, P.; Alcaraz, M. J. Biochem. Pharmacol. 2004, 68,
417. (b) Fernandez, P.; Guillen, M. I.; Ubeda, A.; Lopez-
Cremades, P.; Aller, E.; Lorenzo, A. Molina, P.; Alcaraz, M. J.
Naunyn-Schmiedeberg's Arch. Pharmacol. 2003, 368, 26.
13. Zhao, F.-F.; Yan, Y.-M.; Zhang, R.; Ding, M.-W. Synlett
2012, 2850.
0. Molina, P.; Conesa, C.; Alias, A.; Arques, A.; Velasco, M. D.;
Llamas-Saiz, A. L.; Foces-Foces, C. Tetrahedron 1993, 49,
7599.
1. (a) Saczewski, F.; Kornicka, A.; Rybczynska, A.; Hudson, A. L.;
Miao, S. S.; Gdaniec, M.; Boblewski, K.; Lehmann, A. J.
Med. Chem. 2008, 51, 3599. (b) Widdowson, K. L.; Nie, H.;
Rutledge, M. C., Jr. US Patent 6015908, 2000.
14. Capperucci, A.; Degl'Innocenti, A.; Funicello, M.; Mauriello, G.;
Scafato, P.; Spagnolo, P. J. Org. Chem. 1995, 60, 2254.
15. Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38, 5603.
16. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
17. Abaev, V. T.; Plieva, A. T.; Chalikidi, P. N.; Uchuskin, M. G.;
Trushkov, I. V.; Butin, A. V. Org. Lett. 2014, 16, 4150.
18. Sheldrick, G. M. Acta Crystallogr., Sect. C: Struct. Chem.
2015, C71, 3.
(c) Widdowson, K. L. WO Patent 99/65310, 1999. (d) Klein, J. T.;
Davis, L.; Olsen, G. E.; Wong, G. S.; Huger, F. P.; Smith, C. P.;
Petko, W. W.; Cornfeldt, M.; Wilker, J. C.; Blitzer, R. D.;
Landau, E.; Haroutunian, V.; Martin, L. L.; Effland, R. C.
J. Med. Chem. 1996, 39, 570. (e) da Silva, K. V. C. L.; Mester, B.;
Henriques, J. A. P. Mutat. Res., Fundam. Mol. Mech.
Mutagen. 1994, 305, 119. (f) Mester, B.; Claramunt, R. M.;
5
61