Reaction of 3-Amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxamides with Ninhydrin

Article abstract of DOI:10.1134/S1070363220060043

Abstract: The reaction of N-substituted amides of 3-amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxylic acids with ninhydrin in the presence of catalytic amounts of sulfuric acid gave 1′-spiro[indene-2,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine]-1,3,4′(3′

Full text of DOI:10.1134/S1070363220060043

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 6, pp. 948–960. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 6, pp. 843–857.
Reaction of
3-Amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxamides
with Ninhydrin
V. V. Dotsenkoa,b,*, V. S. Muravieva,c, D. Yu. Lukinaa, V. D. Strelkova, N. A. Aksenovb,
I. V. Aksenovab, G. D. Krapivind, and L. V. Dyadyuchenkoc
a Kuban State University, Krasnodar, 350040 Russia
b North Caucasus University, Stavropol, 355009 Russia
c All-Russian Research Institute of Biological Plant Protection, Krasnodar, 350039 Russia
d Kuban State Technological University, Krasnodar, 350072 Russia
*e-mail: victor_dotsenko_@mail.ru
Received February 16, 2020; revised February 16, 2020; accepted February 23, 2020
Abstract—The reaction of N-substituted amides of 3-amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxylic acids
with ninhydrin in the presence of catalytic amounts of sulfuric acid gave 1′-spiro[indene-2,2′-pyrido[3′,2′:4,5]-
thieno[3,2-d]pyrimidine]-1,3,4′(3′H)-triones. Structure of a number of key compounds was studied using 2D NMR
spectroscopy; the bioavailability parameters of the obtained compounds in silico were calculated. In a laboratory
experiment, a moderate antidote effect was revealed with respect to the 2,4-D herbicide for one compound.
Keywords: thieno[2,3-b]pyridines, Thorpe–Ziegler reaction, ninhydrin, heterocyclization, 2,4-D herbicide antidotes
DOI: 10.1134/S1070363220060043
Compounds with thieno[2,3-b]pyridine fragment are
of special interest due to a wide spectrum of biological
activity (see reviews [1–7]). On the other hand,
3-aminothieno[2,3-b]pyridines obtained by the Thorpe–
Ziegler reaction from 3-cyanopyridine-2(1H)-thiones
[8–12] open the way to design various polycyclic systems.
The latter, in turn, are also of interest as promising
candidate substances for bioscreening [2–4].
2 have antidote activity against the herbicide 2,4-D [36]
and growth-regulating effect [37]. Continuing studies in
the synthesis of thieno[2,3-b]pyridine derivatives [38–48]
and the potential of their use in agrochemical practice
[49, 50], we examined the reactions of a number of
3-aminothieno[2,3-b]pyridine-2-carboxylic acids amides
with ninhydrin as a highly reactive carbonyl compound
(for a review of the chemistry of ninhydrin see [51, 52]).
There are no data on reactions of thieno[2,3-b]pyridines
with ninhydrin. At the same time, some examples of
reactions of anthranylamides and related compounds with
ninhydrin show that the reaction outcome substantially
depends on the conditions and the substrate structure
(Scheme 2). Thus, ortho-aminobenzamides 7 react with
ninhydrin in the presence of catalytic amounts of Lewis
acids (FeCl3, CuBr, CuI) [53], iodine in boiling alcohol
[54] or in ionic liquids [55] with the formation of the
expected spiro derivatives of quinazoline 8. However,
according to other data, under conditions of heterogeneous
acid catalysis (Fe3O4/SiO2-Propyl-Pip-SO3H in PEG-400
[56] or ZnO nanoparticles on a peptide nanofiber [57]),
or when treating with HCl in boiling dioxane [58], a
sequential reaction of isatoic anhydride with primary
Amides of 3-aminothieno[2,3-b]pyridine-2-carboxylic
acids are known to react readily with carbonyl compounds,
aldehydes [13–27] or cyclic ketones [15–17, 22, 26,
28 –34], in boiling AcOH or toluene in the presence
of catalytic amounts of acids to form pyrido[3′,2′:4,5]-
thieno[3,2-d]pyrimidine derivatives 1 and 2 (Scheme 1).
Tricyclic compounds of this type exhibit various types
of biological activity. Thus, compounds 3 [15] have
an antibacterial effect; compounds 4 are inhibitors
of pim-1 kinases with anti-cancer effects [24, 25].
Pyridothienopyrimidines 5 and 6 inhibit gluconeogenesis
and are promising for the treatment of type 2 diabetes
mellitus [35].
Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines are also of
interest for agrochemistry. Thus, a number of compounds
948

REACTION OF 3-AMINO-4,6-DIARYLTHIENO[2,3-b]PYRIDINE-2-CARBOXAMIDES
949
Scheme 1.
Scheme 2.
amine and ninhydrin proceeds more deeply and leads to
products of further transformation of spiroquinazoline
intermediates 8, isoquino[2,3-a]quinazoline-5,7,12-
triones 9, with yields of 60–92%. As was shown in [59],
structure of the products of the catalyst-free reaction of
anthranylamides with ninhydrin in boiling water depends
on the substituent nature at the amide nitrogen atom:
in the case of ortho-substituted anilides, quinazolines
8 were formed, while in the presence of other substi-
tuents formation of 11-hydroxy-11,11a-dihydro-
benzo[e]indeno[2,1-b][1,4]diazepine-10,12-dione 10
occurred.
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DOTSENKO et al.
Table 1. Main correlation in the 1H–13C HSQC and HMBC NMR spectra of 3-amino-4-(4-methoxyphenyl)-6-phenyl N-(o-tolyl)-
thieno[2,3-b]pyridine-2-carboxamide 11ba
δС, ppm
δН, ppm
1H–13C HSQC
17.9* (ArСН3)
1H–13C HMBC
130.2* (С3, 2-MeC6H4NH), 134.1 (С2, 2-MeC6H4NH),
136.3 (С1, 2-MeC6H4NH)
2.22 s (3Н, ArСН3)
3.85 s (3Н, MeO)
6.02 s (2Н, NН2)
7.14 d (2H, Н3, Н5, 4-MeOC6H4)
55.3* (MeO)
159.9 (C4, 4-MeOC6H4)
98.0 (C2), 121.1 (C3a)
–
114.2* (C3, С5,
114.2* (C3, С5, 4-MeOC6H4), 128.9* (С2, С6,
4-MeOC6H4), 159.9 (C4, 4-MeOC6H4)
127.0* (С6, 2-MeC6H4NH), 130.2* (С3,
2-MeC6H4NH), 134.1 (С2, 2-MeC6H4NH),
136.3 (С1, 2-MeC6H4NH)
4-MeOC6H4)
7.15-7.22 m (2H, Н4,Н5, 2-MeC6H4NH) 125.9*, 126.0* (С4, C5,
2-MeC6H4NH)
7.25 d. d (1H, Н3, 2-MeC6H4NH)
7.29 d. d (1H, Н6, 2-MeC6H4NH)
130.2* (С3,
2-MeC6H4NH)
127.0* (С6,
17.9* (ArСН3), 125.9* (С4/5, 2-MeC6H4NH), 126.0*
(С5/4, 2-MeC6H4NH), 136.3 (С1, 2-MeC6H4NH)
134.1 (С2, 2-MeC6H4NH), 125.9* (С4/5
,
2-MeC6H4NH)
2-MeC6H4NH), 126.0* (С5/4, 2-MeC6H4NH)
7.49–7.55 m (5H, Н2,Н6, 4-MeOC6H4 + 128.9* (С2, С6,
114.2* (C3, С5, 4-MeOC6H4), 127.1* (С2, С6, Ph),
Н3–Н5, Ph)
4-MeOC6H4), 129.8* (С4, 128.5 (C1, 4-MeOC6H4), 130.1* (С3, С5, Ph), 137.5
Ph), 130.1* (С3, С5, Ph)
118.5* (C5)
(С1, Ph), 147.5 (C4), 159.9 (C4, 4-MeOC6H4)
121.1 (C3a), 128.5 (C1, 4-MeOC6H4), 137.5 (С1, Ph),
147.5 (C4), 155.7 (C6)
7.75 s (1H, Н5)
8.22 d. d (2H, Н2, Н6, Ph)
9.25 s (CONH)
127.1* (С2, С6, Ph)
127.1* (С2, С6, Ph), 129.8* (С4, Ph), 130.1* (С3, С5,
Ph), 155.7 (C6)
–
127.0* (С6, 2-MeC6H4NH), 134.1 (С2, 2-MeC6H4NH),
163.8 (CONH)
а Hereinafter, an asterisk denotes signals of carbon atoms that are in antiphase in the 13C DEPTQ NMR spectrum (СН, СН3).
The aim of this work was to reveal the conditions and
directions of the raction of ninhydrin with 3-amino-4,6-
diarylthieno[2,3-b]pyridine-2-carboxamides, which are
structural analogues of anthranylamides, as well as the
study of the possible biological activity of the products.
Structure of reaction products was studied using 13C
DEPTQ, 1H–13C HSQC, 1H–13C HMBC, 1H–1Н COSY,
NOESY NMR spectroscopy methods (Tables 3, 4). The
reaction products were found to be uniquely correspond
to 1′-spiro[indene-2,2′-pyrido[3′,2′:4,5]thieno[3,2-d]-
pyrimidine]-1,3,4′(3′H)-triones 13a–13f. According to
the results of a detailed comparative analysis of the NMR
spectra of the reaction products and compounds described
in [53–59], possible alternative structures 14 and 15 were
excluded from consideration.
The starting 3-amino-4,6-diarylthieno[2,3-b]pyri-
dine-2-carboxamides 11a–11f were prepared by
reacting 3-cyanopyridine-2(1H)-thiones 12a and 12b
with N-substituted α-chloroacetanilides followed by
cyclization of S-alkylation intermediates according to
Thorpe–Ziegler mechanism (Scheme 3). Thiones 12 were
obtained by a known procedure from the corresponding
chalcone, malononitrile and sulfur [60–62]. Compounds
11 were not previously described in the literature;
therefore, we have spectrally characterized them in detail,
including two-dimensional NMR spectroscopy methods
(Tables 1, 2).
It should be noted that, in our opinion, in [56–58],
quite convincing evidence of the structure of compounds
9 is not presented. So, in these works there is no detailed
discussion of the structural features of compounds 9,
there are no X-ray diffraction or 2D NMR spectroscopy
data, the description of the spectra is lacking in detail and
1
partially incorrect, and copies of the H and 13C NMR
spectra presented cannot be unambiguously attributed to
the claimed structures.
A signal at 76.9–77.1 ppm is found in the 13C NMR
spectra of the compounds 13a–13f, which is consistent
with the data from [58] (74.0–77.3 ppm for the putative
It was found that thienopyridines 11a–11f do not
react with ninhydrin in boiling AcOH or in the presence
of HCl in boiling dioxane. However, the reaction
proceeds easily with brief heating in ice-cold AcOH
in the presence of catalytic amounts of conc. H2SO4.
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REACTION OF 3-AMINO-4,6-DIARYLTHIENO[2,3-b]PYRIDINE-2-CARBOXAMIDES
951
Scheme 3.
methine carbon signal C6aH in 9). However, according
to the results of the DEPTQ experiment, the signal at
76.9–77.1 ppm should be unambiguously attributed to
the quaternary carbon atom, which excludes structure
14. The obtained values of chemical shifts also correlate
well with the data on the position of signals given in
[53, 55] for spirocarbon atoms in the 13C NMR spectra
of spiroquinazolines 8 (68.7–74.2 ppm).
are detected in the 13C NMR DEPTQ spectra: two carbon
atoms of keto groups (189.8–190.9 and 191.0–193.0 ppm)
and the amide carbon atom (162.4–162.7 ppm). Such
a spectral picture does not correspond to structures
14 and 15, but it correlates well with the spectra of
spiroquinazolines 8 given by Devi and coauthors [59].
In our opinion, the non-symmetrical nature of the
signals of the indane-1,3-dione fragment in the spectra
of compounds 13b–13f is due to non-valence contacts
between a part of the atoms of the indanedione fragment
and the ortho-substituents of the C(O)N-Ar fragment.
1
In the H NMR spectrum of compound 13a, a
highly symmetric picture of the AA′BB′-system of four
aromatic protons of the indane-1,3-dione fragment (7.89–
8.00 ppm) is revealed. The 13C NMR spectrum of
compound 13a contains signals of two carbons of
carbonyl groups: the amide at 162.6 ppm and the
ketone at 192.80 ppm. However, the spectra of the
other thienopyridine derivatives 13b–13f show some
differences. Thus, in the 1H NMR spectra of compounds
13b–13f, the aromatic protons of the indane-1,3-dione
fragment form a non-symmetrical set of three distinct
multiplets, and three signals of carbonyl carbon atoms
1
In the H NMR spectra of compounds 13, a broadened
singlet of NH protons is observed at 6.70–7.07 ppm. This
1
signal in the H–13C NMR spectra of compound 13b
(Tables 3, 4) gives correlation cross peaks through 2–
3 bonds with the signals of the 1,3-indanedione fragment
[76.9–77.1 (С2′spiro), 190.7–190.9 and 192.9–193.0 (keto
groups)], and with the signals of the thienopyridine core
[108.7–110.1 (C4а′), 120.5 (C9a′)]. This also makes it
possible to unambiguously exclude structures 14 and 15
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DOTSENKO et al.
Table 2. Main correlation in the 1H–1H COSYand NOESYNMR spectra of 3-amino-4-(4-methoxyphenyl)-6-phenyl N-(o-tolyl)-
thieno[2,3-b]pyridine-2-carboxamide 11b
δН, ppm
δН, ppm
1H–1H COSY
–
1H–1H NOESY
7.25 d. d (1H, Н3, 2-MeC6H4NH)
9.25 s (CONH)
2.22 s (3Н, ArСН3)
3.85 s (3Н, MeO)
6.02 s (2Н, NН2)
7.14 d (2H, Н3, Н5, 4-MeOC6H4)
–
–
7.14 d (2H, Н3, Н5, 4-MeOC6H4)
9.25 s (CONH)
3.85 s (3Н, MeO), 7.49–7.55 m (5H, Н2, Н6,
4-MeOC6H4 + Н3–Н5, Ph)
7.49–7.55 m (5H, Н2, Н6,
4-MeOC6H4 + Н3–Н5, Ph)
7.15–7.22 m (2H, Н4, Н5,
2-MeC6H4NH)
7.25 d. d (1H, Н3, 2-MeC6H4NH)
7.25 d. d (1H, Н3 2-MeC6H4NH), 7.25 d. d (1H, Н3, 2-MeC6H4NH),
7.29 d. d (1H, Н6, 2-MeC6H4NH) 7.29 d. d (1H, Н6, 2-MeC6H4NH)
7.15–7.22 m (2H, Н4, Н5,
2-MeC6H4NH)
7.15–7.22 m (2H, Н4, Н5,
2-MeC6H4NH)
2.22 s (3Н, ArСН3), 7.15–7.22 m (2H, Н4, Н5,
2-MeC6H4NH)
7.15–7.22 m (2H, Н4, Н5, 2-MeC6H4NH), 9.25 s
7.29 d. d (1H, Н6, 2-MeC6H4NH)
(CONH)
7.49–7.55 m (5H, Н2, Н6,
4-MeOC6H4 + Н3–Н5, Ph)
7.14 d (2H, Н3, Н5, 4-MeOC6H4), 6.02 s (2Н, NН2), 7.14 d (2H, Н3, Н5,
8.22 d. d (2H, Н2, Н6, Ph)
4-MeOC6H4), 7.75 s (1H, Н5)
8.22 d. d (2H, Н2, Н6, Ph)
7.75 s (1H, Н5)
8.22 d. d (2H, Н2, Н6, Ph)
–
7.49–7.55 m (5H, Н2, Н6,
4-MeOC6H4 + Н3–Н5, Ph)
–
8.22 d. d (2H, Н2, Н6, Ph)
7.49–7.55 m (5H, Н2, Н6, 4-MeOC6H4 + Н3–Н5,
Ph), 7.75 s (1H, Н5)
9.25 s (CONH)
2.22 s (3Н, ArСН3), 6.02 s (2Н, NН2)
7.29 d. d (1H, Н6, 2-MeC6H4NH)
from consideration. The presence of absorption bands in
the IR spectra of the obtained compounds corresponding
to N–H bond vibrations (3193–3356 cm–1), two ketone
(1752–1755 and 1713–1722 cm–1) and one amide
(1657–1666 cm–1) carbonyl groups confirms the structure
of compounds 13.
oncogenic, reproductive effects), similarities with known
drugs (drug-likeness), as well as a general assessment
of the pharmacological potential of the compound (drug
score). The obtained calculated data are presented in
Table 6. In general, they show low prospectivity of tested
compounds from the point of view of bioscreening (the
drug score parameter value is not higher than 0.11). In
all cases cLogP >> 5.0, the values of logS and molecular
weight of all compounds 13a–13f also do not meet the
criteria for oral bioavailability. As the calculation shows,
compounds 13a–13f have rather high TPSAvalues close
to or even exceeding 140 Å2, which indicates a probable
low ability to penetrate through the cell membrane
or blood-brain barrier. All compounds show a risk of
potential effects on the reproductive system. At the same
time, the calculation of the drug-likeness parameter gives
unexpectedly high values for compounds 13a and 13b.
We studied the synthesized compounds as antidotes
for the 2,4-D herbicide (2,4-dichlorophenoxyacetic
acid) and as plant growth regulators. Of the series of
compounds tested, only thienopyridine 13d possesses
moderate antidote activity (Table 5). At the same time,
compound 13d does not show any noticeable growth-
regulating effect.
We also calculated the bioavailability parameters
for compounds 13a–13f in silico. The initial analysis
of the structures for compliance with K. Lipinski rule
[cLogP ≤ 5.0, molecular weight (MW) ≤ 500, TPSA
≤ 140 Å2, the number of hydrogen bond acceptors ≤
10, donors ≤ 5] [63–65] was done using the OSIRIS
Property Explorer software [66]. The parameters cLogP
[calculated logarithm of the partition coefficient between
n-octanol and water log (coctanol/cwater)], solubility (log S),
topological polar surface area (TPSA), toxicological
parameters such as risks of side effects (mutagenic,
In conclusion, the reaction of 3-amino-4,6-diaryl-
thieno[2,3-b]pyridine-2-carboxamides with ninhydrin in
the presence of catalytic amounts of sulfuric acid afforded
new series of 1′-spiro[indene-2,2′-pyrido[3′,2′:4,5]-
thieno[3,2-d]pyrimidine]-1,3,4′(3′H)-triones, structure
of which was unambiguous proved using 2D NMR
spectroscopy methods. The analysis of bioavailability
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REACTION OF 3-AMINO-4,6-DIARYLTHIENO[2,3-b]PYRIDINE-2-CARBOXAMIDES
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Table 3. Main correlation in the 1H–13C HSQC and HMBC NMR spectra of 9′-(4-methoxyphenyl)-3′-(o-tolyl)-7′-phenyl-1′H-
spiro[indene-2,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine]-1,3,4′(3′H)-trione 13b
δС, ppm
δН, ppm
1H–13C HSQC
18.0* (MeAr)
1H–13C HMBC
130.8* (C3, 2-СН3С6Н4), 136.0 (C1, 2-СН3С6Н4), 138.2
(C2, 2-СН3С6Н4)
2.23 s (2-СН3С6Н4)
3.63 s (3Н, MeO)
6.58 d (1Н, Н6, 2-СН3С6Н4)
55.1* (MeO)
159.8 (C4, 4-MeOC6H4)
127.7* (C6, 2-СН3С6Н4) 128.5* (C4, 2-СН3С6Н4), 136.0 (C1, 2-СН3С6Н4), 138.2
(C2, 2-СН3С6Н4)
6.64 d (2Н, Н3, Н5, 4-MeOC6H4)
113.1* (C3, С5,
4-MeOC6H4)
–
113.1* (C3, С5, 4-MeOC6H4), 127.9 (C1, 4-MeOC6H4),
159.8 (C4, 4-MeOC6H4)
76.9 (С2′spiro), 110.1 (C4а′), 190.9 (С=Оketone), 193.0
6.71 s (1H, NH)
(С=Оketone
)
6.89–6.93 m (1Н, Н5, 2-СН3С6Н4)
7.10–7.13 m (1Н, Н4, 2-СН3С6Н4)
126.5* (C5, 2-СН3С6Н4) 130.8* (C3, 2-СН3С6Н4), 136.0 (C1, 2-СН3С6Н4)
128.5* (C4, 2-СН3С6Н4) 126.5* (C5, 2-СН3С6Н4), 127.7* (C6, 2-СН3С6Н4),
138.2 (C2, 2-СН3С6Н4)
7.21 d (1Н, Н3, 2-СН3С6Н4)
7.41 d (2Н, Н2, Н6, 4-MeOC6H4)
7.50–7.55 m (3Н, Н3–Н5, Ph)
130.8* (C3, 2-СН3С6Н4) 18.0* (MeAr), 126.5* (C5, 2-СН3С6Н4), 136.0 (C1,
2-СН3С6Н4)
131.1* (C2, С6,
4-MeOC6H4)
128.9* (C3, С5, Ph),
129.9* (C4, Ph)
123.8* (CH-Ar)
118.6* (C8′)
131.1* (C2, С6, 4-MeOC6H4), 147.7 (C9′), 159.8 (C4,
4-MeOC6H4)
127.3* (C2, С6, Ph), 128.9* (C3, С5, Ph), 129.9* (C4,
Ph), 137.5 (C1, Ph)
137.9* (CH, Ar), 139.5 (С, Ar), 190.9 (С=Оketone)
120.8* (C9a′), 127.9 (C1, 4-MeOC6H4), 137.5 (C1, Ph),
142.3 (C9b′), 155.9 (C7′)
7.78 d (1Н, Н-Ar)
7.86 s (1Н, H8′)
7.97–8.00 m (1Н, H-Ar)
8.10–8.11 m (2Н, H-Ar)
137.2* (CH, Ar)
124.7* (CH, Ar), 137.9*
(CH, Ar)
127.3* (C2, С6, Ph)
124.7* (CH, Ar), 139.5 (С, Ar)
123.8* (CH, Ar), 124.7* (CH, Ar), 137.2* (CH, Ar),
138.7 (С, Ar), 139.5 (С, Ar), 193.0 (С=Оketone
127.3* (C2, С6, Ph), 128.9* (C3, С5, Ph), 129.9* (C4,
Ph), 155.9 (C7′)
)
8.25 d. d (2H, Н2, Н6, Ph)
parameters indicate a low pharmacological potential of
the obtained compounds. At the same time, in the course
of laboratory experiments, a moderate antidote activity
was established with respect to the 2,4-D herbicide for
one of the synthesized substances.
on a Carlo Erba 1106 instrument. Purity of the obtained
compounds and the reaction progress were monitored
by TLC on Sorbfil PTSX-AF-A plates (Imid LLC,
Krasnodar), eluting with acetone–hexane mixture (1 : 1)
and developing with iodine vapors or UV detector.
General procedure for the synthesis of 3-amino-
thieno[2,3-b]pyridine-2-carboxamides 11a–11f.
To a suspension of 3.1 mmol of the corresponding
4-aryl-6-phenyl-2-thioxo-1,2-dihydropyridine-3-
carbonitrile 12a in 7–8 mL of DMF was added an
aqueous 10% solution of KOH (d = 1.09 g/mL, 1.7 mL,
3.3 mmol). The resulting mixture was stirred while
heating to dissolution, then 3.1 mmol of the corresponding
α-chloroacetanilide in 2 mL of DMF was added to a
solution through a paper filter. The mixture was stirred for
30 min, another 1.7 mL of a 10% aqueous KOH solution
was added to the resulting suspension of the S-alkylation
product, and the reaction mixture was brought to boiling
with stirring, heated for 1–3 min, then cooled to room
EXPERIMENTAL
NMR spectra for all compounds (except 11e) were
recorded on a BrukerAvance III HD 400MHz instrument
[400.17 (1H), 100.63 MHz (13C)] from a DMSO-d6
solution. Due to insufficient solubility in DMSO-d6,
the NMR spectra of compound 11e were recorded from
a CDCl3–CF3CO2D solution on an Agilent 400/54
instrument (399.94 and 100.57 MHz, respectively).
Residual solvent signals were used as a standard. IR
spectra were recorded on a Bruker Vertex 70 Fourier
transform IR spectrometer with an ATR attachment
on a diamond crystal with a spectral resolution of
±4 cm–1. Elemental analysis for C, H, N was carried out
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DOTSENKO et al.
Table 4. Main correlation in the 1H–1H COSY and NOESY NMR spectra of 9′-(4-methoxyphenyl)-3′-(o-tolyl)-7′-phenyl-1′H-
spiro[indene-2,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine]-1,3,4′(3′H)-trione 13b
δН, ppm
δН, ppm
1H–1H COSY
1H–1H NOESY
2.23 s (2-СН3С6Н4)
3.63 s (3Н, MeO)
6.58 d (1Н, Н6, 2-СН3С6Н4)
–
–
7.21 d (1Н, Н3, 2-СН3С6Н4)
6.64 d (2Н, Н3, Н5, 4-MeOC6H4)
6.89–6.93 m (1Н, Н5, 2-СН3С6Н4)
6.89–6.93 m (1Н, Н5,
2-СН3С6Н4)
6.64 d (2Н, Н3, Н5, 4-MeOC6H4)
7.41 d (2Н, Н2, Н6, 4-MeOC6H4) 3.63 s (3Н, MeO), 7.41 d (2Н, Н2, Н6,
4-MeOC6H4)
6.71 s (1H, NH)
–
–
6.89–6.93 m (1Н, Н5, 2-СН3С6Н4)
6.58 d (1Н, Н6, 2-СН3С6Н4),
7.10–7.13 m (1Н, Н4,
2-СН3С6Н4)
6.58 d (1Н, Н6, 2-СН3С6Н4), 7.10–7.13 m (1Н, Н4,
2-СН3С6Н4)
7.10–7.13 m (1Н, Н4, 2-СН3С6Н4)
6.89–6.93 m (1Н, Н5,
2-СН3С6Н4), 7.21 d (1Н, Н3,
2-СН3С6Н4)
6.89–6.93 m (1Н, Н5, 2-СН3С6Н4), 7.21 d (1Н, Н3,
2-СН3С6Н4)
7.21 d (1Н, Н3, 2-СН3С6Н4)
7.10–7.13 m (1Н, Н4,
2-СН3С6Н4)
2.23 s (2-СН3С6Н4), 7.10–7.13 m (1Н, Н4,
2-СН3С6Н4)
7.41 d (2Н, Н2, Н6, 4-MeOC6H4)
7.50–7.55 m (3Н, Н3–Н5, Ph)
7.78 d (1Н, Н-Ar)
6.64 d (2Н, Н3, Н5, 4-MeOC6H4) 6.64 d (2Н, Н3, Н5, 4-MeOC6H4)
8.25 d. d (2H, Н2, Н6, Ph)
7.97–8.00 m (1Н, H-Ar)
8.25 d. d (2H, Н2, Н6, Ph)
7.97–8.00 m (1Н, H-Ar)
8.25 d. d (2H, Н2, Н6, Ph)
7.86 s (1Н, H8′)
–
7.97–8.00 m (1Н, H-Ar)
7.78 d (1Н, Н-Ar), 8.10–8.11 m 7.78 d (1Н, Н-Ar), 8.10–8.11 m (2Н, H-Ar)
(2Н, H-Ar)
8.10–8.11 m (2Н, H-Ar)
8.25 d. d (2H, Н2, Н6, Ph)
7.97–8.00 m (1Н, H-Ar)
7.50–7.55 m (3Н, Н3–Н5, Ph)
7.97–8.00 m (1Н, H-Ar)
7.50–7.55 m (3Н, Н3–Н5, Ph), 7.86 s (1Н, H8′)
temperature and diluted with an equal volume of 50%
aqueous alcohol. After 24 h, the precipitate was filtered
off, washed with 50% ethanol and petroleum ether. For
analytical purposes, the sample was recrystallized from
a suitable solvent (acetone, AcOH, DMF).
(MeO), 97.7* (C2), 114.2 (C3, С5 4-MeOC6H4), 118.6
(C5), 121.0* (C3a), 121.3 (C2, С6, NHC6H5), 123.5 (C4,
NHC6H5), 127.1 (С2, С6, Ph), 128.4 (C3, С5, NHC6H5),
128.5* (C1, 4-MeOC6H4), 128.9 (С2, С6, 4-MeOC6H4),
129.8 (С4, Ph), 130.1 (С3, С5, Ph), 137.5* (С1, Ph), 138.8*
(C1, NHPh), 146.8* (C3), 147.5* (C4), 155.8* (C6),
159.9* (C4, 4-MeOC6H4), 160.0* (C7a), 163.8* (CONH).
*Antiphase signals. Found, %: C 71.75; H 4.80; N 9.34.
C27H21N3О2S. Calculated, %: C 71.82; H 4.69; N 9.31.
3-Amino-4-(4-methoxyphenyl)-N,6-diphenyl-
thieno[2,3-b]pyridine-2-carboxamide (11a). Yield 76%,
mp 210°С, yellow powder. IR spectrum, ν, cm–1: 3474,
1
3283 (N–Н), 1657 (С=О). Н NMR spectrum, δ, ppm:
3-Amino-4-(4-methoxyphenyl)-6-phenyl-N-(o-
tolyl)thieno[2,3-b]pyridine-2-carboxamide (11b).
Yield 71%, mp 265°С, yellow powder. IR spectrum, ν,
3.85 s (3Н, MeO), 6.11 br. s (2Н, NH2), 7.05–7.09 m
3
(1Н, Н4 PhNH), 7.15 d (2Н, Н3, Н5, 4-MeOC6H4, J =
8.6 Hz), 7.29–7.33 m (2Н, Н-Ar), 7.50–7.55 m (4Н,
Н-Ar), 7.67 d (2Н, Н-Ar, 3J = 7.6 Hz), 7.74 s (1Н, H5),
1
cm–1: 3483, 3348, 3300 (N–Н), 1684 (С=О). Н NMR
spectrum, δ, ppm: 2.22 s (3Н,ArСН3), 3.85 s (3Н, MeO),
6.02 br. s (2Н, NН2), 7.14 d (2H, Н3, Н5, 4-MeOC6H4,
3J = 8.8 Hz), 7.15–7.22 m (2H, Н4, Н5, 2-MeC6H4NH),
7.25 d. d (1H, Н3, 2-MeC6H4NH, 3J = 7.2, 4J = 1.5 Hz),
7.29 d. d (1H, Н6, 2-MeC6H4NH, 3J = 7.8, 4J = 1.5 Hz),
7.49–7.55 m (5H, Н2, Н6, 4-MeOC6H4 + Н3–Н5, Ph),
7.75 s (1H, Н5), 8.22 d. d (2H, Н2, Н6, Ph, 3J = 8.0, 4J =
1.7 Hz), 9.25 br. s (CONH). 13С NMR spectrum (DEPTQ),
δC, ppm: 17.9* (ArСН3), 55.3* (MeO), 98.0 (C2), 114.2*
3
8.21 d (2Н, Н2, Н6 Ph, J = 7.9 Hz), 9.53 br. s (1Н,
CONH). 13С NMR spectrum (DEPTQ), δC, ppm: 55.3
Table 5. Antidote activity of compound 13d
Antidote effect A at various concentrations,%
Part
10–2
111
102
10–3
111
96
10–4
111
100
10–5
114
98
Root
Stem
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 6 2020

REACTION OF 3-AMINO-4,6-DIARYLTHIENO[2,3-b]PYRIDINE-2-CARBOXAMIDES
955
Table 6. Toxicity risks and physico-chemical parameters of compounds 13a–13f predicted by the OSIRIS Property Explorer
software
Toxicity risksa
Physico-chemical parameters
Compound
А
–
–
–
–
–
–
В
–
–
–
–
–
–
С
–
–
–
–
–
–
D
+
+
+
+
+
+
сLogP logS MW TPSA
6.5 –10.6 593 116.8
drug likeness
3.43
drug score
0.109
0.101
0.090
0.060
13а
13b
13c
13d
13e
13f
6.85 –10.9 607 116.8
7.45 –11.6 641 116.8
5.58 –11.1 638 162.6
6.31 –11.8 716 162.6
7.64 –11.8 655 107.6
3.01
2.38
–4.09
–5.51
0.89
0.048
0.077
а The “+” sign indicates a high risk of toxicity, “–”—the absence of toxicity; A—mutagenicity, B—carcinogenicity, C—irritant effect, D—
reproductive effects.
(C3, С5, 4-MeOC6H4), 118.5* (C5), 121.1 (C3a), 125.9*
(С4/5, 2-MeC6H4NH), 126.0* (С5/4, 2-MeC6H4NH),
127.0* (С6, 2-MeC6H4NH), 127.1* (С2, С6, Ph), 128.5
(C1, 4-MeOC6H4), 128.9* (С2, С6, 4-MeOC6H4), 129.8*
(С4, Ph), 130.1* (С3, С5, Ph), 130.2* (С3, 2-MeC6H4NH),
134.1 (С2, 2-MeC6H4NH), 136.3 (С1, 2-MeC6H4NH),
137.5 (С1, Ph), 146.3 (C3), 147.5 (C4), 155.7 (C6), 159.9
(C4, 4-MeOC6H4), 160.0 (C7a), 163.8 (CONH). Found,
%: C 72.20; H 5.09; N 9.05. C28H23N3О2S. Calculated,
%: C 72.23; H 4.98; N 9.03.
Yield 58%, mp 192–193°С, yellow orange powder. IR
spectrum, ν, cm–1: 3467, 3330 (N–Н), 1646 (С=О),
1585 (NO2, as), 1340 (NO2, s). Н NMR spectrum, δ,
1
ppm: 3.85 s (3Н, MeO), 6.15 br. s (2Н, NН2), 7.15 d
3
(2H, Н3, Н5, 4-MeOC6H4, J = 8.8 Hz), 7.30–7.34 m
(1Н, Н4, 2-NO2C6H4NH), 7.49–7.56 m (5H, H-Ar),
7.69–7.73 m (1Н, H-Ar), 7.78 s (1H, Н5), 8.00–8.04 m
3
4
(2Н, H-Ar), 8.23 d. d (2H, Н2,Н6, Ph, J = 8.1, J =
1.5Hz), 10.29br. s(CONH).13СNMRspectrum(DEPTQ),
δC, ppm: 55.3* (MeO), 114.3* (C3, С5, 4-MeOC6H4),
117.0 (C2), 118.7* (C5), 121.0 (C3a), 124.96* (C4/6,
2-NO2C6H4NH), 125.04* (C6/4, 2-NO2C6H4NH), 127.2*
(С2, С6, Ph), 128.3 (C1, 4-MeOC6H4), 128.9* (С2, С6,
4-MeOC6H4), 129.8* (С3/5, 2-NO2C6H4NH), 129.9* (С4,
Ph), 130.1* (С3, С5, Ph), 134.3* (С5/3, 2-NO2C6H4NH),
137.4 (С1, 2-NO2C6H4NH), 137.6 (С1, Ph), 141.2 (С2,
2-NO2C6H4NH), 147.9 (C4), 154.4 (C3), 156.2 (C6), 160.0
(C4, 4-MeOC6H4), 160.1 (C7a), 163.7 (CONH). Found,
%: C 65.22; H 4.20; N 11.34. C27H20N4О4S. Calculated,
%: C 65.31; H 4.06; N 11.28.
3-Amino-N-(5-chloro-2-methylphenyl)-4-(4-
methoxyphenyl)-6-phenylthieno[2,3-b]pyridine-2-
carboxamide (11c). Yield 63%, mp 239°С, yellow
powder. IR spectrum, ν, cm–1: 3481, 3381, 3273 (N–Н),
1
1653 (С=О). Н NMR spectrum, δ, ppm: 2.21 s (3Н,
ArСН3), 3.85 s (3Н, MeO), 6.04 br. s (2Н, NН2), 7.14 d
3
(2H, Н3, Н5, 4-MeOC6H4, J = 8.7 Hz), 7.20 d. d (1H,
3
4
Н4 2-Me-5-ClC6H3NH, J = 8.2, J = 2.1 Hz), 7.28 d
(1H, Н3, 2-Me-5-ClC6H3NH, J = 8.2 Hz), 7.43 d (1H,
3
Н6, 2-Me-5-ClC6H3NH, 4J = 2.1 Hz), 7.48–7.55 m (5H,
Н2,Н6, 4-MeOC6H4 + Н3–Н5, Ph), 7.75 s (1H, Н5),
8.22 br. d (2H, Н2,Н6,Ph, 3J= 8.0 Hz), 9.29 br. s (CONH).
13С NMR spectrum (DEPTQ), δC, ppm: 17.4* (ArСН3),
55.3* (MeO), 97.7 (C2), 114.3* (C3, С5, 4-MeOC6H4),
118.6* (C5), 121.1 (C3a), 125.5* (С6, 2-Me-5-ClC6H3NH),
126.1* (C4, 2-Me-5-ClC6H3NH), 127.1* (С2, С6, Ph),
128.5 (C1, 4-MeOC6H4), 128.9* (С2, С6, 4-MeOC6H4),
129.7 (C2, 2-Me-5-ClC6H3NH), 129.8* (С4, Ph), 130.2*
(С3, С5, Ph), 131.7* (С3, 2-Me-5-ClC6H3NH), 132.7 (С5,
2-Me-5-ClC6H3NH), 137.5 (С1, Ph), 137.8 (С1, 2-Me-5-
ClC6H3NH), 146.7 (C3), 147.6 (C4), 155.8 (C6), 159.9 (C4,
4-MeOC6H4), 160.0 (C7a), 163.8 (CONH). Found, %: C
67.20; H 4.50; N 8.38. C28H22ClN3О2S. Calculated, %:
C 67.26; H 4.43; N 8.40.
3-Amino-N-(2-bromo-4-nitrophenyl)4-(4-
methoxyphenyl)-6-phenylthieno[2,3-b]pyridine-2-
carboxamide (11e). Yield 52%, mp 252°С, yellow
orange powder. IR spectrum, ν, cm–1: 3483, 3350, 3323
(N–Н), 1651 (С=О), 1584 (NO2, as), 1344 (NO2, s). 1Н
NMR spectrum, δ, ppm: 4.00 s (3Н, MeO), 7.25 d (2H,
3
Н3, Н5, 4-MeOC6H4, J = 8.6 Hz), 7.61 d (2H, Н2, Н6,
3
4-MeOC6H4, J = 8.6 Hz), 7.66–7.70 m (2H, H-Ph),
7.74–7.77 m (1H, H-Ph), 7.87 s (1H, Н5), 7.95 d (2H,
Н2,Н6,Ph, 3J= 7.5 Hz), 8.26–8.27 m (2H, H6, H5,ArNH),
8.54 br. s (1H, H3,ArNH). Signals of NH and NH2 protons
do not appear due to deutero exchange with СF3CO2D.
13С NMR spectrum (DEPTQ), δC, ppm: 55.6 (MeO), 97.2
(C2), 115.4 (CBr), 115.6 (C3, С5, 4-MeOC6H4), 122.1
(C5), 122.6 (C5/6, ArNH), 123.9 (C6/5, ArNH), 125.17
(C3a), 125.23 (C1, 4-MeOC6H4), 127.8 (С2, С6, Ph), 128.4
3-Amino-4-(4-methoxyphenyl)-N-(2-nitrophenyl)-
6-phenylthieno[2,3-b]pyridine-2-carboxamide (11d).
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DOTSENKO et al.
(С1, Ph), 129.4 (C3,ArNH), 130.0 (С2, С6, 4-MeOC6H4),
130.4 (С3, С5, Ph), 134.0 (С4, Ph), 140.5 (CNO2), 144.2
(C1, ArNH), 148.1 (C3), 151.3 (C7a), 153.3 (C6), 157.5
(C4), 162.3 (C4, 4-MeOC6H4), 163.2 (CONH). Found, %:
C 56.22; H 3.45; N 9.66. C27H19BrN4О4S. Calculated, %:
C 56.36; H 3.33; N 9.74.
118.6* (C8′), 120.5* (C9a′), 124.1* (2CH, Ar), 127.3*
(2CH,Ar), 128.0 (C1, 4-MeOC6H4), 128.3* (C4H, Ph–N),
128.9* (2CH, Ar), 129.0* (2CH, Ar), 129.6* (2CH, Ar),
130.0* (C4H, Ph), 131.1* (2CH, Ar), 136.4 (Ar), 137.46
(Ar), 137.49* (2CH, Ar), 139.1 (Ar), 142.4 (C9b′), 147.7
(C9′), 155.7 (C7′), 159.9 (C4, 4-MeOC6H4), 160.2* (C5a′),
162.6 (C=Оamide), 192.8 (С=Оketone). Found, %: C 72.90;
H 4.09; N 6.98. C36H23N3О4S. Calculated, %: C 72.83;
H 3.91; N 7.08.
3-Amino-4-(4-bromophenyl)-6-phenyl-N-(o-tolyl)-
thieno[2,3-b]pyridine-2-carboxamide (11f). Yield 43%,
mp 208°С, yellow powder. IR spectrum, ν, cm–1: 3473,
3390, 3325 (N–Н), 1634 (С=О). 1Н NMR spectrum, δ,
ppm:2.22s(3Н,ArСН3), 5.98br. s(2Н, NН2), 7.16–7.30m
(4H, Н-Ar), 7.51–7.57 m (5H, Н-Ar), 7.78 d (2H, Н-Ar,
3J = 8.1 Hz), 7.80 s (1H, Н5), 8.22 d (2H, Н2, Н6, Ph,
3J = 8.0 Hz), 9.30 br. s (CONH). 13С NMR spectrum
(DEPTQ), δC, ppm: 17.9 (ArСН3), 98.7* (C2), 118.3 (C5),
120.8* (C3a), 122.8* (CBr), 125.95 (С4/5, 2-MeC6H4NH),
126.0 (С5/4, 2-MeC6H4NH), 127.0 (С6, 2-MeC6H4NH),
127.1 (С2, С6, Ph), 128.9 (2CH, Ar), 129.9 (С4, Ph),
130.2 (С3, 2-MeC6H4NH), 131.0 (2CH,Ar), 131.6 (2CH,
Ar), 134.2* (С2, 2-MeC6H4NH), 135.7* (С1, 4-BrC6H4),
136.3* (С1, 2-MeC6H4NH), 137.4* (С1, Ph), 146.2* (C3),
146.4* (C4), 155.7* (C6), 159.9* (C7a), 163.8* (CONH).
Found, %: C 63.02; H 4.06; N 8.14. C27H20BrN3ОS.
Calculated, %: C 63.04; H 3.92; N 8.17.
9′-(4-Methoxyphenyl)-7′-phenyl-3′-(o-tolyl)-1′H-
spiro[indene-2,2′-pyrido[3′,2′:4,5]thieno[3,2-d]-
pyrimidine]-1,3,4′(3′H)-trione (13b). Yield 56%, mp
208°С, yellow powder. IR spectrum, ν, cm–1: 3263 (N–Н),
1753, 1713, 1661 (3С=О). 1Н NMR spectrum, δ, ppm:
2.23 s (2-СH3С6Н4), 3.63 s (3Н, MeO), 6.58 d (1Н, Н6,
2-СН3С6Н4, 3J= 7.6 Hz), 6.64 d (2Н, Н3, Н5,4-MeOC6H4,
3J = 8.6 Hz), 6.71 s (1H, NH), 6.89–6.93 m (1Н, Н5,
2-СН3С6Н4), 7.10–7.13 m (1Н, Н4, 2-СН3С6Н4), 7.21 d
(1Н, Н3, 2-СН3С6Н4, 3J = 7.3 Hz), 7.41 d (2Н, Н2, Н6,
4-MeOC6H4, 3J= 8.6 Hz), 7.50–7.55 m (3Н, Н3–Н5,Ph),
7.78d(1Н, Н-Ar, 3J=7.7Hz), 7.86s(1Н, H8′), 7.97–8.00m
(1Н, H-Ar), 8.10–8.11 m (2Н, H-Ar), 8.25 d. d (2H,
3
4
Н2,Н6, Ph, J = 8.1, J = 1.7 Hz). 13С NMR spectrum
(DEPTQ), δC, ppm: 18.0* (MeAr), 55.1* (MeO), 76.9
(С2′spiro), 110.1 (C4а′), 113.1* (C3, С5, 4-MeOC6H4),
118.6* (C8′), 120.8* (C9a′), 123.8* (CH,Ar), 124.7* (CH,
Ar), 126.5* (C5, 2-СН3С6Н4), 127.3* (C2, С6, Ph), 127.7*
(C6, 2-СН3С6Н4), 127.9 (C1, 4-MeOC6H4), 128.5* (C4,
2-СН3С6Н4), 128.9* (C3, С5, Ph), 129.9* (C4, Ph), 130.8*
(C3, 2-СН3С6Н4), 131.1* (C2, С6, 4-MeOC6H4), 136.0
(C2, 2-СН3С6Н4), 137.2* (CH,Ar), 137.5 (C1, Ph), 137.9*
(CH,Ar), 138.2 (C1, 2-СН3С6Н4), 138.7 (Ar), 139.5 (Ar),
142.3 (C9b′), 147.7 (C9′), 155.9 (C7′), 159.1 (C5a′), 159.8
(C4, 4-MeOC6H4), 162.5 (C=Оamide), 190.9 (С=Оketone),
193.0 (С=Оketone). Found, %: C 73.10; H 4.23; N 6.89.
C37H25N3О4S. Calculated, %: C 73.13; H 4.15; N 6.91.
General procedure for the synthesis 3′,7′,9′-triaryl-
1′H-spiro[indene-2,2′-pyrido[3′,2′:4,5]thieno[3,2-d]-
pyrimidine]-1,3,4′(3′H)-triones 13a–13f. To a
suspension of 0.3 g of the starting thienopyridine 11a–11f
in 5 mL of glacial AcOH were added 2–3 drops of conc.
sulfuric acid. The mixture was refluxed, and then an
equimolar amount of ninhydrin was added. The resulting
black solution was boiled for 3–5 min. After cooling to
room temperature, the mixture was poured into 20 mL of
cold water and kept for 24 h. The precipitate was filtered
off, washed with water and recrystallized from EtOH.
9′-(4-Methoxyphenyl)-3′,7′-diphenyl-1′H-spiro-
[indene-2,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyri-
midine]-1,3,4′(3′H)-trione (13a). Yield 51%, mp 211°С,
yellow powder. IR spectrum, ν, cm–1: 3300 (N–Н), 1753,
1720, 1659 (3 С=О). 1Н NMR spectrum, δ, ppm: 3.64 s
3′-(5-Chloro-2-methylphenyl)-9′-(4-methoxy-
phenyl)-7′-phenyl-1′H-spiro[indene-2,2′-pyrido-
[3′,2′:4,5]thieno[3,2-d]pyrimidine]1,3,4′(3′H)-trione
(13c). Yield 62%, mp 203°С, yellow powder. IR
spectrum, ν, cm–1: 3242 (N–Н), 1755, 1715, 1661 (3
С=О). 1Н NMR spectrum, δ, ppm: 2.20 s (2-СH3С6Н4),
3.65 s (3Н, MeO), 6.57 d (1Н, Н6, 2-СН3-5-ClС6Н3, 4J=
1.8 Hz), 6.69 d (2Н, Н3, Н5, 4-MeOC6H4, 3J = 8.5 Hz),
6.79 s (1H, NH), 7.21 d. d (1Н, Н4, 2-СН3-5-ClС6Н3,
3J = 8.3, 4J = 1.8 Hz), 7.26 d (1Н, Н3, 2-СН3-5-ClС6Н3,
3
(3Н, MeO), 6.69 d (2Н, Н3, Н5, 4-MeOC6H4, J =
8.6 Hz), 6.72 s (1H, NH), 6.93 d (2Н, Н2, Н6, Ph–N,
3J = 7.0 Hz), 7.14–7.23 m (3Н, Н3–Н5, Ph–N), 7.44 d
(2Н, Н2, Н6,4-MeOC6H4, 3J= 8.6 Hz), 7.50–7.56 m (3Н,
Н3–Н5, Ph), 7.86 s (1Н, H8′), 7.89–8.00 m (4Н, H-Ar,
3
AA′BB′-system), 8.25 d (2Н, Н2, Н6, Ph, J = 8.1 Hz).
3
13С NMR spectrum (DEPTQ), δC, ppm: 55.1* (MeO),
77.0 (С2′spiro), 108.5 (C4а′), 113.3* (C3, С5, 4-MeOC6H4),
3J = 8.3 Hz), 7.44 d (2Н, Н2, Н6, 4-MeOC6H4, J =
8.5 Hz), 7.50–7.56 m (3Н, Н3–Н5,Ph), 7.80 d (1Н, Н-Ar,
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REACTION OF 3-AMINO-4,6-DIARYLTHIENO[2,3-b]PYRIDINE-2-CARBOXAMIDES
957
3J = 7.7 Hz), 7.87 s (1Н, H8′), 7.98–8.02 m (1Н, H-Ar),
(1H, NH), 7.06 d (1H, Н6,2-Br-4-NO2С6Н3, 3J= 8.6 Hz),
7.37 d (2Н, Н3, Н5,4-MeOC6H4, 3J= 8.6 Hz), 7.50–7.56 m
(3Н, Н3–Н5, Ph), 7.87 s (1Н, H8′), 7.89 d (1Н, H-Ar,
3J = 7.7 Hz), 8.03–8.06 m (2Н, Н-Ar), 8.14–8.15 m
3
8.11–8.13 m (2Н, H-Ar), 8.26 d (2H, Н2,Н6, Ph, J =
8.0 Hz). 13С NMR spectrum (DEPTQ), δC, ppm: 17.5*
(MeAr), 55.1* (MeO), 77.1 (С2′spiro), 108.7 (C4а′), 113.3*
(C3, С5, 4-MeOC6H4), 118.6* (C8′), 120.5 (C9a′), 123.9*
(CH, Ar), 124.6* (CH, Ar), 127.3* (C2, С6, Ph), 127.9
(C1, 4-MeOC6H4), 128.2* (C6, 2-СН3С6Н4), 128.6* (C4,
2-СН3С6Н4), 128.9* (C3, С5, Ph), 129.9 (C5, 2-СН3С6Н4),
130.0* (C4, Ph), 131.1* (C2, С6, 4-MeOC6H4), 132.3*
(C3, 2-СН3С6Н4), 137.1 (C2, 2-СН3С6Н4), 137.3* (CH,
Ar), 137.4 (C1, Ph), 137.7 (C1, 2-СН3С6Н4), 138.0* (CH,
Ar), 138.8 (Ar), 139.6 (Ar), 142.9 (C9b′), 147.8 (C9′),
156.1 (C7′), 159.1 (C5a′), 159.9 (C4, 4-MeOC6H4), 162.6
(C=Оamide), 190.7 (С=Оketone), 192.9 (С=Оketone). Found,
%: C 69.16; H 3.89; N 6.52. C37H24ClN3О4S. Calculated,
%: C 69.21; H 3.77; N 6.54.
(2Н, H-Ar), 8.25 d. d (2H, Н2,Н6, Ph, J = 8.2, J =
1.8 Hz), 8.44 d (1H, Н3, 2-Br-4-NO2С6Н3, 4J = 2.7 Hz).
13С NMR spectrum (DEPTQ), δC, ppm: 55.1* (MeO),
77.4 (С2′spiro), 109.4 (C4а′), 113.0* (C3, С5, 4-MeOC6H4),
118.7* (C8′), 120.6 (C9a′), 123.8* (CH,Ar), 124.5* (CH,
Ar), 125.0* (CH, Ar), 126.5 (CBr), 127.4* (C2, С6, Ph),
127.8 (C1, 4-MeOC6H4), 127.9* (CH, Ar), 128.9* (C3,
С5, Ph), 130.1* (C4, Ph), 130.8* (CH,Ar), 131.1* (C2, С6,
4-MeOC6H4), 137.4 (C1, Ph), 137.5* (CH, Ar), 138.1*
(CH,Ar), 138.5 (Ar), 139.4 (Ar), 142.6 (Ar), 142.8 (C9b′),
147.2 (C9′), 148.1 (СAr), 156.3 (C7′), 158.5 (C5a′), 159.8
(C4, 4-MeOC6H4), 162.7 (C=Оamide), 189.8 (С=Оketone),
191.0 (С=Оketone). Found, %: C 60.21; H 3.09; N 7.89.
C36H21BrN4О6S. Calculated, %: C 60.26; H 2.95; N 7.81.
3
4
9′-(4-Methoxyphenyl)-3′-(2-nitrophenyl)-7′-
phenyl-1′H-spiro[indene-2,2′-pyrido[3′,2′:4,5]-
thieno[3,2-d]pyrimidine]1,3,4′(3′H)-trione (13d). Yield
60%, mp 160°С, yellow powder. IR spectrum, ν, cm–1:
3356 (N–Н), 1753, 1722, 1665 (3С=О), 1531 (NO2,
9′-(4-Bromophenyl)-7′-phenyl-3′-(o-tolyl)-1′H-
spiro[indene-2,2′-pyrido[3′,2′:4,5]thieno[3,2-d]-
pyrimidine]-1,3,4′(3′H)-trione (13f). Yield 72%, mp
163°С, yellow powder. IR spectrum, ν, cm–1: 3193 (N–Н),
1752, 1717, 1657 (3 С=О). 1Н NMR spectrum, δ, ppm:
1
as), 1354 (NO2, s). Н NMR spectrum, δ, ppm: 3.62 s
3
(3Н, MeO), 6.56 d (2Н, Н3, Н5, 4-MeOC6H4, J = 8.6
Hz), 7.00 s (1H, NH), 7.06 d. d (1H, Н6, 2-NO2С6Н4,
3J = 7.7, 4J = 1.3 Hz), 7.36 d (2Н, Н2, Н6, 4-MeOC6H4,
3J = 8.6 Hz), 7.50–7.57 m (5Н, H-Ar), 7.84–7.86 m
(1Н, Н-Ar), 7.86 s (1Н, H8′), 8.01–8.04 m (2Н, Н-Ar),
8.10–8.11 m (2Н, H-Ar), 8.25 d. d (2H, Н2,Н6, Ph, 3J =
8.2, 4J= 1.7 Hz). 13С NMR spectrum (DEPTQ), δC, ppm:
55.1* (MeO), 77.4 (С2′spiro), 109.5 (C4а′), 113.0* (C3, С5,
4-MeOC6H4), 118.7* (C8′), 120.6 (C9a′), 124.3* (CH,
Ar), 124.8* (CH, Ar), 125.6* (CH, Ar), 127.4* (C2, С6
Ph), 127.8 (C1, 4-MeOC6H4), 128.9* (C3, С5, Ph), 129.9*
(C4, Ph), 130.0 * (CH, Ar), 130.15* (CH, Ar), 130.2 (C2,
2-NO2С6Н4), 131.1* (C2, С6, 4-MeOC6H4), 134.6* (CH,
Ar), 137.38* (CH, Ar), 137.41 (C1, Ph), 138.0* (CH,
Ar), 138.4 (Ar), 139.3 (Ar), 142.8 (C9b′), 147.2 (C9′),
148.0 (C1, 2-NO2С6Н4), 156.3 (C7′), 159.4 (C5a′), 159.8
(C4, 4-MeOC6H4), 162.7 (C=Оamide), 190.3 (С=Оketone),
191.2 (С=Оketone). Found, %: C 67.60; H 3.59; N 8.92.
C36H22N4О6S. Calculated, %: C 67.70; H 3.47; N 8.77.
2.23 s (2-СH3С6Н4), 6.59 d (1Н, Н6, 2-СН3С6Н4, J =
3
7.6 Hz), 6.70 s (1H, NH), 6.89–6.93 m (1Н, Н5,
2-СН3С6Н4), 7.10–7.14 m (1Н, Н4, 2-СН3С6Н4), 7.22 d
(1Н, Н3, 2-СН3С6Н4, 3J= 7.7 Hz), 7.25 d (2Н, 4-BrС6Н4,
3J = 8.6 Hz), 7.40 d (2Н, 4-BrС6Н4, 3J = 8.6 Hz), 7.50–
7.55 m (3Н, Н3–Н5, Ph), 7.79 d (1Н, Н-Ar, 3J = 7.7 Hz),
7.92 s (1Н, H8′), 7.97–8.02 m (1Н, H-Ar), 8.11–8.12 m
3
4
(2Н, H-Ar), 8.26 d. d (2H, Н2, Н6, Ph, J = 8.1, J =
1.6 Hz). 13С NMR spectrum (DEPTQ), δC, ppm: 18.0*
(MeAr), 76.9 (С2′spiro), 111.1 (C4а′), 118.7* (C8′), 120.7*
(C9a′), 122.5 (CBr), 123.8* (CH, Ar), 124.7* (CH, Ar),
126.5* (C5, 2-СН3С6Н4), 127.3* (C2, С6, Ph), 127.6* (C6,
2-СН3С6Н4), 128.5* (C4, 2-СН3С6Н4), 128.9* (C3, С5,
Ph), 130.1* (C4, Ph), 130.4* (C3, С5, 4-BrC6H4), 130.8*
(C3, 2-СН3С6Н4), 131.7* (C2, С6, 4-BrC6H4), 134.8 (C1,
4-BrC6H4), 136.0 (C2, 2-СН3С6Н4), 137.2* (CH, Ar),
137.3 (C1, Ph), 137.9* (CH,Ar), 138.2 (C1, 2-СН3С6Н4),
138.7 (Ar), 139.4 (Ar), 141.9 (C9b′), 146.6 (C9′), 156.1
(C7′), 159.0 (C5a′), 162.4 (C=Оamide), 190.9 (С=Оketone),
192.9 (С=Оketone). Found, %: C 65.80; H 3.51; N 6.39.
C36H22BrN3О3S. Calculated, %: C 65.86; H 3.38; N 6.40.
3′-(2-Bromo-4-nitrophenyl)-9′-(4-methoxyphenyl)-
7′-phenyl-1′H-spiro[indene-2,2′-pyrido[3′,2′:4,5]-
thieno[3,2-d]pyrimidine]1,3,4′(3′H)-trione (13e). Yield
75%, mp 156°С, yellow powder. IR spectrum, ν, cm–1:
3356 (N–Н), 1753, 1720, 1666 (С=О), 1528 (NO2, as),
1346 (NO2, s). 1Н NMR spectrum, δ, ppm: 3.61 s (3Н,
MeO), 6.56 d (2Н, Н3, Н5,4-MeOC6H4, 3J= 8.6 Hz), 7.07 s
A study of the effectiveness of compounds as
antidotes 2,4-D was carried out on sunflower seedlings
at the All-Russian Research Institute of Biological Plant
Protection (Krasnodar) using the roll method according
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958
DOTSENKO et al.
6. Paronikyan, E.G., Arutyunyan, A.S., and Da-
shyan, Sh.Sh., Khim. Zh. Arm., 2017, vol. 70, nos. 1–2,
p. 179.
7. Sajadikhah, S.S. and Marandi, G., Chem. Heterocycl.
Compd., 2019, vol. 55, no. 12, p. 1171.
https://doi.org/10.1007/s10593-019-02596-1
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Yu.A., Shestopalov, A.M., and Senning, A., J. Sulfur
Chem., 1992, vol. 13, no. 1, p. 1.
to the procedure reported in [67, 68]. The protective
(antidote) effect was determined by increasing the length
of the hypocotyl and root in the herbicide + antidote
experiment relative to the indicated values in the case
of seed treatment with only 2,4-D [variant “herbicide”
(standard)]. The experimental data were statistically
processed using Student’s t-test at p = 0.95. The antidote
effect (%) was calculated by the formula (1).
А = (Lо/Le)×100,
(1)
https://doi.org/10.1080/01961779208048951
9. Litvinov, V.P., Phosphorus, Sulfur, Silicon, Relat.
Elem., 1993, vol. 74, no. 1, p. 139.
https://doi.org/10.1080/10426509308038105
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p. 2053.
where А—antidote effect, Lо—the length of the organ
(mm) in the experimental group of seedlings (in the
“herbicide + antidote” experiment); Le—organ length
(mm) in a group of seedlings treated with a 2,4-D
standard.
https://doi.org/10.1007/BF02494257
The growth regulator activity was studied using
solutions of the studied compounds of various con-
centrations (10–2–10–5%). The effect was evaluated by
increasing the length of the stem and root in the group of
seedlings treated with substances relative to the indicated
values in the control group.
11. Litvinov, V.P., Krivokolysko, S.G., and Dyachenko, V.D.,
Chem. Heterocycl. Compd., 1999, vol. 35, no. 5, p. 509.
https://doi.org/10.1007/BF02324634
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FUNDING
https://doi.org/10.1002/jhet.5570290704
This work was financially supported by the Russian
Foundation for Basic Research (project no. 19-43-230007
р_а_), the Administration of the Krasnodar Region, the
Ministry of Education and Science of the Russian Federation
(topic no. 0795-2020-0031). Biological studies were performed
as part of the governmental task of the Ministry of Science and
Higher Education of the Russian Federation (no. 075-00376-
19-00, and grant no. 0686-2019-0013).
14. Quintela, J.M., Peinador, C., Veiga, C., Gonzalez, L.,
Botana, L.M., Alfonso, A., and Riguera, R., Bioorg.
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J. Heterocycl. Chem., 2005, vol. 42, no. 6, p. 1069.
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CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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