Synthesis and Prediction of the Ubiquinol-cytochrome c Reductase Inhibitory Activity of 3,4-Dihydroisoquinolines and 2-Azaspiro[4.5]decanes (Spiropyrrolines)

Article abstract of DOI:10.1002/jhet.3551

Isoquinolines rank as the second largest group among the plant alkaloids. Natural isoquinolines and synthetic isoquinoline derivatives exhibit numerous biological activities. In this study, the approaches to synthesis of new 3,4-dihydroisoquinoline and 2-azaspiro[4.5]decane (spiropyrroline) derivatives annelated by C(3)─C(4) bonds with a cyclohexyl or cyclopentyl moiety have been developed. In accord with the results of biological activity prediction by the pass software, molecular docking was carried out on the ubiquinol-cytochrome c reductase (bc₁ complex) model. Compounds 6e and 12a,d were found out as potential Q₀ site inhibitors of the bovine bc₁ complex.

Full text of DOI:10.1002/jhet.3551

Month 2019
Synthesis and Prediction of the Ubiquinol-cytochrome c Reductase
Inhibitory Activity of 3,4-Dihydroisoquinolines and 2-Azaspiro[4.5]dec-
anes (Spiropyrrolines)
a
Anna N. Perevoshchikova,
Daria V. Eroshenko,a Maksim V. Dmitriev,b Victoria V. Grishko,a and Yurii V. Shklyaeva
*
aInstitute of Technical Chemistry of Ural Branch of the Russian Academy of Sciences, Academician Korolev Street 3,
614013 Perm, Russia
bPerm State National Research University, Bukirev Street 15, 614990 Perm, Russia
E-mail: annper87@gmail.com
Received November 12, 2018
DOI 10.1002/jhet.3551
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Isoquinolines rank as the second largest group among the plant alkaloids. Natural isoquinolines and syn-
thetic isoquinoline derivatives exhibit numerous biological activities. In this study, the approaches to synthe-
sis of new 3,4-dihydroisoquinoline and 2-azaspiro[4.5]decane (spiropyrroline) derivatives annelated by
C(3)–C(4) bonds with a cyclohexyl or cyclopentyl moiety have been developed. In accord with the results
of biological activity prediction by the PASS software, molecular docking was carried out on the
ubiquinol-cytochrome c reductase (bc1 complex) model. Compounds 6e and 12a,d were found out as poten-
tial Q0 site inhibitors of the bovine bc1 complex.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
Earlier, we showed that the Wagner–Meerwein
rearrangement of 1-(4-methoxyphenyl)-2,2-
Isoquinoline derivatives evince a wide range of
biological activities. For example, partially hydrogenated
isoquinoline derivatives can act as antagonists of
dopamine receptors, exhibit antiproliferative, antitumor,
anthelmintic, analgesic, antimicrobial, antibacterial, and
other activities [1–7]. In synthesis of 3,4-
dihydroisoquinolines and their derivatives, the most
frequently used reactions are those of Bischler–
Napieralsky, Pictet–Spengler, and Pomeranz–Fritsch [8].
The Ritter reaction, along with a possibility of forming
amides in the classical variant of the reaction [9], can
also be used in synthesis of 3,4-dihydroisoquinoline and
2-azaspiro[4.5]decane (spiropyrroline) derivatives [10,11].
dimethylpropan-1-ol, 3,3-dimethyl-2-phenylbutane-2-ol
and 1-(4-methoxyphenyl)-1-(1-methylcyclohexyl)ethan-1-
ol allows to obtain a carbocation, whose interaction with
nitrile leads to the formation of heterocyclic compounds
[12–14].
In the presented work, a possibility of the synthesis new
3,4-polyalkyl derivatives of 3,4-dihydroisoquinoline by
interaction of nitriles with insufficiently studied 1-
cycloalkyl-1-(4-methoxyphenyl)ethane-1-ol and 1-(4-
methoxyphenyl)-1-(1-methylcyclopentyl)ethane-1-ol, as
well as 4-(1-cyclobutenyl-ethyl)-1,2-dimethoxybenzene
was explored. Potential biological activity of synthesized
compounds was studied by the in silico methods.
© 2019 Wiley Periodicals, Inc.

A. N. Perevoshchikova, D. V. Eroshenko, M. V. Dmitriev, V. V. Grishko, and Y. V. Shklyaev
Vol 000
RESULTS AND DISCUSSION
Chemistry.
New carbinols 1–3 synthesized by the
standard methods [14–16] underwent interaction with
nitriles 4a–f in the presence of 94% sulfuric acid
(Scheme 1).
In the case of carbinol 1, the cycloalkyl moiety was
supposed to expand at the expense of the Wagner–
Meerwein rearrangement, but the cyclopentyl part,
apparently, was not sterically stressed markedly, with
6-methyl-13,14-azadispiro [4.1.5.2]tetradec-8,11,13-trien-
10-ones 5a–c obtained as products of the Ritter reaction.
Earlier [17,18], we had shown a similar dependence in
the formation of spiropyrrolines for some substituted
alkoxyphenylcarbinols. According to GC/MS, the
reaction of compound 1 with 2-cyanopyridine resulted in
the formation of compounds 5e and 6e mixed at the
ratio 2: 1. Compounds 5e,f were unstable, and in the
process of chromatographic purification on silica gel
turned into products of the dienone-phenolic
Figure 1. The structure of compound 10 according to X-ray diffraction
data.
Scheme 2. Obtaining compound 10.
1
rearrangement—amides 6e,f. In the H NMR spectra of
compounds 5a–c and 6e,f, a signal of the methyl group
was observed as a doublet (J = 7.2–7.5 Hz) in the
0.82–0.84 ppm range for spiropyrrolines 5a–c and in
the range of 1.18–1.31 ppm for amides 6e and 6f, and
the proton signal at C(6) was in the form of a
quadruplet (J = 7.2–7.5 Hz, J = 14.55–15.0 Hz) in the
2.56–2.59 ppm range for spiropyrrolines 5a–c or in the
range of 3.60–3.66 ppm for amides 6e and 6f.
With carbinol 2 used, a 1,2-sigmatropic shift of the
cyclopentane ring was observed with the formation of
hexahydrofenanthridine derivatives 7a–f, instead of the
expected migration of the methyl group [14]. The cis-
configuration of the methyl groups was found out by the
X-ray diffraction analysis performed for crystalline
isocarbostyril 10 (Fig. 1) synthesized from compound 7b
(Scheme 2). Thus, we succeeded in ascertaining the
structure of the remaining compounds 7a,c–f and
confirming the location of the methoxy group at position
1
9 for this series of compounds. The H NMR spectra of
compounds 7a–f at 6.61–6.75 ppm include a doublet of
doublets of H(8), a doublet of H(10) is located at 6.85–
6.93 ppm, and a doublet of H(7) at 7.09–7.57 ppm.
In the reaction with carbinol 3, 2-azaspiro[4,5]decans
1
9b–d were isolated as the main products. In the H NMR
spectra of compounds 9b–d, the singlet of the methyl
group in the range of 1.52–1.62 ppm and the doublet of
doublets at 2.53–2.61 ppm indicate the methyl group as
being located at the C(60a) atom, and the proton at C(30a).
Thus, during the reaction, the Wagner–Meerwein
rearrangement proceeds twice and results in the
expansion of the ring and migration of the methyl group.
The structures of compounds 9c,d were confirmed by
X-ray structural analysis (Fig. 2).
Scheme 1. 1: n = 2, R1 = H; 2: n = 2, R1 = CH3; 3: n = 1, R1 = H; 4a–f, 5a–d, 6e,f, 7a–f, 9b–d: R2 = Ph(a), SMe(b), CH2COOEt(c), 4-NO2C6H4(d), 2-
Py(e), Me(f). [Color figure can be viewed at wileyonlinelibrary.com]
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Scheme 3. 4a–d and 12a–d: R = Ph(a), SMe(b), CH2COOEt(c), 4-
NO2C6H4(d). [Color figure can be viewed at wileyonlinelibrary.com]
The reaction with benzonitrile 4a resulting in only
isoquinoline 8 was an exception. The H NMR spectrum
1
of compound 8 at 1.13 ppm includes a singlet with an
integral intensity equaling 3 that is assigned to the signal
of the methyl group at the atom C(3a) and a triplet at
2.75 ppm (J = 9.6 Hz) to the proton signal at C(9b). This
phenomenon again indicates the double proceeding of the
Wagner–Meerwein rearrangement. The signals of protons
of the aromatic part of compound 8 are located as those
for compounds 7a–f at 6.65 ppm—doublet of doublets of
H(7) (J = 8.4 Hz, J = 2.7 Hz), at 6.76 ppm—doublet of
H(9) (J = 8.4 Hz), and doublet of H(6)—at 7.14 ppm
(J = 8.7 Hz); thus, the methoxy group is in position 8.
We did not succeed in receiving carbinol of type 3 with
two methoxy groups in the aromatic part. In all cases,
styrene 11 was formed which, when reacts with nitriles
4a–d, forms, as expected, the annelated 3,4-
dihydroisoquinolines 12a–d (Scheme 3). The signal of
the methyl group at C(3a) position in the 1H NMR
spectra of compounds 12a–d is also presented as singlet
in the range of 1.05–1.20 ppm, like for compound 8, and
the signal of the proton at C(9b) is observed as triplet at
2.64–2.76 ppm(J = 9.0–9.6 Hz), with all these signals
also indicating the double proceeding of the Wagner–
Meerwein rearrangement. The structure of compound 12c
was confirmed by X-ray diffraction (Fig. 3).
Thus, the formation of products 8, 9b–d, and 12a–d
indicates the double proceeding of the Wagner–Meerwein
rearrangement followed by the Ritter heterocyclization in
accord with Scheme 4.
Figure 3. The structure of compound 12с according to X-ray diffraction
data.
Substances” (PASS) predicting over 4000 kinds of
biological activity was opted because of its high (about
95%) accuracy [19]. The main observation of the PASS
prediction was a high degree of probability (Ра 0.545–
0.884) of ubiquinol-cytochrome c reductase inhibitory
Biology.
synthesized
Keeping in mind that the structure of
compounds contained heterocyclic
pharmacophoric moieties, we tried to predict their
potential biological activities by the in silico methods. So
the online service “Prediction of Activity Spectra for
Figure 2. The structures of compounds 9с,d according to X-ray diffraction data.
Journal of Heterocyclic Chemistry
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A. N. Perevoshchikova, D. V. Eroshenko, M. V. Dmitriev, V. V. Grishko, and Y. V. Shklyaev
Vol 000
Scheme 4. Possible reaction mechanism.
activity for compounds 5a–c, 6f, 7a,b,d,f, 8, 9b,d, and 12a
among synthesized derivatives (Table S1).
complex co-crystallized with myxothiazol (PDB: 1SQP)
(Table 1). Comparison of the structures of compounds
12a and 12d with high GOLD scores revealed that the 3,4-
dihydroisoquinoline structure with an aromatic substituent
at the first position should presumably be essential for
bc1 complex inhibitory activity. Conformations of
the dihydropyridine ring and aromatic radical of the
compound 12a and 12d were similar to the
myxothiazol’s heterocycles (Fig. 4c,d). The absence of an
aromatic fragment (12b) or replacement of the planar 3,4-
dihydroisoquinoline structure (12d) with the non-planar
one of spiropyrroline (9d) resulted in a decrease in the
calculated GOLD score values (Table S1). The presence of
the alkyl and alkoxy substituents did not significantly
influence the GOLD score. The docking study also
revealed the (S,S)-enantiomers of 12a,d to be better in the
binding site as compared with (R,R)-enantiomer of these
compounds.
Along with the compounds 12a and 12d, the highest
GOLD score (60.93) was calculated for the product of
dienone-phenolic regrouping—amide 6e. But, in this
case, conformation of only the pyridine radical of
compound 6e was similar to the one of the thiazole rings
of myxothiazol (Fig. 4b). The GOLD score for the (S)- and
(R)-enantiomers of compound 6e equaled 59.58 and
60.93, respectively, suggesting more affinity to the (R)-
enantiomer.
Ubiquinol-cytochrome c reductase, or the cytochrome
bc1 complex (EC 1.10.2.2, bc1), has been identified as a
promising target for agricultural fungicides [20] and
antimalarial drugs [21] due to its important role in the
cellular respiratory chain [22]. The binding to Q0 pocket
of the bc1 complex has been known as the crucial step
for the action of several conventional inhibitors [23].
Possible ligand-receptor interactions for each of the
synthesized compounds with the Q0 binding site of the
bc1 complex were investigated in detail by the docking
studies with the GOLD software widely used for virtual
screening [24]. The crystal structures of the bovine bc1
complex with conventional inhibitor class P (AZ, MOAS,
myxothiazol, UHDBT, and stigmatellin) bonded at the Q0
site were downloaded from the Protein Data Bank. The
GOLD scores between all synthesized compounds and
the targeted protein were calculated (Table S1). As the
compounds 6e,f, 7a–f, 8, 9b–d, 10, and 12a–d have
chiral centers, 37 synthetically possible enantiomers were
applied in docking simulations. We did not find out any
correlation between the PASS prediction activity and the
GOLD data not only for the synthesized compounds but
also for conventional inhibitors (particularly, AZ and
MOAS) (Table S1), probably due to the presence of
asymmetric centers in the structure of these compounds
that create additional restrictions for accurate prediction
of biological activity by PASS software designed for 2D
structures [25].
According to the structural information determined by
the crystallographic studies [23], myxothiazol has a high
potency as bc1 complex inhibitor because its thiazole
rings form the π–π stacking with the phenyl group of
Phe274 (Fig. 4a) [26,27]. Similarly to myxothiazol, the
π–π interaction between the Phe274 and the aromatic
The results of molecular docking showed three
compounds (6e, 12a, and 12d) to have the highest GOLD
score exceeding 57 at molecular docking within the bc1
Table 1
Molecular docking of the compounds 6e and 12a,d with amino acid residues within Q0 pocket of the bc1 complex (PDB: 1SQP).
π–π stacking
with Phe274, Å
H-bonds with amino
acid residues
Ligands
GOLD score
Myxothiazol
6e
12a
12d
99.03
60.93
57.22
59.66
Yes, 3.639
Yes, 3.425
Yes, 3.002
Yes, 3.159
Glu271, Tyr273
Pro270, Ile268, Phe128
Ile146
Ile298, Pro270
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Figure 4. Comparison of the binding modes of myxothiazol and compounds 6e and 12a, d: (a) the simulated binding model of bc1 in complex with
myxothiazol; (b) the simulated binding model of bc1 in complex with compound (R)-6e; (c) the simulated binding model of bc1 in complex with com-
pound (S,S)-12a; (d) the simulated binding model of bc1 in complex with compound (S,S)-12d. [Color figure can be viewed at wileyonlinelibrary.com]
radical of compounds 12a,d was observed as well
(Table 1). These π–π stacking interactions are possible
because of conformational flexibility of Phe274 side
chain [28]. As shown in Table 1, besides the π–π
stacking, compounds 12a,d form hydrogen bonds with
amino acid residues of protein within Q0 pocket. Unlike
myxothiazol that forms H-bond with Glu271 and Tyr273,
compound 12a formed H-bond with Ile146 and 12d
formed H-bond with Ile298. The heteroaromatic fragment
of molecule 6e also resulted in the π–π stacking
interaction with Phe274 (Fig. 4b, Table 1). However, the
conformation of compound 6e within Q0 pocket differs
from that of compounds 12a,d by the presence of three
H-bonds with Pro270, Ile268, and Phe128 within the
active site of the bovine bc1 complex (Table 1).
The GOLD score data for the potential inhibitors of bc1
complex 6e and 12a,d have been supported by the
calculated Lipinski parameters [29] (Table S2). The
predicted octanol/water partition coefficient (ClogP) is
useful for the estimation of the hydrophobic interactions
within the Q0 pocket formed by the side chains of
Phe274, Phe128, Ile146, Pro270, Ala277, Leu294,
Met124, and Ile298 [30]. The ligand-protein interactions
may be possible because of the high value of predicted
lipophilicity (ClogP ranging from 3.96 to 4.22) of the
synthesized compounds 6e and 12a,d. Interestingly, the
ligands 6e and 12d showed highest potential inhibitor
efficiency for bc1 complex due to the similar СlogP
values (3.749 and 3.96, respectively) and correlating high
GOLD scores values (60.93 and 59.66, respectively).
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Methods and materials. Prediction of activity spectra for
substances. A dataset consisting of 20 compounds were
on the Varian Mercury Plus 300 or Bruker DRX 400 Hz
spectrometers, with chemical shifts and coupling constants
(J) expressed in parts per million (ppm) and hertz (Hz),
respectively. Mass spectra were acquired on the Agilent
Technology 6890N/5975B mass spectrometer (ionization
potential 70 eV). Microanalyses (C, H, and N) were
carried out on the Leco CHNS-932 elemental analyzer.
The reactions and purity of the compounds obtained were
overseen by TLC on Sorbfil plates, with the use of 0.5%
solution of chloranil in toluene and UV light.
General procedure for synthesis of 1–3 and 11. To a
freshly prepared 0.036 mole solution of CH3MgI in Et2O,
a solution of 0.030 mole of corresponding ketone in
10 mL of Et2O was added dropwise and stirred at such a
rate that the mixture was slightly boiling. With the
remaining amount of ketone added, the reaction mixture
was additionally refluxed for 2 h. The reaction mass was
then cooled with ice and hydrolyzed by slow dropping
into 35 mL of saturated NH4Cl solution. After separation
of the phases, the aqueous phase was extracted with Et2O
(3 × 15 mL). The combined extracts were washed with
water and dried over MgSO4, whereupon the solvent was
distilled off. The residue (3 and 11) was distilled at
appropriate temperature or isolated by column
chromatography (1 and 2). The yield of compounds 1–3
and 11 equaled 52–93%.
processed through the PASS online service [19] (www.
pharmaexpert.ru/passonline/). As a scoring function, the
PASS estimates the probability of the presence (Pa) and
the absence (Pi) of each activity in the range from 0 to 1.
The Pa value was used as the main criterion; therefore,
only activities with Pa > Pi were considered.
Molecular docking.
Molecular docking studies were
carried out on a laptop PC with Intel® Core™ i3-6100
QM CPU at 3.70 GHz, RAM 8 GB operating under the
Windows 7 Professional OS. Briefly, the 3D crystal
structures of bovine bc1 complex with azoxystrobin (AZ),
β-methoxyacrylate stilbene (MOAS), myxothiazol, 5-
undecyl-6-hydroxy-4,7-dioxobenzothiazole
(UHDBT),
and stigmatellin were downloaded from the RCSB
Protein Data Bank (PDB code 1SQB, 1SQQ, 1SQP,
1SQV, and 1SQX, respectively) [23] and loaded into the
GOLD 5.0.1 version (CCDC Software, http://www.ccdc.
cam.ac.uk/products) [31]. All types of atoms, charges,
and bond hybridization were carefully checked. Protons
were added, and all crystallographic water molecules
were removed. The native ligand was removed, and the
binding site was defined as all atoms within 5 Å of the
crystallographic ligand. The GOLD software was
benchmarked by docking AZ, MOAS, myxothiazol,
UHDBT, and stigmatellin into the native binding site of
the bc1 complex [32].
General procedure for synthesis of 5a–с, 6e,f, 7a–f, 8, 9b–d,
10, and 12a–d.
A mixture composed of 1 mmol of
The ChemBio3D Ultra 14.0 software (Perkin Elmer)
was used to draw the 3D structures of synthesized
compounds that were further pre-optimized with MM2
force field and saved in mol2 file format. The docking
was performed 10 times using standard parameters, and
the GOLD score was determined. Conformation of the
ligands with the highest GOLD score value was selected as
the best and then compared with the conformation of
native co-crystallized ligand by the PyMOL Molecular
Graphics System 2.0 (Schrödinger LLC).
To assess compliance of the compounds 6e and 12a,d
with the Lipinski rule of five [14], their molecular weight
(Mw) and octanol/water partition coefficient (ClogP)
were calculated using the ChemBioDraw 14.0 software
(Perkin Elmer).
carbinol 1–3 or styrene 11 and 1 mmol of nitrile was
added dropwise to 1 mL of 92% H2SO4 while vigorously
stirred and cooled with ice water. The reaction mixture
was then stirred for 20 min at room temperature, poured
into a mixture of crushed ice with 4 mL of aqueous
ammonia, and extracted with CH2Cl2 (3 × 5 mL). The
combined extracts were washed with water, dried over
MgSO4, whereupon the solvent was distilled off. The
reaction product was isolated by column chromatography
or crystallization from a suitable solvent.
Compound 10 was obtained from 7b. Compound 7b
(0.2 g) was mixed with 1 mL of freshly prepared
CH3COOK and heated for 10 h at 80°C. The mixture
was then hydrolyzed with 2 mL of ammonia, washed
with hexane, and crystallized from ethyl acetate.
The structures of all the synthesized compounds were
confirmed by 1H NMR, 13C NMR, GC/MS, IR, and
elemental analysis; X-ray diffraction analysis for
compounds 9c,d, 10, and 12c was carried out.
EXPERIMENTAL
All commercially available materials and reagents were
purchased from Alfa Aesar with no further purification.
Melting points were measured in open capillaries on the
Stuart SMP40 melting point device without further
correction. The IR spectra were recorded on Fourier
spectrometers, models FСМ-1201 or Bruker IFS-66/S, in
6-Methyl-13-phenyl-14-azadispiro[4.1.5.2]tetradeca-8,11,13-
trien-10-one (5a).
Yield 79%, white crystals, mp 156–
158°С (from ethyl acetate). IR: 3325, 2960, 2872, 1643,
1
1600, 1514 cmꢀ1. Н NMR (400 MHz, CDCl3), δ: 0.82
(d, 3Н, С(6)НСН3, J = 7.2 Hz), 1.40–2.20 (m, 8Н,
С(1)Н2, С(2)Н2, С(3)Н2, С(4)Н2), 2.59 (q, 1Н, Н(6),
J = 14.6, 7.2 Hz), 6.42 (dd, 1Н, Н(9), J = 1.8, 9.9 Hz),
petroleum jelly. H and 13C NMR spectra were recorded
1
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1
6.49 (dd, 1Н, Н(11), J = 1.5, 10.2 Hz), 6.80 (dd, 1Н, Н(8),
J = 2.7, 9.9 Hz), 6.89 (dd, 1Н, Н(12), J = 2.8, 9.9 Hz),
7.20–7.40 (m, 3Н, НAr(3), НAr(4), НAr(5)), 7.63 (d, 2Н,
НAr(2), НAr(6), J = 7.2 Hz). 13С NMR (100 MHz,
СDCl3), δ: 9.29 (С(6)НСН3), 25.09, 26.54, 34.01, 40.55
(С(1)Н2, С(2)Н2, С(3)Н2, С(4)Н2), 53.07 (С(6)), 64.73
(С(7)), 84.35 (С(5)), 127.61, 128.50, 130.20, 130.73,
131.35 (С(9), С(11), CAr(2), CAr(3), CAr(4), CAr(5),
CAr(6)), 148.55, 152.12 (С(8), С(12)), 166.16, 185.61
(С(10), С(13)). MS, (m/z, %): 291 [М]+ (0.14), 188 [М-
C6H5CN]+ (27), 173 (33), 147 (26), 145 (18), 131 (10),
121 (15), 107 (16), 103 (100), 91 (14), 77 (17), 76 (34),
50 (16). Anal. Calcd for C20H21NO: С, 82.44; Н, 7.26;
1614, 1591, 1515 сmꢀ1. Н NMR (400 MHz, CDCl3), δ:
1.31 (d, 3Н, СНСН3, J = 7.2 Hz), 1.10–2.50 (m, 8Н,
С(СН2)4), 3.66 (q, 1Н, СНСН3, J = 7.2, 15.0 Hz), 6.30–
9.10 (m, 10Н, НAr(2), НAr(3), НAr(5), НAr(6), НPy(3),
НPy(4), НPy(5), НPy(6), ОH, NH). 13С NMR (100 MHz,
СDCl3), δ: 16.60 (СНСН3), 22.99, 23.26, 33.82, 34.84
(С(СН2)4), 43.16 (СНСН3), 68.96 (С(СН2)4), 113.75,
114.42 (CAr(3), CAr(5)), 121.62, 125, 92 (CPy(3), CPy(5)),
129.32, 129.81 (CAr(2), CAr(6)), 134.65 (CAr(1)), 137.41
(CPy(4)), 147.77 (CPy(6)), 150.14 (CPy(2)), 154.96
(CAr(4)), 163.76 (С¼О). MS, (m/z, %): 310 [М]+ (0.07),
189 (100), 171 (13), 106 (21), 78 (40). Anal. Calcd for
C19H22N2O2: С, 73.52; Н, 7.14; N, 9.03. Found: С,
N, 4.81. Found: С, 82.33; Н, 7.16; N, 4.80.
6-Methyl-13-(methylthio)-14-azadispiro[4.1.5.2]tetradeca-
73.75; Н, 7.08; N, 9.10.
N-{1-[1-(4-Hydroxyphenyl)etyl]cyclopentyl}acetamide (6f).
8,11,13-trien-10-one (5b).
Yield 45%, yellow-white
crystals, mp 75°С (eluent: hexane-ethyl acetate 10:1). IR:
3042, 2958, 2930, 2872, 1667, 1579 сmꢀ1 1Н NMR
Yield 57%, white crystals, mp 131°С (eluent: hexane-ethyl
acetate 5:1). IR: 3330, 2953, 2922, 2851, 1744, 1636, 1618,
1
1544 сmꢀ1. Н NMR (400 MHz, CDCl3), δ: 1.18 (d, 3Н,
.
(400 MHz, CDCl3), δ: 0.84 (d, 3Н, С(6)НСН3,
J = 7.2 Hz), 1.20–2.10 (m, 8Н, С(1)Н2, С(2)Н2, С(3)Н2,
С(4)Н2), 2.38 (s, 3Н, SCH3), 2.59 (q, 1Н, Н(6), J = 14.7,
7.2 Hz), 6.30–6.45 (m, 2Н, Н(8), Н(12)), 6.60–6.75 (m,
2Н, Н(9), Н(11)). 13С NMR (100 MHz, СDCl3), δ: 9.43,
13.38 (С(6)НСН3, SCH3), 24.27, 25.86, 34.03, 40.23
(С(1)Н2, С(2)Н2, С(3)Н2, С(4)Н2), 52.78 (С(6)), 64.63
(С(7)), 85.10 (С(5)), 130.73, 131.07 (С(9), С(11)),
146.23, 149.38 (С(8), С(12)), 166.65, 185.29 (С(10),
С(13)). MS, (m/z, %): 261 [М]+ (2), 189 (15), 188 [М-
CH3SCN]+ (100), 173 (27), 147 (15), 145 (14), 131 (19),
126 (13), 121 (72), 120 (38), 108 (16), 107 (33), 92 (17),
91 (33), 82 (14), 81 (29), 77 (12), 67 (29). Anal. Calcd
for C17H23NOS: С, 68.93; Н, 7.33; N, 5.36; S, 12.27.
Found: С, 68.78; Н, 7.51; N, 5.45; S, 12.18.
СНСН3, J = 7.5 Hz), 1.30–2.00 (m, 8Н, С(СН2)4), 1.77
(s, 1Н, СОСН3), 3.60 (q, 1Н, СНСН3, J = 7.2, 14.4 Hz),
6.67 (d, 2Н, НAr(3), НAr(5), J = 8.8 Hz), 6.97 (d, 2Н,
НAr(2), НAr(6), J = 8.8 Hz), 7.09 (s, 1Н, ОH), 9.07 (bs,
1Н, NH). 13С NMR (100 MHz, СDCl3), δ: 16.39
(СНСН3), 22.83 (СОСН3), 22.93, 23.59, 32.75, 33.06
(С(СН2)4), 41.12 (СНСН3), 67.79 (С(СН2)4), 114.42
(CAr(3), CAr(5)), 129.42 (CAr(2), CAr(6)), 134.22 (CAr(1)),
155.45 (CAr(4)), 169.02 (С¼О). MS, (m/z, %): 247 [М]+
(0.2), 126 [С5Н8NHCOCH3]+ (51), 84 [С5Н8NH]+ (100).
Anal. Calcd for C15H21NO2: С, 72.84; Н, 8.56; N, 5.66.
Found: С, 72.58; Н, 8.69; N, 5.41.
9-Methoxy-4a,10b-dimethyl-6-phenyl-1,2,3,4,4a,10b-
hexahydrophenanthridine (7a). Yield 56%, dark yellow oil
(eluent: hexane-ethyl acetate 10:1). IR: 3417, 3200, 2928,
2858, 1665, 1514, 1216 сmꢀ1 1Н NMR (400 MHz,
.
Ethyl
2-(6-methyl-10-oxo-14-azadispiro[4.1.5.2]tetradeca-
8,11-dien-13-ylidene)ethanoate (5с).
Yield 40%, white
crystals, mp 99°С (eluent: hexane-acetone 5:1). IR: 3338,
2963, 2875, 1663, 1600 сmꢀ1 1Н NMR (400 MHz,
CDCl3), δ: 0.8–1.9 (m, 14Н, С(1)Н2, С(2)Н2, С(3)Н2,
С(4)Н2, С(4а)СН3, С(10b)СН3), 3.79 (s, 3Н, ОСН3),
6.61 (dd, 1Н, Н(8), J = 8.4, 2.7 Hz), 6.93 (d, 1Н, Н(10),
J = 2.4 Hz), 7.09 (d, 1Н, Н(7), J = 8.4 Hz), 7.30–7.55
(m, 5Н, НAr). 13С NMR (100 MHz, СDCl3), δ: 21.08,
22.28, 29.52, 35.01 (С(1), С(2), С(3), С(4)), 14.26, 21.44
(С(4а)СН3, С(10b)СН3), 38.39 (С(4а)), 55.01 (ОСН3),
59.16 (С(10b)), 109.01, 111.04, 129.88 (С(7), С(8),
С(10)), 120.49 (С(6а)), 127.93, 128.34 (CAr(2), CAr(3),
CAr(4), CAr(5), CAr(6)), 128.31 (CAr(1)), 139.98, 161.59,
163.53 (С(6), С(9), С(10а)). MS, (m/z, %): 319 [М]+
(80), 318 (100), 304 [M-CH3]+ (16), 290 (20), 265 (19),
264 (54), 248 (17), 242 (23), 236 (14). Anal. Calcd for
C22H25NO: С, 82.72; Н, 7.89; N, 4.38. Found: С, 82.96;
.
CDCl3), δ: 0.84 (d, 3Н, С(6)НСН3, J = 7.5 Hz), 1.20 (t,
3Н, OСН2CH3, J = 7.2 Hz), 1.50–2.00 (m, 8Н, С(1)Н2,
С(2)Н2, С(3)Н2, С(4)Н2), 2.56 (q, 1Н, Н(6), J = 15.0,
7.2 Hz), 4.05 (q, 2Н, OСН2CH3, J = 14.1, 7.2 Hz), 4.27
(s, 1Н, ¼СН–), 6.27 (dd, 1Н, Н(9), J = 1.8, 9.9 Hz),
6.36 (dd, 1Н, Н(11), J = 9.9, 1.8 Hz), 6.68 (dd, 1Н,
Н(8), J = 2.7, 9.9 Hz), 6.78 (dd, 1Н, Н(12), J = 3.0,
9.9 Hz), 8.23 (s, 1Н, NH). 13С NMR (100 MHz, СDCl3),
δ: 8.82, 14.25 (С(6)НСН3, OСН2CH3), 23.17, 24.81,
34.80, 39.48 (С(1)Н2, С(2)Н2, С(3)Н2, С(4)Н2), 48.54
(С(6)), 56.41 (С(7)), 58.51 (OСН2CH3), 72.94 (С(5)),
77.97 (¼СН–), 129.23, 130.44 (С(9), С(11)), 146.47,
149.32 (С(8), С(12)), 160.95, 170.11, 185.08 (С(10),
С(13), С¼О). Anal. Calcd for C18H23NO3: С, 71.73; Н,
Н, 7.71; N, 4.16.
9-Methoxy-4a,10b-dimethyl-6-(methylthio)-1,2,3,4,4a,10b-
hexahydrophenanthridine (7b).
Yield 72%, light yellow
oil (eluent: hexane-ethyl acetate 10:1). IR: 3157, 2927,
2855, 1604, 1485, 1246 сmꢀ1 1Н NMR (400 MHz,
7.69; N, 4.65. Found: С, 71.50; Н, 7.74; N, 4.81.
N-{1-[1-(4-Hydroxyphenyl)ethyl]cyclopentyl}pyridine-2-
carboxamide (6e). Yield 21%, yellow oil (eluent: hexane-
.
CDCl3), δ: 0.70–1.80 (m, 14Н, С(1)Н2, С(2)Н2, С(3)Н2,
С(4)Н2, С(4а)СН3, С(10b)СН3), 2.42 (s, 3Н, SCH3),
ethyl acetate 5:1). IR: 3346, 3060, 2966, 2937, 2875, 1662,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. N. Perevoshchikova, D. V. Eroshenko, M. V. Dmitriev, V. V. Grishko, and Y. V. Shklyaev
Vol 000
3.81 (s, 3Н, ОСН3), 6.75 (dd, 1Н, Н(8), J = 8.6, 2.7 Hz),
6.85 (d, 1Н, Н(10), J = 2.7 Hz), 7.57 (d, 1Н, Н(7),
J = 8.4 Hz). 13С NMR (100 MHz, СDCl3), δ: 12.08
(SCH3), 14.09, 22.16 (С(4а)СН3, С(10b)СН3), 21.18,
22.20, 29.66, 35.98 (С(1), С(2), С(3), С(4)), 38.95
(С(4а)), 55.16 (ОСН3), 60.47 (С(10b)), 109.54, 111.05,
126.17 (С(7), С(8), С(10)), 121.04 (С(6а)), 147.49,
158.47, 161.75 (С(6), С(9), С(10а)). MS, (m/z, %): 289
[М]+ (30), 275 [M-CH3 + 1]+ (19), 274 [M-CH3]+ (100),
256 (13), 234 (17). Anal. Calcd for C17H23NOS: С,
70.54; Н, 8.01; N, 4.84; S, 11.08. Found: С, 70.63; Н,
8.18; N, 4.60; S, 11.01.
С(2)Н2, С(3)Н2, С(4)Н2, С(4а)СН3, С(10b)СН3), 3.82 (s,
3Н, ОСН3), 6.66 (dd, 1Н, Н(8), J = 8.8, 2.7 Hz), 6.92 (d,
1Н, Н(10), J = 2.4 Hz), 7.25 (d, 1Н, Н(7), J = 4.5 Hz),
7.27–7.40 (m, 1Н, НPy(5)), 7.69 (dd, 1Н, НPy(3), J = 9.0,
1.8 Hz), 7.77 (td, 1Н, НPy(4), J = 7.5, 1.8 Hz), 8.65 (m,
1Н, НPy(6)). 13С NMR (100 MHz, СDCl3), δ: 20.72,
21.96, 29.14, 34.68 (С(1), С(2), С(3), С(4)), 13.53, 20.96
(С(4а)СН3, С(10b)СН3), 38.19 (С(4а)), 54.66 (ОСН3),
59.23 (С(10b)), 109.11, 110.74, 129.61 (С(7), С(8),
С(10)), 119.49 (С(6а)), 122.79, 123.32, 136.26, 147.92
(СPy(3), СPy(4), СPy(5), СPy(6)), 157.85, 161.48, 161.76,
166.25 (С(6), С(9), С(10а), СPy(2)). MS, (m/z, %): 320
[М]+ (22), 306 [M-CH3 + 1]+ (23), 305 [M-CH3]+ (100),
264 (27). Anal. Calcd for C21H24N2O: С, 78.71; Н, 7.55;
Ethyl
2-(9-methoxy-4a,10b-dimethyl-1,2,3,4,4a,5-
hexahydrophenanthridin-6(10bH)-ylidene)acetate (7с).
Yield 50%, yellow-green oil (eluent: hexane-ethyl acetate
5:1). IR: 3270, 2974, 2935, 2863, 1737, 1663, 1643,
N, 8.74. Found: С, 78.76; Н, 7.73; N, 8.65.
9-Methoxy-4a,6,10b-trimethyl-1,2,3,4,4a,10b-
hexahydrophenanthridine (7f). Yield 43%, red-orange oil
1
1600, 1484, 1288 сmꢀ1. Н NMR (400 MHz, CDCl3), δ:
0.58–1.74 (m, 17Н, С(1)Н2, С(2)Н2, С(3)Н2, С(4)Н2,
С(4а)СН3, С(10b)СН3, СН2СН3), 3.94 (s, 3Н, ОСН3),
4.40 (q, 2Н, ОСН2СН3, J = 7.2 Hz), 5.06 (s, 1Н,
¼CH–), 6.65–7.00 (m, 2Н, Н(8), Н(10)), 7.65 (d, 1Н,
Н(7), J = 8.8 Hz), 8.97 (bs, 1H, NH). 13С NMR
(100 MHz, СDCl3), δ: 13.55, 14.22, 20.06 (С(4а)СН3,
С(10b)СН3, ОСН2СН3), 20.69, 21.85, 34.56, 35.07
(С(1), С(2), С(3), С(4)), 53.46 (С(4а)), 54.74 (ОСН3),
57.80 (ОСН2СН3), 61.04 (С(10b)), 75.10 (–СН¼),
110.27, 110.88, 126.51 (С(7), С(8), С(10)), 120.36
(С(6а)), 148.32, 154.79, 161.53, 170.93 (С(6), С(9),
С(10а), С¼О). Anal. Calcd for C20H27NO3: С, 72.92; Н,
(eluent: hexane-ethyl acetate 5:1). IR: 3291, 3081, 2929,
2858, 1704, 1631, 1605, 1492, 1241 сmꢀ1 1Н NMR
.
(400 MHz, CDCl3), δ: 0.73–1.77 (m, 14Н, С(1)Н2,
С(2)Н2, С(3)Н2, С(4)Н2, С(4а)СН3, С(10b)СН3), 2.43 (s,
3Н, С(6)СН3), 3.85 (s, 3Н, ОСН3), 6.76 (dd, 1Н, Н(8),
J = 8.5, 2.6 Hz), 6.89 (d, 1Н, Н(10), J = 2.6 Hz), 7.48 (d,
1Н, Н(7), J = 8.5 Hz). 13С NMR (100 MHz, СDCl3), δ:
21.07, 22.07, 29.48, 35.19 (С(1), С(2), С(3), С(4)), 21.75,
22.90 (С(4а)СН3, С(10b)СН3), 29.11 (С(6)СН3), 38.53
(С(4а)), 55.01 (ОСН3), 58.38 (С(10b)), 109.54, 110.92,
127.18 (С(7), С(8), С(10)), 120.97 (С(6а)), 147.99,
160.30, 161.70 (С(6), С(9), С(10а)). MS, (m/z, %): 257
[М]+ (85), 256 (35), 243 [M-CH3 + 1]+ (18), 242 [M-
CH3]+ (100), 228 (50), 214 (23), 203 (42), 202 (43), 188
(27), 187 (34), 174 (21). Anal. Calcd for C17H23NO: С,
8.26; N, 4.25. Found: С, 72.86; Н, 8.43; N, 4.19.
9-Methoxy-4a,10b-dimethyl-6-(4-nitrophenyl)-
1,2,3,4,4a,10b-hexahydrophenanthridine (7d).
Yield 48%,
yellow oil (eluent: hexane-ethyl acetate 10:1). IR: 3107,
3076, 3054, 2827, 2860, 2233, 1941, 1807, 1692, 1528,
79.33; Н, 9.01; N, 5.44. Found: С, 79.18; Н, 9.13; N, 5.29.
8-Methoxy-3a-methyl-5-phenyl-2,3,3a,9b-tetrahydro-1H-
1
1350 сmꢀ1. Н NMR (400 MHz, CDCl3), δ: 0.60–2.00
cyclopenta[c]isoquinoline (8).
Yield 67%, yellow oil
(m, 14Н, С(1)Н2, С(2)Н2, С(3)Н2, С(4)Н2, С(4а)СН3,
С(10b)СН3), 3.83 (s, 3Н, ОСН3), 6.64 (dd, 1Н, Н(8),
J = 8.4, 2.7 Hz), 6.90–7.40 (m, 2Н, Н(7), Н(10)), 7.66
(d, 2Н, НAr(2), НAr(6), J = 8.7 Hz), 8.24 (d, 2Н, НAr(3),
НAr(5), J = 8.7 Hz). 13С NMR (100 MHz, СDCl3), δ:
21.02, 22.31, 29.58, 34.97 (С(1), С(2), С(3), С(4)),
14.28, 21.32 (С(4а)СН3, С(10b)СН3), 38.53 (С(4а)),
55.22 (ОСН3), 59.92 (С(10b)), 109.50, 111.56, 129.32
(С(7), С(8), С(10)), 119.63 (С(6а)), 123.63, 129.51
(CAr(2), CAr(3), CAr(5), CAr(6)), 130.21 (CAr(1)), 146.30,
147.84, 162.08, 162.16 (С(6), С(9), С(10а), CAr(4)). MS,
(m/z, %): 364 [М]+ (100), 363 (91), 349 [M-CH3]+ (18),
335 (22), 317 (21), 310 (25), 309 (65), 242 (32). Anal.
Calcd for C22H24N2O3: С, 72.50; Н, 6.64; N, 7.69.
(eluent: hexane-ethyl acetate 5:1). IR: 2951, 2864, 1664,
1
1606 сmꢀ1. Н NMR (300 MHz, CDCl3), δ: 1.13 (s, 3Н,
С(3a)СН3), 1.45–2.50 (m, 6Н, С(1)Н2, С(2)Н2, С(3)Н2),
2.75 (t, 1Н, С(9b)Н, J = 9.6 Hz), 3.82 (s, 3Н, OСН3), 6.65
(dd, 1Н, Н(7), J = 8.4, 2.7 Hz), 6.76 (d, 1Н, Н(9),
J = 8.4 Hz), 7.14 (d, 1Н, Н(6), J = 8.7 Hz), 7.30–7.55 (m,
5Н, НAr). 13С NMR (75 MHz, СDCl3), δ: 25.36 (С(2)),
28.10 (С(3a)CH3), 31.24 (С(1)), 40.37 (С(3)), 46.60
(С(9b)), 55.24 (ОСН3), 65.76 (С(3a)), 111.29 (С(9)),
115.98 (С(7)), 127.41, 127.70, 128,03, 128.32 (CAr(2),
CAr(3), CAr(5), CAr(6)), 128.34 (С(5a)), 129.28 (С(6)),
130.69 (СAr(4)), 133.51 (СAr(1)), 143.29 (С(9a)), 156.42
(С(5)), 166.21 (С(8)). MS, (m/z, %): 291 [М]+ (100), 290
[M-H]+ (87), 276 [M-CH3]+ (21), 263 (73), 262 (28), 248
(15), 178 (17). Anal. Calcd for C20H21NO: С, 82.44; Н,
Found: С, 72.76; Н, 6.36; N, 7.48.
9-Methoxy-4a,10b-dimethyl-6-(pyridin-2-yl)-1,2,3,4,4a,10b-
7.26; N, 4.81. Found: С, 82.49; Н, 7.39; N, 4.75.
6a0-Methyl-20-(methylthio)-40,50,60,6a0-tetrahydro-3a0H-
spiro[cyclohexa[2,5]diene-1,30-cyclopenta[b]pyrrol]-4-one
(9b). Yield 71%, yellow oil (eluent: hexane-ethyl acetate
hexahydrophenanthridine (7e).
Yield 61%, yellow oil
(eluent: hexane-acetone 5:1). IR: 3453, 3296, 3219, 3057,
2931, 2859, 1694, 1606, 1566, 1491 сmꢀ1 1Н NMR
(400 MHz, CDCl3), δ: 0.80–1.90 (m, 14Н, С(1)Н2,
.
1
5:1). IR: 3381, 3295, 2956, 2870, 1666, 1593 сmꢀ1. Н
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Docking of 3,4-Dihydroisoquinolines, Spiropyrrolines
NMR (300 MHz, CDCl3), δ: 1.45–2.10 (m, 6Н, C(40)H2,
C(50)H2, C(60)H2), 1.52 (s, 3Н, C(6a0)CH3), 2.37 (s, 1H,
SCH3), 2.53 (dd, 1Н, Н(3a0), J = 8.1, 4.2 Hz), 6.23 (dt,
1Н, Н(2), J = 0.9, 9.9 Hz), 6.39 (dt, 1Н, Н(6), J = 0.9,
10.2 Hz), 6.68 (dd, 1Н, Н(3), J = 2.85, 9.9 Hz), 6.79 (dd,
1Н, Н(5), J = 3.0, 10.2 Hz). 13С NMR (75 MHz, СDCl3),
δ: 13.91 (C(50)), 25.42 (SCH3), 28.42 (C(40)), 30.54
(C(6a0)CH3), 40.54 (C(3a0)), 58.29 (C(60)), 63.25 (C(30)),
85.97 (C(6a0)), 127.43 (С(5)), 130.51 (С(3)), 146.32
(С(6)), 150.45 (С(2)), 167.00 (C(20), 184.83 (С(4)). MS,
(m/z, %): 247 [М]+ (1.7), 175 (13), 174 (100), 159 (21),
146 (32), 133 (11), 131 (28), 120 (71), 107 (19), 91 (18),
77 (17), 73 (18), 655 (13), 55 (33), 41 (15), 39 (17). Anal.
Calcd for C14H17NOS: С, 67.98; Н, 6.93; N, 5.66; S,
12.96. Found: С, 67.94; Н, 6.89; N, 5.85; S, 12.88.
imposed on the geometric and anisotropic parameters of
the part of a disordered atom. Final refinement results: R1
0.0649, wR2 0.1626 for 2224 reflections with I > 2σ(I);
R1 0.0988, wR2 0.1936 for all 3492 independent
reflections, S 1.031. Summary of data CCDC 1833626.
6a0-Methyl-20-(4-nitrophenyl)-40,50,60,6a0-tetrahydro-3a0H-
spiro[cyclohexa[2,5]diene-1,30-cyclopenta[b]pyrrol]-4-one
(9d).
Yield 81%, colorless crystals, mp 163°С (from
acetone). IR: 3323, 3115, 2968, 1658, 1605 сmꢀ1 1Н
.
NMR (300 MHz, CDCl3), δ: 1.40–2.25 (m, 6Н, C(40)H2,
C(50)H2, C(60)H2), 1.62 (s, 3Н, C(6a0)CH3), 2.61 (dd, 1Н,
H(3a0), J = 7.35, 4.65 Hz), 6.41 (dd, 1Н, Н(2), J = 1.8,
9.9 Hz), 6.48 (dd, 1Н, Н(6), J = 1.8, 9.9 Hz), 6.91 (dd,
1Н, Н(3), J = 3.0, 9.9 Hz), 6.98 (dd, 1Н, Н(5), J = 3.0,
9.9 Hz), 7.80–7.90 (dm, 2Н, НAr(2), НAr(6)), 8.10–8.20
(dm, 2Н, НAr(3), НAr(5)). 13С NMR (75 MHz, СDCl3),
δ: 25.26 (С(50)), 27.85 (C(6a0)CH3), 31.02 (C(40)), 40.16
(C(60)), 59.46 (C(3a0)), 62.08 (C(30)), 85.07 (C(6a0))
123.28 (CAr(3), CAr(5)), 127.91 (С(5)), 128.64 (CAr(2),
CAr(6)), 130.69 (С(3)), 139.22 (CAr(1)), 147.93 (С(6)),
148.71 (CAr(4)), 151.35 (С(2), 164.27 (C(20)), 184.33
(С(4)). MS, (m/z, %): 322 [М]+ (0.01), 174 (100), 159
(24), 146 (45), 131 (35), 120 (99), 102 (30), 55 (49).
Anal. Calcd for C19H18N2O3: С, 70.79; Н, 5.63; N, 8.69.
Found: С, 70.67; Н, 5.78; N, 8.55.
Ethyl
2-(6a0-methyl-4-oxo-3a0,40,50,60-tetrahydro-10H-
spiro[cyclohexa[2,5]diene-1,30-cyclopenta[b]pyrrole]-20(6a0H)-
ylidene)acetate (9с). Yield 78%, orange crystals, mp 169–
170°С (from acetone). IR: 3323, 3115, 2968, 1658,
1
1605 сmꢀ1. Н NMR (300 MHz, CDCl3), δ: 1.00–2.10
(m, 12Н, C(6a0)CH3, C(40)H2, C(50)H2, C(60)H2,
ОСН2СН3), 2.40–2.50 (m, 1Н, Н(3a0)), 4.12 (q, 2Н,
OСН2СН3, J = 7.2 Hz), 4.23 (s, 1Н, ¼СН–), 6.16 (d,
1Н, Н(2), J = 9 Hz), 6.35 (d, 1Н, Н(6), J = 10.2 Hz),
6.75–6.90 (m, 2Н, Н(3), Н(5)), 7.93 (1Н, NH). 13С NMR
(75 MHz, СDCl3), δ: 14.33 (ОСН2СН3), 25.53 (C(40)),
28.78 (C(6a0)CH3), 30.48 (C(50)), 41.78 (C(60)), 54.47
(C(30)), 55.97 (C(3a0)), 58.62 (OСН2СН3), 72.37
(C(6a0)), 77.43 (¼СН–), 126.09, 129.59 (С(3), С(5)),
147.07, 150.78 (С(2), С(6)), 162.48 (C(20)), 170.36
(С¼О), 184.89 (С(4)). Anal. Calcd for C17H21NO3: С,
71.06; Н, 7.37; N, 4.87. Found: С, 71.18; Н, 7.45; N, 4.69.
X-ray diffraction analysis of compound 9d.
The cell
parameters and the set of experimental reflections of a
sample of compound 9d were measured on a single
crystal X-ray diffractometer equipped with the Xcalibur
Ruby CCD detector by the ω-2θ scanning method on
monochromatized MoKα-radiation at T = 295 (2) K.
Absorption is taken into account empirically using the
algorithm SCALE3 ABSPACK [33]. The structure was
solved by a direct statistical method and refined by the
full-matrix least-squares method in the anisotropic
approximation for all non-hydrogen atoms. The hydrogen
atoms of the NH groups are refined independently in the
isotropic approximation; the rest are placed in
geometrically calculated positions and included in the
refinement using the riding model. All calculations to
determine and refine the structures were performed
using the programs OLEX2 [35] and SHELXL-2014
[36]. To analyze the compound 9d with the gross
formula C19H18N2O3, a colorless crystal measuring
0.48 × 0.29 × 0.23 mm was used. The crystal is
monoclinic, space group P21/c, a 7.1536 (11), b 13.054
(2), c 17.546 (3) Å, β 91.225 (17)°, V 1638.0 (5) Å3, dcalc
1.307 g/cm3, Z 4. Final refinement results: R1 0.0538,
wR2 0.1365 for 2937 reflections with I > 2σ(I); R1
0.0715, wR2 0.1520 for all 3900 independent reflections,
S 1.031. Summary of data CCDC 1833628.
X-ray diffraction analysis of compound 9c.
The cell
parameters and the set of experimental reflections of a
sample of compound 9c were measured on a single
crystal X-ray diffractometer equipped with the Xcalibur
Ruby CCD detector by the ω-2θ scanning method on
monochromatized MoKα-radiation at T = 295 (2) K.
Absorption is taken into account empirically using the
algorithm SCALE3 ABSPACK [33]. The structure was
solved by a direct statistical method and refined by the
full-matrix least-squares method in the anisotropic
approximation for all non-hydrogen atoms. The hydrogen
atoms of the NH groups are refined independently in the
isotropic approximation; the rest are placed in
geometrically calculated positions and included in the
refinement using the riding model. All calculations to
determine and refine the structures were performed using
the program SHELXL-97 [34]. To analyze the compound
9c with the gross formula C17H21NO3, an orange crystal
with a size of 0.55 × 0.30 × 0.20 mm was used. Crystal
rhombic, space group P212121, a 9.468 (2), b 9.704 (4), c
17.245 (6) Å, V 1584.5 (9) Å3, dcalc 1.205 g/cm3, Z 4.
The soft restrictions SADI, DFIX, SIMU, and DELU are
9-Methoxy-4a,10b-dimethyl-1,2,3,4,4a,5-
hexahydrophenanthridin-6(10bH)-one (10).
Yield 60%,
colorless crystals, mp 138°С (from ethyl acetate). 1Н
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. N. Perevoshchikova, D. V. Eroshenko, M. V. Dmitriev, V. V. Grishko, and Y. V. Shklyaev
Vol 000
NMR (400 MHz, CDCl3), δ: 1.17, 1.32 (both s, 6Н,
С(4а)СН3, С(10b)СН3), 1.37–1.84 (m, 8Н, С(1)Н2,
С(2)Н2, С(3)Н2, С(4)Н2), 3.85 (s, 3Н, ОСН3), 5.83 (bs,
1Н, NH), 6.82 (dd, 2Н, Н(8), Н(10), J = 7.3, 2.2 Hz),
8.06 (dd, 1Н, Н(7), J = 9.6, 2.8 Hz). 13С NMR
(100 MHz, СDCl3), δ: 21.15, 21.80, 29.95, 36.01 (С(1),
С(2), С(3), С(4)), 24.01, 24.21 (С(4а)СН3, С(10b)СН3),
41.17 (С(4а)), 55.31 (ОСН3), 56.90 (С(10b)), 110.51,
111.02, 130.34 (С(7), С(8), С(10)), 120.07 (С(6а)),
14951, 163.32, 165.07 (С(6), С(9), С(10а)). MS, (m/z,
%): 259 [М]+ (20), 245 [M-CH3 + 1]+ (17), 244 [M-
CH3]+ (100), 203 (83), 202 (18).
CH3]+ (46), 294 (12), 293 (58), 292 (16), 165 (16). Anal.
Calcd for C21H23NO2: С, 78.47; Н, 7.21; N, 4.36. Found:
С, 78.24; Н, 7.38; N, 4.30.
7,8-Dimethoxy-3a-methyl-5-(methylthio)-2,3,3a,9b-
tetrahydro-1H-cyclopenta[c]isoquinoline (12b). Yield 70%,
white crystals, mp 102–103°С (from hexane). IR: 2929,
1
2859, 1659, 1596 сmꢀ1. Н NMR (300 MHz, CDCl3), δ:
1.05 (s, 3Н, С(3а)СН3), 1.15–2.35 (m, 6Н, С(1)Н2,
С(2)Н2, С(3)Н2), 2.40 (s, 1H, SCH3), 2.64 (t, 1Н,
С(9b)Н, J = 9.6 Hz Hz), 3.84 (s, 6Н, 2хOСН3), 6.64,
7.19 (both s, 2Н, Н(6), Н(9)). 13С NMR (75 MHz,
СDCl3), δ: 12.22 (SCH3), 22.88, 34.94, 42.61 (С(1),
С(2), С(3)), 24.70 (С(3а)СН3), 45.94 (С(9b)), 55.82,
56.00 (2хOCH3), 66.93 (С(3а)), 108.12, 110.94 (C(6),
C(9)), 119.02 (С(5а)), 132.99 (С(9а)), 147.15, 150.89
(С(7), С(8)), 157.62 (С(5)). MS, (m/z, %): 291 [М]+ (35),
290 [M-H]+ (22.7), 277 (17), 276 [M-CH3]+ (100), 243
(8.5), 159 (4.0), 115 (3.3), 41 (3.4). Anal. Calcd for
C16H21NO2S: С, 65.95; Н, 7.26; N, 4.81; S, 11.00.
X-ray diffraction analysis of compound 10.
The cell
xparameters and the set of experimental reflections of a
sample of compound 10 were measured on a single
crystal X-ray diffractometer equipped with the Xcalibur
Ruby CCD detector by the ω-2θ scanning method on
monochromatized MoKα-radiation at T = 295 (2) K.
Absorption is taken into account empirically using the
algorithm SCALE3 ABSPACK [33]. The structure was
solved by a direct statistical method and refined by the
full-matrix least-squares method in the anisotropic
approximation for all non-hydrogen atoms. The
hydrogen atoms of the NH groups are refined
independently in the isotropic approximation; the rest
are placed in geometrically calculated positions and
included in the refinement using the riding model. All
calculations to determine and refine the structures were
performed using the programs OLEX2 [35] and
SHELXL-2014 [36]. To analyze the compound 10 with
Found: С, 65.94; Н, 7.19; N, 4.87; S, 10.88.
Ethyl 2-(7,8-dimethoxy-3a-methyl-2,3,3a,4-tetrahydro-1H-
cyclopenta[c]isoquinolin-5(9bH)-ylidene)acetate (12с).
Yield 78%, colorless crystals, mp 142–143°С (from
acetone). IR: 3105, 2955, 2617, 1721, 1644, 1597 сmꢀ1
.
1Н NMR (300 MHz, CDCl3), δ: 1.20 (s, 3Н, С(3а)СН3),
1.30 (t, 3Н, OСН2СН3, J = 7.2 Hz), 1.50–2.20 (m, 6Н,
С(1)Н2, С(2)Н2, С(3)Н2), 2.73 (t, 1Н, С(9b)Н,
J = 9.6 Hz), 3.83, 3.89 (both s, 6Н, 2хOСН3), 4.05–4.30
(m, 2Н, OСН2CH3), 5.06 (s, 1Н, ¼CH–), 6.64, 7.15
(both s, 2Н, Н(6), Н(9)), 8.80 (bs, 1Н, NН). 13С NMR
(75 MHz, СDCl3), δ: 14.54 (OСН2СН3), 22.02, 33.76,
41.11 (С(1), С(2), С(3)), 25.60 (С(3а)СН3), 49.01
(С(9b)), 55.66, 55.69 (2хOCH3), 58.20 (OСН2СН3),
59.85 (С(3а)), 76.13 (¼CH–), 107.89, 111.17 (C(6),
C(9)), 118.59 (С(5а)), 131.97 (С(9а)), 147.49 (С(8)),
151.08 (С(7)), 154.91 (С(5)), 171.00 (С¼О). Anal. Calcd
for C19H25NO4: С, 68.86; Н, 7.60; N, 4.23. Found: С,
68.73; Н, 7.71; N, 4.39.
the gross formula C19H25NO4,
a colorless crystal
measuring 0.58 × 0.42 × 0.34 mm was used. The
crystal is monoclinic, pr. Gr. P21/n, a 11.034 (2), b
8.8730 (16), c 18.402 (3) Å, β 95.943 (18)°, V 1792.0
(6) Å3, dcalc 1.228 g/cm3, Z 4. Final refinement results:
R1 0.0489, wR2 0.1269 for 3038 reflections with
I > 2σ (I); R1 0.0701, wR2 0.1404 for all 4209
independent reflections, S 1.076. Summary of data
X-ray diffraction analysis of compound 12c.
The cell
CCDC 1833629.
7,8-Dimethoxy-3a-methyl-5-phenyl-2,3,3a,9b-tetrahydro-1H-
parameters and the set of experimental reflections of a
sample of compound 10 were measured on a single
crystal X-ray diffractometer equipped with the Xcalibur
Ruby CCD detector by the ω-2θ scanning method on
monochromatized MoKα-radiation at T = 295 (2) K.
Absorption is taken into account empirically using the
algorithm SCALE3 ABSPACK [33]. The structure was
solved by a direct statistical method and refined by the
full-matrix least-squares method in the anisotropic
approximation for all non-hydrogen atoms. The hydrogen
atoms of the NH groups are refined independently in the
isotropic approximation; the rest are placed in
geometrically calculated positions and included in the
refinement using the riding model. All calculations to
determine and refine the structures were performed using
cyclopenta[c]isoquinoline (12а).
Yield 76%, yellow oil
(eluent: hexane-ethyl acetate 2:1). IR: 2945, 2862, 1603,
1
1507 сmꢀ1. Н NMR (300 MHz, CDCl3), δ: 1.13 (s, 3Н,
С(3а)СН3), 1.40–2.50 (m, 6Н, С(1)Н2, С(2)Н2, С(3)Н2),
2.70 (t, 1Н, С(9b)Н, J = 9.6 Hz), 3.65, 3.91 (both s, 6Н,
2хOСН3), 6.60–6.85, 7.30–7.65 (both m, 7Н, Н(6), Н(9),
НAr(2), НAr(3), НAr(4), НAr(5), НAr(6)). 13С NMR
(75 MHz, СDCl3), δ: 22.65, 34.97, 42.06 (С(1), С(2),
С(3)), 24.72 (С(3а)СН3), 45.74 (С(9b)), 55.84, 55.91
(2хOСН3), 65.62 (С(3а)), 111.26, 111.99 (C(6), C(9)),
128.06, 128.09, 128.44, 128.61, 128.78 (CAr(2), CAr(3),
CAr(4), CAr(5), CAr(6)), 118.46 (С(5а)), 134.80, 139.62
(С(9а), CAr(1)), 146.75, 150.95 (С(7), С(8)), 162.96
(С(5)). MS, (m/z, %): 321 [М]+ (100), 320 (68), 306 [M-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Docking of 3,4-Dihydroisoquinolines, Spiropyrrolines
the program SHELXL-97 [34]. To analyze the compound
12c with the gross formula C19H25NO4, a colorless
crystal with a size of 0.58 × 0.42 × 0.34 mm was used.
The crystal is monoclinic, space group P21/n, a 11.034
(2), b 8.8730 (16), c 18.402 (3) Å, β 95.943 (18)°, V
1792.0 (6) Å3, dcalc 1.228 g/cm3, Z 4. Final refinement
results: R1 0.0489, wR2 0.1269 for 3038 reflections with
I > 2σ(I); R1 0.0701, wR2 0.1404 for all 4209
independent reflections, S 1.076. Summary of data CCDC
Acknowledgment. This work was financially supported by the
Russian Foundation for Basic Research (grant no. 16-33-00350
mol_a and granted access to the GOLD software).
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7,8-dimethoxy-3a-methyl-5-(4-nitrophenyl)-2,3,3a,9b-
tetrahydro-1H-cyclopenta[c]isoquinoline (11d). Yield 76%,
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.
NMR (300 MHz, CDCl3), δ: 1.16 (s, 3Н, С(3а)СН3),
1.40–2.50 (m, 6Н, С(1)Н2, С(2)Н2, С(3)Н2), 2.76 (t, 1Н,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. N. Perevoshchikova, D. V. Eroshenko, M. V. Dmitriev, V. V. Grishko, and Y. V. Shklyaev
Vol 000
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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Journal of Heterocyclic Chemistry
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