Synthesis of 2,3-diaryl-2,3,4,4а-tetrahydro-5Н-indeno[1,2-c]pyridazin-5-ones

Article abstract of DOI:10.1007/s10593-019-02448-y

[Figure not available: see fulltext.] The reaction of 1,3-indanedione-derived donor-acceptor cyclopropanes with phenylhydrazine in the presence of catalytic amounts of scandium trifluoromethanesulfonate leads to the formation of indeno[1,2-c]pyridazine de

Full text of DOI:10.1007/s10593-019-02448-y

DOI 10.1007/s10593-019-02448-y
Chemistry of Heterocyclic Compounds 2019, 55(3), 240–245
Synthesis of 2,3-diaryl-2,3,4,4а-tetrahydro-
5Н-indeno[1,2-c]pyridazin-5-ones
Alexey O. Chagarovskiy1,2, Elena D. Strel'tsova2, Victor B. Rybakov3,
Irina I. Levina4, Igor V. Trushkov1,2*
1 Dmitry Rogachev Federal Research Center of Pediatric Hematology,
Oncology and Immunology,
1 Samory Mashela St., Moscow 117997, Russia; e-mail: alex.chagarovskiy@gmail.com
2 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,,
47 Leninsky Ave., Moscow 119991, Russia; e-mail: itrushkov@mail.ru
3 Lomonosov Moscow State University,
1 Build. 3 Leninskie Gory, Moscow 119991, Russia; e-mail: rybakov20021@yandex.ru
4 N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences,
4 Kosygina St., Moscow, 119334, Russia; e-mail: iilevina@inbox.ru
Submitted February 22, 2019
Accepted March 10, 2019
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(3), 240–245
The reaction of 1,3-indanedione-derived donor-acceptor cyclopropanes with phenylhydrazine in the presence of catalytic amounts of
scandium trifluoromethanesulfonate leads to the formation of indeno[1,2-c]pyridazine derivatives.
Keywords: 2,3,4,4a-tetrahydro-5Н-indeno[1,2-c]pyridazin-5-ones, donor-acceptor cyclopropanes, phenylhydrazine, nucleophilic cleavage.
Cyclopropanes containing donor and acceptor substi-
tuents in vicinal positions are unique compounds exhibiting
high reactivity with respect to nucleophiles, electrophiles,
radicals, dipolarophiles, 1,3-dipoles, 1,3-dienes, and other
types of reagents. Thanks to this they have become
distinguished as a separate subclass of small rings, called
"donor-acceptor cyclopropanes".1,2 Ease of synthesis,
stability, and at the same time high reactivity when
activated by Lewis acids make donor-acceptor (DA)
cyclopropanes important building blocks in the synthesis of
various carbo-3 and heterocycles,3d,e,4 including complex
polycyclic systems5 and natural compounds.6
ing an additional carbonyl group at the C-3 atom reacted
with hydrazines with the participation of this group,
forming pyrazole derivatives (Scheme 1, route d).8 On the
other hand, if cyclopropane is not active enough, as in the
Scheme 1
In particular, the reaction of DA cyclopropanes with
hydrazines, depending on the structure of the reagents and
the conditions of the reactions, resulted in different hetero-
cyclic compounds (Scheme 1). If the cyclopropane is
sufficiently activated, hydrazines attack not only the carbonyl
group of the acceptor substituent, but also the C-2 atom of
the small ring to form pyridazine (Scheme 1, routes a, b)7
or 1-aminopyrrolidin-2-one derivatives (Scheme 1, route c).7b
Furthermore, 2-arylcyclopropane-1,1-dicarboxylates contain-
0009-3122/19/55(3)-0240©2019 Springer Science+Business Media, LLC
240

Chemistry of Heterocyclic Compounds 2019, 55(3), 240–245
case of alkyl-2-arylcyclopropyl ketones, hydrazines
efficiently react only at the carbonyl group and the reaction
products are hydrazones8c,9 or, in the case of phenyl-
hydrazine, the corresponding indole, formed as a result of
Fischer rearrangement (Scheme 1, route e).7c,10
In this work, we studied the reaction of phenylhydrazine
with DA cyclopropanes obtained from 1,3-indanedione.
Considering the high reactivity of these substrates with
respect to nucleophiles11 and our previous results on
studying the reactions of phenylhydrazine with 2-aryl-
cyclopropane-1,1-dicarboxylates,7b we expected the
formation of indeno[1,2-c]pyridazine derivatives which are
promising compounds for medicinal chemists and
pharmacologists. Thus, the tautomeric 2,4,4a,5-tetra-
hydroindeno[1,2-c]pyridazin-3-ones were found to possess
antihypertensive, antithrombotic, and inotropic activity.12
They inhibit STAT3 protein, which is one of the promising
molecular targets in cancer therapy,13 and exhibit other
types of biological activity.14 In addition, the corresponding
aromatic derivatives, 3-arylindeno[1,2-c]pyridazin-5-ones,
selectively inhibit monoamine oxidase B.15
At the first stage of the work, we synthesized a series of
2-aryl(alkenyl)spiro[cyclopropane-1,2'-indane]-1',3'-diones
1a–f using a sequence of transformations involving the
reaction of indane-1,3-dione (2) with corresponding
aldehyde16 followed by cyclopropanation of the
Knoevenagel adducts 3a–f by the Corey–Chaykovsky
reaction17 (Scheme 2).
Figure 1. Molecular structure of compound 1а with atoms
represented as thermal vibration ellipsoids with 50% probability.
and obtained the corresponding derivatives of indeno[1,2-c]-
pyridazine 4a–f (Scheme 3). The yields of the desired
products 4a–f generally correlate well with the donor
properties of the aromatic substituent; the low yield of
compound 4f with a 4-methoxystyryl substituent is
apparently due to side reactions of the highly active
cyclopropane 1f.
The tricyclic products 4a-f are formed as isomers with
the trans arrangement of substituents at C-3 and C-4a
atoms. This conclusion was made on the basis of
comparison of the coupling constants for aliphatic protons
with those of related compounds,19 as well as the values
obtained as a result of optimization of the geometry of
compounds 4a–f by quantum-chemical calculations (see
Supplementary information file). In addition, the structure
of compound 4a was unambiguously proven by single
crystal X-ray analysis (Fig. 2).
The structure of compound 1a was proved by single
crystal X-ray analysis (Fig. 1). It should be noted that the
length of the C(1)–C(2) bond in the three-membered ring
between the carbon atom linked to two carbonyl groups
and a carbon atom bearing a phenyl substituent (1.561 Å) is
much longer than the C–C bond in unsubstituted
cyclopropane (1.513 Å).18
Scheme 3
Scheme 2
In accordance with our expectations, 2-phenylspiro-
[cyclopropane-1,2'-indane]-1',3'-dione 1a was converted to
tetrahydroindeno[1,2-c]pyridazin-5-one 4a under the
conditions previously optimized for the reaction of phenyl-
hydrazine with 2-arylcyclopropane-1,1-diesters (refluxing
in CH2Cl2 in the presence of 20 mol % Ni(ClO4)2·6H2O),7b
albeit in a low yield. Varying the conditions of the model
reaction showed that product 4a can be obtained in a
moderate yield by heating cyclopropane 1a with 1.1 equiv
phenylhydrazine in tetrahydrofuran at 100°C. The best
results were obtained when carrying out the reaction in
CH2Cl2 at room temperature using Sc(OTf)3 as the catalyst.
We carried out the reactions of phenylhydrazine with a
series of DA cyclopropanes 1a–f under these conditions
241

Chemistry of Heterocyclic Compounds 2019, 55(3), 240–245
spectra were acquired on a Bruker Avance-500 (500 and
126 MHz, respectively) spectrometer in CDCl3, using residual
1
solvent signals (7.26 ppm for Н nuclei, 77.2 ppm for 13С
nuclei) to assign chemical shifts. High-resolution mass spectra
were recorded on an LTQ Orbitrap Elite spectrometer with
samples as MeCN–H2O solutions, calibration with
HCO2Na–HCO2H, electrospray ionization. Elemental analysis
was performed on a Fisons EA-1108 analyzer. Melting points
were determined on an Electrothermal IA9100 apparatus.
Knoevenagel adducts 3а–f were obtained following a
published method.16
Synthesis of spiro[cyclopropane-1,2'-indane]-1',3'-
diones 1a–f (General method).16 Trimethylsulfoxonium
iodide (1.05 equiv) was added in one portion to a stirred
suspension of NaH (60% dispersion in mineral oil,
1.05 equiv) in anhydrous DMF (1.25 ml per 1 mmol NaH)
at room temperature under argon atmosphere. The reaction
mixture was stirred for 45 min, thereafter the formed
solution was added dropwise to a prepared 0.33 М solution
of alkene 3a–f (1.0–1.8 mmol, 1 equiv) in DMF under
argon atmosphere at 0°C. The reaction mixture was stirred
for 50 min at 0°C, then poured into aqueous NH4Cl with
ice (10–15 ml) and extracted with EtOAc (5×5 ml). The
combined organic layers were washed with H2O (5×5 ml)
followed by saturated aqueous NaCl (1×5 ml), and dried
with Na2SO4. The solvent was evaporated under reduced
pressure, and the residue was purified by column
chromatography on silica gel.
Figure 2. Molecular structure of compound 4а with atoms
represented as thermal vibration ellipsoids with 50% probability.
2-Phenylspiro[cyclopropane-1,2'-indane]-1',3'-dione
(1a). Yield 285 mg (77%), light-yellow crystals, mp 130–
132°С (mp 126–128°С,20 mp 129–131°С,21 mp 133–134°С22).
The spectral data correspond to the literature.20,21
2-(4-Methylphenyl)spiro[cyclopropane-1,2'-indane]-
1',3'-dione (1b). Yield 224 mg (61%), light-yellow
crystals, mp 120–122°С (mp 90–92°С,20 mp 126–128°С22).
The spectral data correspond to the literature.21
2-(4-Methoxyphenyl)spiro[cyclopropane-1,2'-indane]-
1',3'-dione (1с). Yield 240 mg (79%), yellow crystals,
mp 145–147°С (mp 148–150°С20). The spectral data
correspond to the literature.20
2-(4-Fluorophenyl)spiro[cyclopropane-1,2'-indane]-
1',3'-dione (1d). Yield 212 mg (57%), colorless crystals,
mp 147–148°С (mp 150–151 °С20). The spectral data
correspond to the literature.20
2-(3,4,5-Trimethoxyphenyl)spiro[cyclopropane-1,2'-
indane]-1',3'-dione (1e). Yield 274 mg (75%), light-
yellow crystals, mp 132–134 °С, Rf 0.68 (petroleum ether –
EtOAc, 1:1). IR spectrum, ν, cm–1: 2990, 2935, 2835, 1740,
1705, 1590, 1510, 1460, 1420, 1385, 1330, 1245, 1130,
1000, 855, 760, 720. 1H NMR spectrum, δ, ppm (J, Hz): 2.21–
2.25 (1H, m, CH2); 2.36–2.40 (1H, m, CH2); 3.27–3.31
(1Н, m, CH); 3.77 (3H, s, OCH3); 3.78 (6H, s, 2OCH3);
6.51 (2Н, s, Н Ar); 7.65–7.71 (2Н, m, Н Ar); 7.72–7.76 (1Н,
m, Н Ar); 7.85–7.90 (1Н, m, Н Ar). 13C NMR spectrum,
δ, ppm: 22.6 (CH2); 41.7 (CH); 42.9 (C); 56.0 (2OCH3);
60.7 (OCH3); 106.3 (2CH); 122.3 (2CH); 129.2 (C); 134.6
(CH); 134.8 (CH); 137.6 (C); 141.4 (C); 142.6 (C); 152.7
(2C); 195.6 (CO); 197.8 (CO). Found, m/z: 361.1043
[M+Na]+. C20H18NaO5. Calculated, m/z: 361.1046.
Figure 3. The calculated (HF/6-311G**) absolute and relative
energies of compound 4a, its cis-isomer 4a', and enehydrazino
ketone 4a''.
Compounds 4a–f do not undergo epimerization or
isomerization to enehydrazino ketones, which means that
they are thermodynamically controlled products. Indeed,
quantum-chemical calculations using the HF/6-311G**
method showed that the model compound 4a is more stable
than cis-isomer 4a' and the corresponding enehydrazino
ketone 4a'' by 13.1 and 39.5 kJ/mol, respectively (Fig. 3,
see Supplementary information file).
To conclude, the scandium triflate-catalyzed reaction of
spiro[cyclopropane-1,2'-indane]-1',3'-diones containing a
donor aromatic or alkenyl substituent in the three-
membered ring with phenylhydrazine leads to the
formation of 2,3-substituted 2,3,4,4a-tetrahydro-5H-indeno-
[1,2-c]pyridazin-5-ones in moderate to good yields.
Experimental
IR spectra were registered on an Infralum FT-801
spectrometer in KBr pellets. 1H, 13C and NOESY 2D NMR
242

Chemistry of Heterocyclic Compounds 2019, 55(3), 240–245
2
3
3
ddd, J = 12.8, J = 5.6, J = 2.0, CH2); 2.93 (1Н, dd,
(E)-2-[2-(4-Methoxyphenyl)ethenyl]spiro[cyclopro-
pane-1,2'-indane]-1',3'-dione (1f). Yield 220 mg (61%),
light-yellow crystals, mp 128–129°С, Rf 0.77 (petroleum
ether – EtOAc, 1:1). IR spectrum, ν, cm–1: 2955, 2924,
2855, 1740, 1705, 1605, 1575, 1510, 1465, 1335, 1300,
1250, 1175, 1030, 965, 815, 735. 1H NMR spectrum, δ, ppm
(J, Hz): 2.10 (1H, dd, 3J = 8.1, 2J = 4.1, CH2); 2.23 (1H, dd,
3J = 8.7, 2J = 4.1, CH2); 2.94–3.00 (1Н, m, CH); 3.79 (3H,
3J = 12.8, J = 5.7, CH); 5.37 (1H, dd, J = 4.9, J = 2.1,
CH); 6.91–6.94 (1Н, m, Н Ar); 7.14–7.19 (4Н, m, Н Ar);
7.26–7.29 (2Н, m, Н Ar); 7.34–7.36 (2Н, m, Н Ar); 7.43–
7.47 (1Н, m, Н Ar); 7.71–7.74 (1Н, m, Н Ar); 7.79 (1Н, d,
3
3
3
3J = 7.7, Н Ar); 8.05 (1Н, d, J = 7.8, Н Ar). 13C NMR
3
spectrum, δ, ppm: 21.2; 27.3; 39.7; 57.5; 114.3 (2C); 120.9;
121.2; 123.7; 126.2 (2C); 129.2 (3C); 129.9 (2C); 135.6;
137.2; 137.6; 137.7; 140.0; 146.5; 146.9; 201.0. Found, m/z:
353.1645 [M+H]+. C24H21N2O. Calculated, m/z: 353.1648.
(3RS,4aSR)-3-(4-Methoxyphenyl)-2-phenyl-2,3,4,4a-
tetrahydro-5Н-indeno[1,2-с]pyridazin-5-one (4с). The
reaction mixture was stirred at room temperature for 50 min.
Yield 150 mg (68%), orange foam, Rf 0.41 (petroleum
3
3
s, OCH3); 6.30 (1H, dd, J = 15.9, J = 9.6, CH=); 6.55
3
3
(1Н, d, J = 15.9, CH=); 6.82 (2Н, d, J = 8.7, H Ar); 7.29
3
(2Н, d, J = 8.7, H Ar); 7.75–7.79 (2Н, m, Н Ar); 7.89–
7.96 (2Н, m, Н Ar). 13C NMR spectrum, δ, ppm: 25.1;
41.4; 43.2; 55.4; 114.1 (2C); 122.6 (2C); 122.7; 127.7
(2C); 129.6; 133.3; 134.8; 134.9; 142.0; 142.7; 159.5;
197.3; 198.1 (CO). Found, m/z: 305.1171 [M+H]+.
C20H17O3. Calculated, m/z: 305.1172.
1
ether – EtOAc, 4:1). H NMR spectrum, δ, ppm (J, Hz):
2.01–2.08 (1H, m, CH2); 2.70 (1H, ddd, 2J = 12.6, 3J = 5.6,
3J = 2.0, CH2); 2.93 (1Н, dd, J = 12.8, J = 5.6, CH); 3.80
(3H, s, OCH3); 5.34–5.37 (1H, m, CH); 6.91 (2H, d,
3J = 8.7, H Ar); 6.92–6.95 (1Н, m, Н Ar); 7.18 (2H, d,
3J = 8.7, H Ar); 7.28–7.31 (2Н, m, Н Ar); 7.35–7.37 (2Н,
m, Н Ar); 7.43–7.47 (1Н, m, Н Ar); 7.71–7.74 (1Н, m,
3
3
Synthesis of 2-aryl(alkenyl)-3-phenyl-2,3,4,4а-tetrahydro-
5Н-indeno[1,2-c]pyridazin-5-ones 4a–f (General method).
Sc(OTf)3 (36 mg, 20 mol %) was added to a solution of
cyclopropane 1a–f (0.6 mmol) and phenylhydrazine
(0.63 mmol, 1.05 equiv) in dry CH2Cl2 (0.08 М solution) in
the presence of 4 Å molecular sieves. The reaction mixture
was stirred until complete conversion of the starting
cyclopropane (TLC control) at room temperature (unless
indicated otherwise) under argon atmosphere. The mixture
was poured into saturated aqueous NaHCO3 (15 ml), and
extracted with CH2Cl2 (3×8 ml). The organic layer was
washed with saturated aqueous NaHCO3 (3×8 ml) followed
by H2O (2×4 ml). The solvent was evaporated under
reduced pressure, and the product was purified by column
chromatography on silica gel, eluent petroleum ether –
EtOAc, gradient from 10:1 to 4:1.
3
3
Н Ar); 7.80 (1Н, d, J = 7.7, Н Ar); 8.05 (1Н, d, J = 7.8,
Н Ar). 13C NMR spectrum, δ, ppm: 27.3; 39.6; 55.4; 57.0;
114.2 (2C); 114.6 (2C); 120.8; 121.1; 123.6; 127.3 (2C);
129.1 (3C); 132.4; 135.5; 137.2; 139.9; 146.4; 146.8; 159.3;
200.9 (CO). Found, m/z: 369.1595 [M+H]+. C24H21N2O2.
Calculated, m/z: 369.1598.
(3RS,4aSR)-3-(4-Fluorophenyl)-2-phenyl-2,3,4,4а-tetra-
hydro-5Н-indeno[1,2-c]pyridazin-5-one (4d). The reaction
mixture was heated under reflux for 5 h. Yield 103 mg
(48%), orange foam, Rf 0.58 (petroleum ether – EtOAc,
4:1). IR spectrum, ν, cm–1: 2995, 2935, 2835, 1715, 1590,
1495, 1455, 1415, 1375, 1330, 1290, 1235, 1125, 1005,
(3RS,4aSR)-2,3-Diphenyl-2,3,4,4а-tetrahydro-5Н-
indeno[1,2-с]pyridazin-5-one (4a). The reaction mixture
was heated under reflux for 3 h. Yield 115 mg (57%), dark-
yellow crystals, mp 162–163°С (decomp.), Rf 0.59
(petroleum ether – EtOAc, 4:1). IR spectrum, ν, cm–1:
3060, 3035, 2945, 2870, 1715, 1590, 1495, 1455, 1380,
1
970, 750, 700. H NMR spectrum, δ, ppm (J, Hz): 2.04–
2
3
2.11 (1H, m, CH2); 2.72 (1H, ddd, J = 12.7, J = 5.7,
3J = 1.7, CH2); 2.87 (1Н, dd, 3J = 12.9, 3J = 5.7, CH); 5.37–
5.40 (1H, m, CH); 6.92–6.97 (1Н, m, Н Ar); 7.04–7.09
(2Н, m, Н Ar); 7.22–7.34 (5Н, m, Н Ar); 7.44–7.46 (1Н,
m, Н Ar); 7.71–7.75 (1Н, m, Н Ar); 7.78–7.81 (1Н, m,
1
1285, 1255, 1135, 990, 865, 750, 695. H NMR spectrum,
3
3
δ, ppm (J, Hz): 2.08–2.10 (1H, m, CH2); 2.74 (1H, ddd,
Н Ar); 7.80 (1Н, d, J = 7.7, Н Ar); 8.05 (1Н, d, J = 7.8,
Н Ar). 13C NMR spectrum, δ, ppm (J, Hz): 27.2; 39.4;
57.0; 114.2 (2C); 116.2 (2C, d, JCF = 22.0); 121.0; 121.2;
123.7; 127.9 (2C, d, JCF = 8.0); 129.2 (2C); 129.3; 135.7;
136.4; 137.2; 140.0; 146.2; 146.7; 163.3 (С, d, JCF = 254.0);
200.6. Found, m/z: 357.1401 [M+H]+. C23H18FN2O.
Calculated, m/z: 357.1398.
2J = 12.6, 3J = 5.7, 3J = 2.0, CH2); 2.90 (1Н, dd, 3J = 12.8,
3
3
3J = 5.6, CH); 5.38 (1H, dd, J = 5.0, J = 2.0, CH); 6.89–
6.93 (1Н, m, Н Ar); 7.24–7.29 (5Н, m, Н Ar); 7.33–7.38
(4Н, m, Н Ar); 7.44–7.46 (1Н, m, Н Ar); 7.71–7.74 (1Н,
3
m, Н Ar); 7.78 (1Н, d, J = 7.7, Н Ar); 8.05 (1Н, d,
3J = 7.8, Н Ar). 13C NMR spectrum, δ, ppm: 27.2 (CH2);
39.6 (CH); 57.6 (CH); 114.3 (2CH); 120.9 (CH); 121.2
(CH); 123.6 (CH); 126.3 (2CH); 127.9 (CH); 129.2 (5CH);
135.6 (CH); 137.2 (C); 140.0 (C); 140.7 (2C); 146.4 (C);
146.8 (C); 200.8 (CO). Found, m/z: 339.1487 [M+H]+.
C23H19N2O. Calculated, m/z: 339.1492.
3-(3,4,5-Trimethoxyphenyl)-2-phenyl-2,3,4,4а-tetrahydro-
5Н-indeno[1,2-с]pyridazin-5-one (4e). The reaction mixture
was stirred at room temperature for 1.5 h. Yield 157 mg
(61%), orange foam, Rf 0.36 (petroleum ether – EtOAc,
4:1). IR spectrum, ν, cm–1: 3070, 3055, 2950, 1705, 1595,
1510, 1420, 1375, 1335, 1235, 1160, 1040, 990, 835, 735,
670. 1H NMR spectrum, δ, ppm (J, Hz): 1.99–2.07 (1H, m,
(3RS,4aSR)-3-(4-Methylphenyl)-2-phenyl-2,3,4,4a-tetra-
hydro-5H-indeno[1,2-с]pyridazin-5-one (4b). The reaction
mixture was heated under reflux for 3 h. Yield 125 mg
(59%), orange foam, Rf 0.67 (petroleum ether – EtOAc,
4:1). IR spectrum, ν, cm–1: 3060, 3030, 2955, 2930, 2835,
1715, 1595, 1510, 1495, 1375, 1290, 1250, 1175, 1130,
2
3
3
CH2); 2.74 (1H, ddd, J = 12.5, J = 5.6, J = 1.7, CH2);
3
3
2.97 (1Н, dd, J = 12.8, J = 5.6, CH); 3.82 (6H, s,
3
2OCH3); 3.85 (3H, s, OCH3); 5.31 (1H, dd, J = 5.0,
3J = 1.7, CH); 6.46 (2H, s, H Ar); 6.93–6.97 (1Н, m, Н Ar);
7.27–7.31 (2Н, m, Н Ar); 7.33–7.36 (2Н, m, Н Ar); 7.44–
7.48 (1Н, m, Н Ar); 7.71–7.75 (1Н, m, Н Ar); 7.81 (1Н, d,
1
1030, 990, 865, 750, 690. H NMR spectrum, δ, ppm
(J, Hz): 2.01–2.08 (1H, m, CH2); 2.35 (3H, s, CH3); 2.74 (1H,
243

Chemistry of Heterocyclic Compounds 2019, 55(3), 240–245
3
3J = 7.7, Н Ar); 8.05 (1Н, d, J = 7.8, Н Ar). 13C NMR
spectrum, δ, ppm: 27.3; 39.8; 56.4 (2C); 58.2; 61.0; 103.2
(2C); 114.6 (2C); 121.1; 121.2; 123.7; 129.2 (2C); 129.3;
135.7; 136.4; 137.2; 137.7; 140.2; 146.7 (2С); 154.0 (2C);
200.9. Found, m/z: 429.1812 [M+H]+. C26H25N2O4.
Calculated, m/z: 429.1809.
2. (a) Isr. J. Chem. 2016, 6-7, Special Issue: Chemistry of Donor-
Acceptor Cyclopropanes and Cyclobutanes. (b) Schneider, T. F.;
Kaschel, J.; Werz, D. B. Angew. Chem., Int. Ed. 2014, 53,
5504. (c) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
3. (a) Grover, H. K.; Emmett, M. R.; Kerr, M. A. Org. Biomol.
Chem. 2015, 13, 655. (b) Novikov, R. A.; Tomilov, Y. V.
Mendeleev Commun. 2015, 25, 1. (c) Di Grandi, M. J. Org.
Biomol. Chem. 2014, 12, 5331. (d) Cavitt, M. A.; Phun, L. H.;
France, S. Chem. Soc. Rev. 2014, 43, 804. (e) Mel'nikov, M. Ya.;
Budynina, E. M.; Ivanova, O. A.; Trushkov, I. V. Mendeleev
Commun. 2011, 21, 293.
4. (a) Pagenkopf, B. L.; Vemula, N. Eur. J. Org. Chem. 2017, 2561.
(b) Kumar, I. RSC Adv. 2014, 4, 16397. (c) Campbell, M. J.;
Johnson, J. S.; Parsons, A. T.; Pohlhaus, P. D.; Sanders, S. D.
J. Org. Chem. 2010, 75, 6317.
5. (a) Verma, K.; Banerjee, P. Adv. Synth. Catal. 2018, 360,
3687. (b) Qian, S.; Xie, Z.; Liu, J.; Li, M.; Wang, S.; Luo, N.;
Wang, C. J. Org. Chem. 2018, 83, 14768. (c) Zhang, J.; Jiang, H.;
Zhu, S. Adv. Synth. Catal. 2017, 359, 2924. (d) Villemson, E. V.;
Budynina, E. M.; Ivanova, O. A.; Skvortsov, D. A.;
Trushkov, I. V.; Melnikov, M. Ya. RSC Adv. 2016, 6, 62014.
(e) Xiao, J.-A.; Li, J.; Xia, P.-Y.; Zhou, Z.-F.; Deng, Z.-X.;
Xiang, H.-Y.; Chen, X.-Q.; Yang, H. J. Org. Chem. 2016, 81,
11185. (f) Liu, C.; Zhou, L.; Huang, W.; Wang, M.; Gu, Y.
Tetrahedron 2016, 72, 563.
6. (a) Gharpure, S. J.; Nanda, L. N. Tetrahedron Lett. 2017, 58,
711. (b) Tang, P.; Qin, Y. Synthesis 2012, 2969. (c) Wang, Z.
Synlett 2012, 2311. (d) Carson, C. A.; Kerr, M. A. Chem. Soc.
Rev. 2009, 38, 3051. (e) O'Connor, N. R.; Wood, J. L.;
Stolz, B. M. Isr. J. Chem. 2016, 56, 431.
7. (a) Dey, R.; Kumar, P.; Banerjee, P. J. Org. Chem. 2018, 83,
5438. (b) Chagarovskiy, A. O.; Ivanova, O. A.; Shumsky, A. N.;
Trushkov, I. V. Chem. Heterocycl. Compd. 2017, 53, 1220.
[Khim. Geterotsikl. Soedin. 2017, 53, 1220.] (c) Gladow, D.;
Reissig, H.-U. Helv. Chim. Acta 2012, 95, 1818. (d) Reichelt, I.;
Reissig, H.-U. Synthesis 1984, 786.
8. (a) Sathishkannan, G.; Tamilarasan, V. J.; Srinivasan, K. Org.
Biomol. Chem. 2017, 15, 1400. (b) Xue, S.; Liu, J.; Qing, X.;
Wang, C. RSC Adv. 2016, 6, 67724. (с) Cao, W.; Zhang, H.;
Chen, J.; Deng, H.; Shao, M.; Lei, L.; Qian, J.; Zhu, Y.
Tetrahedron 2008, 64, 6670.
9. (a) Braun, J.; Ariens, M. I.; Matsuo, B. T.; de Vries, S.; van
Wordragen, E. D. H.; Ellenbroek, B. D.; Vande Velde, C. M. L.;
Orru, R. V. A.; Ruijter, E. Org. Lett. 2018, 20, 6611.
(b) El-Kholy, I. E.-S.; Fuid-Alla, H. M.; Mishrikey, M. M.
J. Heterocycl. Chem. 1980, 17, 541. (c) Sasaki, T.; Eguchi, S.;
Ohno, M.; Umemura, T. J. Org. Chem. 1973, 38, 4095.
10. (a) Salikov, R. F.; Trainov, K. P.; Belousova, I. K.; Belyy, A. Yu.;
Fatkullina, Y. Sh.; Mulyukova, R. V.; Zainullina, L. F.;
Vakhitova, Y. V.; Tomilov, Y. V. Eur. J. Med. Chem. 2018,
144, 211. (b) Salikov, R. F.; Trainov, K. P.; Levina, A. A.;
Belousova, I. K.; Medvedev, M. G.; Tomilov, Y. V. J. Org.
Chem. 2017, 82, 790.
3-[2-(4-Methoxyphenyl)ethenyl]-2-phenyl-2,3,4,4а-
tetrahydro-5Н-indeno[1,2-с]pyridazin-5-one (4f). The
reaction mixture was stirred at room temperature for 1 h. Yield
111 mg (47%), yellow-green foam, Rf 0.65 (petroleum
ether – EtOAc, 4:1). IR spectrum, ν, cm–1: 3060, 3030,
2930, 2835, 1710, 1595, 1510, 1495, 1470, 1375, 1285,
1
1250, 1175, 1135, 1035, 970, 820, 750, 690. H NMR
spectrum, δ, ppm (J, Hz): 1.82–1.90 (1H, m, CH2); 2.64
2
3
3
(1H, ddd, J = 12.7, J = 5.8, J = 1.8, CH2); 3.28 (1Н, dd,
3J = 12.8, J = 5.8, CH); 3.80 (3H, s, ОCH3); 4.93–4.97
3
(1H, m, CH); 6.12 (1H, dd, 3J = 15.9, 3J = 3.8, CH=); 6.38
3
4
3
(1H, dd, J = 15.9, J = 1.3, CH=); 6.84 (2H, d, J = 8.8,
H Ar); 6.97–7.00 (1Н, m, Н Ar); 7.29 (2Н, d, 3J = 8.8, Н Ar);
7.35–7.38 (2Н, m, Н Ar); 7.44–7.50 (3Н, m, Н Ar); 7.70–
7.73 (1Н, m, Н Ar); 7.81 (1Н, d, 3J = 7.7, Н Ar); 8.02 (1Н, d,
3J = 7.8, Н Ar). 13C NMR spectrum, δ, ppm: 24.4; 40.1; 55.4;
55.5; 114.1 (2C); 114.3 (2C); 120.8; 121.1; 123.6; 124.2;
127.9 (2C); 128.7; 129.1; 129.2 (2C); 132.1; 135.5; 137.1;
139.7; 146.6; 146.7; 159.6; 201.0. Found, m/z: 395.1755
[M+H]+. C26H23N2O2. Calculated, m/z: 395.1754.
X-ray structural analysis of compounds 1а and 4а.
Crystals of compounds 1а and 4а suitable for X-ray
analysis were obtained from petroleum ether – EtOAc
solutions by slow evaporation of the solvent at room
temperature. Analysis was performed on
a STOE
STADIVARI PILATUS-100K diffractometer, acquired
within the framework of the program for the development
of Moscow State University. The structures were solved by
the direct method. All calculations were done using
SHELXT and SHELXL-15 program sets.23 Tables of
atomic coordinates, bond lengths, valence and torsion
angles, and anisotropic temperature parameters for
compounds 1a and 4a were deposited at the Cambridge
Crystallographic Data Center (deposits CCDC 1581845
and CCDC 1891023, respectively).
Supplementary information file containing H and 13C
1
NMR data for compounds 1e,f and 4a–f, X-ray structural
analysis data for compounds 1а and 4а, analysis of
stereochemistry data for compounds 4a–f, as well as
quantum-chemical calculations results for compound 4а
and its isomers 4a' and 4a'' using the HF/6-311G**
method, is available at the journal website at http://
link.springer.com/journal/10593.
11. Ivanov, K. L.; Villemson, E. V.; Budynina, E. M.;
Ivanova, O. A.; Trushkov, I. V.; Melnikov, M. Ya. Chem.–
Eur. J. 2015, 21, 4975.
12. (a) Toma, L.; Cignarella, G.; Barlocco, D.; Ronchetti, F. J.
Med. Chem. 1990, 33, 1591. (b) Cignarella, G.; Barlocco, D.;
Pinna, G. A.; Loriga, M.; Tofanetti, O.; Germini, M.; Sala, F.
J. Med. Chem. 1986, 29, 2191. (c) Sircar, I.; Duell, B. L.;
Cain, M. H.; Burke, S. E.; Bristol, J. A. J. Med. Chem. 1986,
29, 2142.
13. Masciocchi, D.; Gelain, A.; Porta, F.; Meneghetti, F.; Pedretti, A.;
Celentano, G.; Barlocco, D.; Legnani, L.; Toma, L.; Kwon, B.-M.;
Asai, A.; Villa, S. MedChemComm 2013, 4, 1181.
This work was supported by the Russian Science
Foundation (grant 18-13-00449).
References
1. Tomilov, Y. V.; Menchikov, L. G.; Novikov, R. A.; Ivanova, O. A.;
Trushkov, I. V. Russ. Chem. Rev. 2018, 87, 201. [Usp. Khim.
2018, 87, 201.]
244

Chemistry of Heterocyclic Compounds 2019, 55(3), 240–245
14. (a)
Niculescu-Duvaz,
D.;
Niculescu-Duvaz,
I.;
16. Ivanova, O. A.; Chagarovskiy, A. O.; Shumsky, A. N.;
Krasnobrov, V. D.; Levina, I. I.; Trushkov, I. V. J. Org.
Chem. 2018, 83, 543.
Suijkerbuijk, B. M. J. M.; Menard, D.; Zambon, A.; Nourry, A.;
Davies, L.; Manne, H. A.; Friedlos, F.; Ogilvie, L.; Hedley, D.;
Takle, A. K.; Wilson, D. M.; Pons, J.-F.; Coulter, T.; Kirk, R.;
Cantarino, N.; Whittaker, S.; Marais, R.; Springer, C. J. Bioorg.
Med. Chem. 2010, 18, 6934. (b) Campagna, F.; Palluotto, F.;
Carotti, A.; Casini, G.; Genchi, G. Bioorg. Med. Chem. 1999, 7,
1533. (c) Barlocco, D.; Bergomi, M.; Menta, E.; Palumbo, M.;
Cignarella, G. Recl. Trav. Chim. Pays-Bas 1996, 115, 25.
(d) Bakewell, S. J.; Coates, W. J.; Comer, M. B.; Reeves, M. L.;
Warrington, B. H. Eur. J. Med. Chem. 1990, 25, 765. (e) Moos, W. H.;
Humblet, C. C.; Sircar, I.; Rithner, C.; Weishaar, R. E.;
Bristol, J. A.; McPhail, A. T. J. Med. Chem. 1987, 30, 1963.
15. (a) Carotti, A.; Catto, M.; Leonetti, F.; Campagna, F.; Soto-
Otero, R.; Mendez-Alvarez, E.; Thull, U.; Testa, B.;
Altomare, C. J. Med. Chem. 2007, 50, 5364. (b) Novaroli, L.;
Daina, A.; Favre, E.; Bravo, J.; Carotti, A.; Leonetti, F.;
Catto, M.; Carrupt, P.-A.; Reist, M. J. Med. Chem. 2006, 49,
6264. (c) Frederick, R.; Dumont, W.; Ooms, F.; Aschenbach, L.;
Van der Schyf, C. J.; Castagnoli, N.; Wouters, J.; Krief, A. J.
Med. Chem. 2006, 49, 3743. (d) Altomare, C.; Cellamare, S.;
Summo, L.; Catto, M.; Carotti, A.; Thull, U.; Carrupt, P.-A.;
Testa, B.; Stoeckli-Evans, H. J. Med. Chem. 1998, 41, 3812.
17. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87,
1353.
18. Bastiansen, O.; Fritsch, F. N.; Hedberg, K. Acta Crystallogr.
1964, 17, 538.
19. (a) Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Fringuelli, F.; Mantellini, F.; Matteucci, M.; Piermatti, O.;
Pizzo, F. Helv. Chim. Acta 2001, 84, 513. (b) Sucrow, W.;
Ellermann, K.-H.; Flörke, U.; Haupt, H.-J. Chem. Ber. 1988,
121, 2007. (c) Sommer, S. Tetrahedron Lett. 1977, 18, 117.
(d) Tomilov, Yu. V.; Platonov, D. N.; Averkiev, B. B.;
Shulishov, E. V.; Nefedov, O. M. Russ. Chem. Bull., Int. Ed.
2003, 52, 187. [Izv. Akad. Nauk, Ser. Khim. 2003, 176.]
20. Qian, P.; Du, B.; Song, R.; Wu, X.; Mei, H.; Han, J.; Pan, Y.
J. Org. Chem. 2016, 81, 6546.
21. Nambu, H.; Fukumoto, M.; Hirota, W.; Ono, N.; Yakura, T.
Tetrahedron Lett. 2015, 56, 4312.
22. Rosenfeld, M. J.; Ravi Shankar, B. K.; Shechter, H. J. Org.
Chem. 1988, 53, 2699.
23. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found
Crystallogr. 2015, 71, 3.
245