Synthesis of Amides of Carboxylic Acids with an Imide and Alicyclic Fragments and a Study of Their Genotoxic Activity in the Allium Test

Article abstract of DOI:10.1134/S1068162019030026

A method for the high-yield synthesis of several amides of carboxylic acids containing an imide, a cyclohexene, and a norbornene cycle as well as fragments of natural amino acids has been developed. The compounds synthesized have been tested for mutagenic activity on plant objects using the Allium test. It has been shown that the presence of a nitro group endows the compound with inhibitory property and the capacity to induce chromosomal rearrangements, whereas the presence of an aliphatic carbon chain, a methyl group, and a morpholine fragment, on the contrary, confers growth-regulating properties without inducing the mutagenic effect. The study has confirmed that the resulting biologically active compounds are of interest for practical implementation in agriculture.

Full text of DOI:10.1134/S1068162019030026

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2019, Vol. 45, No. 3, pp. 204–213. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Bioorganicheskaya Khimiya, 2019, Vol. 45, No. 4, pp. 430–440.
Synthesis of Amides of Carboxylic Acids with an Imide and Alicyclic
Fragments and a Study of Their Genotoxic Activity in the Allium Test
A. A. Firstovaa, 1, E. R. Kofanova, V. M. Zakshevskayaa, and M. I. Kovalevab
aYaroslavl State Technical University, Yaroslavl, 150001 Russia
bDemidov Yaroslavl State University, Yaroslavl, 150003 Russia
Received October 30, 2018; revised November 25, 2018; accepted December 14, 2018
Abstract—A method for the high-yield synthesis of several amides of carboxylic acids containing an imide, a
cyclohexene, and a norbornene cycle as well as fragments of natural amino acids has been developed. The
compounds synthesized have been tested for mutagenic activity on plant objects using the Allium test. It has
been shown that the presence of a nitro group endows the compound with inhibitory property and the capac-
ity to induce chromosomal rearrangements, whereas the presence of an aliphatic carbon chain, a methyl
group, and a morpholine fragment, on the contrary, confers growth-regulating properties without inducing
the mutagenic effect. The study has confirmed that the resulting biologically active compounds are of interest
for practical implementation in agriculture.
Keywords: amides of carboxylic acids, cyclohexene and norbornene fragments, imide cycle, biological activ-
ity, Allium test
DOI: 10.1134/S1068162019030026
INTRODUCTION
containing an imide fragment that are known to pos-
sess biological activity and low cytotoxicity [19] have
found application as growth-regulating reagents [20].
A search for new compounds capable of improving
the properties of seeding material, increasing the pro-
ductivity, and enhancing the resistance of crops to
phytopathogens, drought, and cold is currently a top-
ical problem in the optimization of agriculture. It is
known that compounds containing an amide fragment
possess a high biological activity and constitute a wide
spectrum of fungicidal [1, 2], insecticidal [3], and her-
bicidal [4] preparations [5–7]. However, at present,
there are problems associated with the stable resis-
tance of pathogens to available preparations, large
amounts of wastes during their production, and, as a
consequence, harmful effects on the environment.
Thus, the search for, and the creation of, compounds
free from these shortcomings is a timely task in the
chemistry of pesticides [8, 9].
Our work is devoted to the synthesis of amides of
carboxylic acids containing an imide and cycloalkenyl
fragments and the study of their mutagenic activity
and influence on farm crops. We synthesized several
potentially bioactive compounds in which we com-
bined the active structure of an amide with imide and
cycloalkenyl fragments and selected biologically active
samples from them using the Allium test. The results
showed that most of the compounds have growth-reg-
ulating activity. As far as we know, this study is the first
to show the growth-regulating properties of a compar-
atively large series of amide derivatives.
RESULTS AND DISCUSSION
It is worth noting that the imide group is an integral
structural part of some known biologically active com-
pounds, such as fumaramidmycin [10, 11], granu-
latimide [12], isogranulatimide [13], and rebekkamy-
cin [14]. These compounds exhibit a wide spectrum of
biological activities: antitumor [15, 16], anti-inflam-
matory [17], and antimicrobial [18]. Some compounds
Compounds (III)–(VII), (XI), (XII), (XVII)–
(XXV) have been synthesized earlier [21–25]; how-
ever, the methods of their synthesis are very compli-
cated and involve the use of either expensive reagents
or elaborate procedures.
Alicyclic endic (I) and tetrahydrophthalic anhy-
drides (II) were used as initial compounds. These
compounds were chosen because they are readily
available, inexpensive, and easily obtainable from
petroleum chemical products (divinyl, maleic anhy-
dride) [26].
Abbreviations: CDI, N,N'-carbonyldiimidazole; QSAR,
Quantitative Structure-Activity Relationship.
1Corresponding author: phone: +7(960)528-25-77; e-mail:
firstova.a.a@mail.ru.
204

SYNTHESIS OF AMIDES OF CARBOXYLIC ACIDS
205
O
R
C4H8ONH
R'C6H4NH2
C6H11NH2
(CH2)n
N
N
O
O
O
(XI)−(XVI)
R'
(1) i, ii
(2) iii
(3) iv
O
O
O
R
N
aa, AcOH
reflux, 4 h
R
(CH2)n
(CH2)n
(CH2)n
O
N
O
NH
HO
O
O
O
O
(XVII)−(XXV)
(I)−(II)
(III)−(X)
O
R
N
(4) v, vi
(CH2)n
NH
O
O
(XXVI)−(XXX)
Reagents and conditions: (1) i: SOCl2, DMF, reflux for 3 h or PCl5, CH2Cl2, ii: amine, Et3N, reflux for 5 h;
(2) iii: CDI, amine, reflux for 4−7 h; (3) iv: EtOCOCl, amine, Et3N, reflux for 2−4 h;
(4) v: amino acid, DMSO, 1% K2CO3; reflux for 1 h; vi: amine, reflux for 1 h;
(I) n = 0; (II) n = 1; (III) n = 0, R = H; (IV) n = 1, R = H; (V) n = 0, R = iPr; (VI) n = 1, R = iPr; (VII) n = 0, R = CH2Ph;
(VIII) n = 1, R = CH2Ph; (IX) n = 0, R = iBu; (X) n = 1, R = iBu; (XI) n = 0, R = H; (XII) n = 1, R = H; (XIII) n = 0, R = iPr;
(XIV) n = 1, R = iPr; (XV) n = 1, R = CH2Ph; (XVI) n = 0, R = iBu; (XVII) n = 0, R = H, R' = NO2; (XVIII) n = 1, R = iBu,
R' = NO2; (XIX) n = 0, R = iBu, R' = NO2; (XX) n = 1, R = H, R' = OH; (XXI) n = 1, R = iPr, R' = OH; (XXII) n = 0, R = iBu,
R' = OH; (XXIII) n = 1, R = iBu, R' = OH; (XXIV) n = 1, R = CH2Ph, R' = CH3; (XXV) n = 0, R = i-Bu, R' = CH3;
(XXVI) n = 1, R = H; (XXVII) n = 1, R = iBu; (XXVIII) n = 0, R = H; (XXIX) n = 1, R = iPr; (XXX) n = 0, R = iBu
Scheme 1. Synthesis of amides of carboxylic acids containing cycloalkenyl and imide fragments.
N-Substituted imides of dicarboxylic acids (III)– tive; the reaction proceeded in one stage for 3.5 h, and
(X) were obtained by refluxing anhydrides (I) and (II) the yield of target products was 60–95%. The struc-
with native amino acids (L-leucine, L-alanine, and tures of compounds (XI)–(XXX) were confirmed by
glycine) in acetic acid. For the synthesis, the reagents spectroscopy.
were taken in the equimolar ratio (scheme) [27]. Then,
the functionalization of N-substituted imides of acids
(III)–(X) at the carboxyl group was carried out using
the known and available methods for the synthesis of
amides of carboxylic acid. At the first stage, acid chlo-
rides of N-substituted alicyclic acids were obtained by
method 1 (Scheme 1) using phosphorus pentachloride
(PCl5) or thionyl chloride (SOCl2). Methylene chlo-
ride served as a solvent. In both cases, acid chlorides
were obtained in good yields (75–95%). They were not
subjected to additional purification and were immedi-
ately introduced into the acylation reaction of amines.
However, the yield of the resulting amides (XI)–
(XXX) was no higher than 50%, and the final reaction
mixtures contained the corresponding initial N-sub-
stituted imides (III)–(X). It may be suggested that the
acyl derivative that forms during amidation is unstable
and either dissociates yielding the initial acid or forms
in minor amounts.
However, it should be noted that, the reaction time
during the synthesis of amides (XVII)–(XIX)
increased from 8 to 12 h as compared with the synthe-
sis of compounds (III)–(X), which is explained by a
low nucleophilicity of p-nitroaniline. Therefore, the
problem facing us was to develop a method that would
make it possible to minimize the reaction time. This
problem was solved by using ethyl chloroformate as an
agent activating the carboxyl group in compounds
(III)–(X) (method 3) [28, 29]. With this method, tar-
get amides were obtained with high yields, and the
reaction time was reduced from eight to two hours,
compared with method 2. Acetone and 1,4-dioxane
were used as solvents; no substantial differences in the
reaction course with the use of the two reagents were
observed.
Although these methods of amidation are widely
used for synthesizing carboxylic acid amides and
afford high yields, it should be noted that they had
In the amidation reaction of compounds (III)– some limitations in our case, namely, a high cost of
(X), we also tested method 2 in which CDI serves as an reagents and particular terms and conditions of stor-
activation agent. This approach appeared to be effec- age. It should also be taken into account that the com-
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FIRSTOVA et al.
(XXX)
(XXIX)
(XXVIII)
(XXVI)
(XXV)
(XXIV)
(XIX)
(XVI)
(XV)
(XI)
C
0
0.5
1.0
1.5
Root length, cm
0.01% 0.1%
2.0
2.5
3.0
3.5
4.0
0.001%
0.5%
Fig. 1. Effect of the concentration of test compounds on the length of Allium cepa roots in the experiment on the determination
of total genotoxicity. Here and below, differences between the experimental and control samples were significant at p < 0.05.
pounds synthesized are intended for use in agriculture capacity, compatibility with water, and low toxicity
where the cost price of materials is an important fac- toward biological organisms [37].
tor. Therefore, the next step was to develop a method
A characteristic that adequately estimates the gen-
of synthesis using available and inexpensive reagents.
eral toxicity of organic compounds is the capacity to
In the literature, the methods of amidation with the
use of weakly alkaline dioxane–water solvents [30, 31]
or an inert solvent (e.g., toluene) in the presence of tri-
ethylamine [32, 33] are described. Based on the litera-
ture data, we developed a new method, which is pre-
sented on the scheme (method 4). N-Substituted
imides of alicyclic dicarboxylic acids were obtained in
the in situ reaction of the corresponding amines with
the products of the reaction of anhydrides (I) and (II)
with natural amino acids in the equimolar ratio in the
presence of a 1% solution of K2CO3 in DMSO. This
method makes it possible to obtain target compounds
with high yields over a short time without intermediate
isolation and with the use of readily available reagents.
affect seed germination [38]. The biological activity of
the compounds was determined under laboratory con-
ditions on onion Allium cepa plantlets. In control
experiments, distilled water was used. The results of
tests are shown in Fig. 1.
It can be concluded from the data on Fig. 1 that the
optimal concentration of test compounds that affects
germination is 0.1%. Therefore, in subsequent experi-
ments, we used this concentration of the solutions.
Compounds (XXV), (XXVI), (XXIX), and (XXX) at a
concentration of 0.1 and 0.01% increase seed germination.
Compounds (XVI), (XIX), and (XXIV) decrease germina-
tion, i.e., act as inhibitors. Compounds with these proper-
ties can be used in agriculture for weed control.
For the primary estimation of the biological activ-
ity and toxicity, a computer screening of QSAR was
performed. Compounds having a low (from 0.5 to
1.0 mmol/kg) factor of bioaccumulation ((XI), (XV),
(XVI), (XIX), (XXIV)–(XXX)) were chosen [34–36].
Because the compounds synthesized are poten-
tially useful for agricultural applications, it was neces-
sary to estimate their biological effects, such as geno-
toxicity, i.e., the capacity to adversely affect the
genetic material of the cell. To examine the mutagenic
It is known that many organic compounds possess- activity, which characterizes the genotoxicity of prepa-
ing biological activity are capable of passing through rations, we analyzed the frequency of induced chro-
biological membranes but are poorly soluble in water. mosome aberrations in the meristematic tissue of
However, a necessary condition for biological testing Allium cepa plantlet roots (the Allium test). This
is the use of liquid forms of preparations. Therefore, in method has been recommended by the World Health
experiments on biological objects, we used test com- Organization for the primary estimation of mutagen-
pounds in the form of their aqueous solutions contain- icity; the results of the test correlate well with the data
ing 1% DMSO. This compound has a high solvent on mutagenicity obtained on mammalian and human
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SYNTHESIS OF AMIDES OF CARBOXYLIC ACIDS
207
(XXX)
(XXIX)
(XXVIII)
(XXVI)
(XXV)
(XXIV)
(XIX)
(XVI)
(XV)
(XI)
C
0
5
10
15
20
25
Mitotic index, %
Fig. 2. Mitotic index (%) by the action of compounds at a concentration of 0.1% on onion Allium cepa.
cells [39]. A major characteristic that enables one to
It may be concluded from the results of biotesting
estimate the cytotoxicity of compounds is the mitotic that the compounds synthesized possess growth-regu-
index. It shows the ratio of the number of cells in mito- lating properties. Evidence from three biotests indi-
sis to the total number of cells in a tissue preparation cates that compounds (XXV), (XXVI), (XXIX) and
being analyzed. The mitotic index may indicate a nor- (XXX) are the safest toward the plant test objects and
mal course of mitosis, an inhibition of cell division, or, can be recommended for further studies as plant
conversely, an enhancement of the mitotic activity of growth regulators.
tissues [39, 40]. The data on the effect of the com-
pounds on the proliferative activity are given in Fig. 2.
Based on the study of the structure–activity rela-
tionship for the test compounds, it may be suggested
that the presence of a nitro group in the structure of a
compound endows it with inhibitory properties and
the capacity to induce chromosome rearrangements,
whereas the presence of an aliphatic carbon chain, a
methyl group, and a morpholine fragment, on the
contrary, imparts growth-regulating properties with-
out inducing a mutagenic effect.
As seen from Fig. 2, all test compounds possess
proliferative activity; however, the mitotic index of
compounds (XXIII), (XXV), (XXVI), and (XXVIII)–
(XXX) is 1.5–4 times higher than that of the control
(distilled water), indicating an increase in the mitosis
rate and, as a consequence, the appearance of growth-
regulating properties. The mitotic indices for com-
pounds (IX) and (XI) are comparable with the control;
these compounds had no modifying effect on mitosis.
The mutagenic activity was estimated by the ana-
telophase assay [41]. This method makes it possible to
record chromosome aberrations such as fragments,
bridges, and lagging chromosomes, which result from
chromosome mutations and abnormal behavior of
chromosomes on the mitotic spindle [40]. The data
obtained by this assay are given in Fig. 3.
EXPERIMENTAL
The following commercially available domestic
reagents of pure or chemically pure grade were used:
morpholine, aromatic amines, maleic anhydride, divi-
nyl, cyclopentadiene, triethylamine, and phosphorus
pentachloride. Ethyl chloroformate and CDI were
from Sigma-Aldrich. Endic anhydride (I) and tetrahy-
drophthaleic anhydride (II) were obtained as
described in [26]. Before use, solvents were dried and
distilled by standard methods [26].
Spectroscopy. 1H and 13C NMR spectra (δ, ppm, J,
Hz) were recorded on a Bruker MSL-300 spectrome-
ter (Germany) with a working frequency of 300 and
75.5 MHz, respectively. The spectra were recorded for
the solutions of test compounds in DMSO-d6 relative
The frequency of induced chromosome aberrations
of compounds (XI), (XV), (XVI), and (XXIV)–(XXX)
does not exceed the control level (C); consequently,
these compounds do not exhibit mutagenic activity in
this test system. At the same time, compound (XIX)
increases the frequency of induced chromosome aber-
rations to 6.00 0.0049%, which exceeds the control
level three times, with the frequency of lagging chro-
mosomes being unchanged. Compound (XIX) is capa- to residual protons of the solvent. IR spectra (ν, cm–1)
ble of inducing chromosome rearrangements but does were measured in KBr pellets in Vaseline oil on a Spec-
not affect the formation and behavior of the mitotic trum RXI FT-IR device (Great Britain). High-resolu-
spindle.
tion mass spectra were recorded on a MicrOTOF-Q II
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FIRSTOVA et al.
(XXX)
(XXIX)
(XXVIII)
(XXVI)
(XXV)
(XXIV)
(XIX)
(XVI)
(XV)
(1), %
(2), %
(XI)
C
0
1
2
3
4
5
6
Frequency of induced chromosome aberrations (1)
and the degree of chromosome lagging (2), %
Fig. 3. Frequency of chromosome aberrations (%, 1) and the degree of chromosome lagging (%, 2) by the action of compounds
at a concentration of 0.1% on Allium cepa bulbs during their sprouting.
1744, 1673 (C=O, imide); 1192 (C–O); 1Н NMR: 1.20
(3 Н, m, CH3), 1.50 (3 Н, m, CH3), 1.80 (1 Н, m, HC-
C=O), 2.51 (1 Н, m, HC–C=O), 3.42 (2 Н, m, CH2),
3.72 (1 Н, m, CHN), 4.10 (2 Н, m, CH2), 4.45 (1 Н, m,
CH), 6.03 (2 Н, m, HC=CH), 12.61 (1 Н, s, СООН);
MS, m/z: found [M + H]+ 252.125. Calculated for
С13H17NO4: 252.115.
mass spectrometer (Bruker Daltonics) using the elec-
trospray ionization method; the temperature of the
ionization source was 180°С, and the eluent was ace-
tonitrile. TLC was performed on Sulifol 201S plates in
a petroleum ether–toluene–acetone–acetic acid sys-
tem 100 : 60 : 100 : 2 (v). The melting temperature of
compounds was determined on an Electrothermal
IA9300 Series device (Great Britain).
The general method of the synthesis of N-substituted
imides of alicyclic dicarboxylic acids (III)–(X). Acyclic
anhydride (I) or (II) (0.05 mol), an amino acid
(55 mmol), and acetic acid (15 mL) were placed in a
round-bottomed flask equipped with a reflux con-
denser and refluxed for 4 h. Then, the reaction mix-
ture was poured into water (100 mL), and the sediment
was filtered, washed with water, and dried at 40°С.
2-(3,5-Dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-
4-yl)-3-methylbutanoic acid (VI). Yield 73%; mp 105–
108°С; IR: 2728, 2603, 901 (OH); 1769, 1706 (C=O,
1
imide); 1682 (С=С); 1192 (С–О); Н NMR: 0.84
(6 Н, m, CH3). 1.31 (2 Н, m, CH2 bridge), 1.63 (1 Н,
m, HC–C=O), 1.81 (1 Н, m, HC–C=O), 3.37 (1 Н,
m, CHN), 3.42 (2 Н, m, CH), 4.41 (1 Н, m, CH), 6.03
(2 Н, m, CH=CH), 12.86 (1 Н, s, COOH); MS, m/z:
found [M + H]+ 264.128. Calculated for C14H17NO4:
264.115.
(1,3-Dioxo-1,3,3a,4,7,7a-hexahydro-2H-isoindol-
2-yl)acetic acid (III). Yield 93%; mp 69–72°С; IR:
2724, 2671, 923 (OH); 1791, 1757, 1684 (C=O, imide);
2-(1,3-Dioxo-3a,4-dihydro-1H-isoindol-2(3H,7H,
7aH)-yl)-3-phenylpropanoic acid (VII). Yield 60%; mp
123–127°С; IR: 2728, 2661, 2594, 901 (OH); 1769,
1
1633 (С=С); 1178 (C–O); Н NMR: 2.37 (4 H, m,
CH2), 3.22 (2 H, m, HC–C=O), 4.04 (2 H, s, NCH2),
5.87 (2 H, m, HC=CH), 13.07 (1 Н, s, COOH); MS, m/z:
found [M + H]+ 210.076. Calculated for С10H11NO4:
210.068.
1
1744, 1673 (C=O, imide); 1192 (C–O); Н NMR:
2.08 (2 H, m, CH2–Ph), 2.33 (1 H, m, HC–C=O),
3.18 (1 H, m, HC–C=O), 3.43 (4 H, m, CH2), 4.85 (1
H, m, CHN), 5.57 (2 H, m, HC=CH), 7.12 (2 Н, d, J
7.0, Ar), 7.27 (1Н, d, J 7.5 Ar), 7.29 (2Н, t, J 14.2, Ar),
13.01 (1Н, s, СООН); MS, m/z: found [M + H]+
300.124. Calculated for С17H17NO4: 300.115.
(3,5-Dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl)-
acetic acid (IV). Yield 83%; mp 139–143°С; IR: 2725,
2669, 920 (OH); 1791, 1758, 1680 (C=O, imide); 1643
1
(С=С); 1128 (C–O); Н NMR: 1.58 (2 Н, m, CH2
2-(3,5-Dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-
4-yl)-3-phenylpropanoic acid (VIII). Yield 74%; mp
136–139°С; IR: 2721, 2661, 929 (OH); 1769, 1751
(C=O, imide); 1684 (С=С); 1603, 1398 (Ar); 1169
(С–О); 1Н NMR: 1.42 (2 H, m, CH2–Ph), 2.49 (2 H,
m, CH2 bridge), 3.11 (1 H, m, HC-C=O), 3.19 (1 H,
bridge), 2.51 (1 Н, m, HC–C=O), 3.26 (1 Н, m, HC–
C=O), 3.44 (2 Н, m, CH), 3.89 (2 Н, m, NCH2), 6.02
(2 H, m, HC=CH), 12.95 (1 Н, s, COOH); MS, m/z:
found [M + H]+ 222.088. Calculated for С11H11NO4:
222.068.
2-(1,3-Dioxo-3a,4-dihydro-1H-isoindol-2(3H,7H,
7aH)-yl)-3-methylbutanoic acid (V). Yield 60%; mp m, HC-C=O), 3.33 (2 H, m, CH), 4.86 (1 H, m,
123–127°С; IR: 2728, 2661, 2594, 901 (OH); 1769, CHN), 5.24 (1 H, m, HC=CH), 5.67 (1 H, m,
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SYNTHESIS OF AMIDES OF CARBOXYLIC ACIDS
209
HC=CH), 7.12 (2 Н, d, J 7.0, Ar), 7.20 (1 Н, d, J 7.5, (0.01 mol), dioxane (10 mL), and CDI (0.11 mol) were
Ar), 7.26 (2 Н, t, J 14.2, Ar), 13.02 (1 Н, s, СООН); placed in a flask equipped with a stirrer and a reflux
MS, m/z: found [M + H]+ 312.123. Calculated for
condenser, and the reaction mixture was heated for
1.5 h to 70°С. Then, an amine (morpholine, p-tolui-
dine, p-nitroaniline, o-hydroxyaniline, cyclohexyl-
amine) was added, and the mixture was heated for an
additional two hours. The reaction mass was poured
into water (100 mL), and the resulting residue was fil-
tered and dried at 40°С.
Method 3. Synthesis of amides of N-substituted
imides of dicarboxylic acids (XI)–(XXX) using chloro-
ethylformate. An N-substituted imide of a dicarboxylic
acid (III)–(X) (0.01 mol), acetone (15 mL), and tri-
ethylamine (0.012 mol) were placed in a flask
equipped with a stirrer and a reflux condenser. Ethyl-
chloroformate (0.012 mol) was added gradually under
intensive stirring, and the reaction mixture was refluxed
for 0.5 h. Then, an amine (morpholine, p-toluidine,
p-nitroaniline, o-hydroxyaniline, cyclohexylamine)
was added, and the mixture was further boiled for 5 h.
The reaction mixture was poured into water (100 mL),
and the residue was filtered and dried at 40°С.
Method 4. One-top synthesis of amides of N-substi-
tuted imides of dicarboxylic acids (XI)–(XXX). A natu-
ral amino acid (glycine, L-valine, L-leucine, L-phe-
nylalanine) (0.011 mol), DMSO (15 mL), K2CO3
(1 mmol), and then acyclic anhydride (I) or (II)
(0.01 mol) were placed in a flask equipped with a stir-
rer and a reflux condenser. The mixture was heated for
1 h to 70°С after which an amine (morpholine, p-tolu-
idine, p-nitroaniline, o-hydroxyaniline, cyclohexyl-
amine) was added, and the mixture was refluxed for 2 h.
The reaction mixture was poured into water (100 mL),
and the residue was filtered and dried at 40°С.
С18H17NO4: 312.115.
2-(1,3-Dioxo-3a,4-dihydro-1H-isoindol-2(3H,7H,
7aH)-yl)-3-methylpentanoic acid (IX). Yield 80%; mp
132–134°С; IR: 2591, 950 (OH); 1701 (C=O, imide);
1616 (С=С); 1263 (С–О–); 1Н NMR: 0.79 (6 Н, m,
CH3), 1.28 (1 Н, m, CH), 1.67 (2 Н, m, CH2), 1.97
(1 Н, m, HC–C=O), 2.22 (1 Н, m, HC–C=O), 3.17
(4 Н, m, CH2), 4.49 (1 Н, m, CHN), 5.84 (2 Н, m,
HC=CH), 12.77 (1 Н, s, COOH); MS, m/z: found
[M + H]+ 266.139. Calculated for С14H19NO4: 266.131.
2-(3,5-Dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-
4-yl)-3-methylpentanoic acid (X). Yield 93%; mp 103–
105°С; IR: 2723, 2656, 2597, 904 (OH); 1746, 1706
1
(C=O, imide); 1677 (С=С); 1190 (С–О); Н NMR:
0.71 (3 Н, m, CH3), 0.93 (3 Н, m, CH3), 1.56 (2 Н, m,
CH2 bridge), 2.23 (1 Н, m, CH), 2.34 (2 Н, m, CH2),
3.37 (2 Н, m, HC–C=O), 3.45 (2 Н, m, CH), 4.07
(1 Н, m, CHN), 6.01 (2Н, m, HC=CH), 11.95 (1 Н,
s, COOH); MS, m/z: found [M + H]+ 278.135. Calcu-
lated for С15H19NO4: 278.131.
Synthesis of Amides of N-Substituted Imides
of Dicarboxylic Acids (XI)–(XXX).
Method 1. Synthesis of amides of N-substituted
imides of dicarboxylic acids from the corresponding acid
chlorides. 1. An N-substituted imide of a dicarboxylic
acid (III)–(X) (0.01 mol), thionyl chloride (0.07 mol),
and a catalytic amount of DMF were placed in a flask
equipped with a stirrer and a reflux condenser, and the
reaction mixture was boiled for 4 h. Excess thionyl
chloride was distilled under vacuum. The resulting
sediment was used without additional purification in
the next stages.
2. An N-substituted imide of a dicarboxylic acid
(III)–(X) (0.01 mol) dissolved in dichloromethane
(15 mL) was added to a flask, and phosphorus penta-
chloride (0.012 mol) was added in portions. The reac-
tion mixture was refluxed for 4 h. Dichloromethane
was distilled under vacuum. n-Hexane was added to
the remaining reaction mixture, and the precipitate
was filtered. The resulting sediment was used at the
next stages without additional purification.
Triethylamine (0.013 mol) and then the acid chlo-
ride of an N-substituted imide of a dicarboxylic acid
(1 mol) obtained earlier were added to a solution of
amine (morpholine, p-toluidine, p-nitroaniline,
o-hydroxyaniline, cyclohexylamine) (0.011 mol) in
dichloromethane (15 mL). The reaction mixture was
refluxed for 4 h and then poured into water (100 mL).
The residue was filtered and dried at 40°С.
2-(2-(Morpholin-4-yl)-2-oxoethyl-3a,4,7,7a-tet-
rahydro-1H-isoindol-1,3(2H)dione (XI). Yield 67%;
mp 167–171°С; IR: 1762, 1690 (C=O, imide); 1667
1
(C=O, amide); 1625 (С=С); 1116 (–О–); Н NMR:
2.23 (2 H, m, CH2), 2.33 (2 H, m, CH2), 3.19 (2 H, m,
CH2), 3.39 (2 H, m, CH2), 3.49 (1 H, m, HC=O),
3.55 (1 H, m, HC=O), 3.60 (4 H, m, CH2), 4.25 (2 H,
m, NCH2), 5.85 (2 H, m, HC=CH); 13C NMR: 23.57,
39.05, 39.56, 39.77, 40.09, 40.19, 40.40, 42.52, 45.13,
66.02, 67.02, 127.97, 164.31, 180.14; MS, m/z: found
[M + H]+ 279.128. Calculated for С14H18N2O4:
279.126.
2-(2-(Morpholin-4-yl)-2-oxoethyl-4-azatricyclo-
[5,2,1,0]dec-8-en-3,5-dione (XII). Yield 68%; mp
93–95°С; IR: 1768, 1703 (C=O, imide), 1673 (C=O,
1
amide); 1630 (С=С); 1114 (–О–); Н NMR: 1.55
(2 Н, m, CH2 bridge), 3.34 (2 H, m, CH2), 3.38 (2 H,
m, CH2), 3.42 (4 Н, m, CH2), 3.46 (2 Н, m, HC=O),
3.54 (2 H, m, CH), 4.10 (2 H, m, NCH2), 6.04 (2 H,
13
m, HC=CH); C NMR: 25.72, 26.04, 27.03, 39.74,
40.36, 40.47, 40.68, 41.12, 52.23, 53.35, 133.13, 135.48,
164.24, 174.44, 175.68; MS, m/z: found [M + H]+
291.175. Calculated for С15H18N2O4: 291.167.
Method 2. Synthesis of amides of N-substituted
imides of dicarboxylic acids (XI)–(XXX) using CDI. An
N-substituted imide of a dicarboxylic acid (III)–(X)
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FIRSTOVA et al.
2-(1,3-Dioxo-3a,4-dihydro-1H-isoindol-2(3H,7H,
2-(2-Methyl-1-(morpholin-4-yl)-1-oxobytan-2-yl]-
3a,4,7,7a-tetrahydro-1H-isoindol-1,3-dione (XIII). 7aH)-yl-N-(4-nitrophenyl)acetamide (XVII). Yield
78%; mp 171–174°С; IR: 3481, 3359 (NH), 1748,
(C=O, imide), 1712 (C=O, I amide), 1631 (C=C),
1597 (Ar), 1549, 1325 (NO2); 1H NMR: 1.57 (1 Н, m,
HC=O), 2.50 (1 H, m, HC=O), 3.27 (4 H, m, CH2),
4.12 (2 H, m, NCH2), 6.07 (2 H, m, HC=CH), 6.75 (1
H, d, Ar, J 7.2), 6.86 (1 H, d, Ar, J 6.8), 6.92 (1 H, d,
Ar, J 7.2), 7.77 (1 H, d, Ar, J 7.9), 9.81 (1 H, s, NH);
13C NMR: 23.88, 39.78, 40.18, 40.41, 40.60, 40.83,
53.45, 120.37, 126.46, 127.19, 128.28, 143.83, 145.58,
168.59, 180.55, 180.78; MS, m/z: found [M + H]+
330.109. Calculated for С16H15N3O5: 330.101.
Yield 80%; mp 87–90°С; IR: 1776, 1702, 1657 (С=О,
1
imide); 1116 (–О–); Н NMR: 0.69 (3 Н, m, CH3),
0.87 (3 Н, m, CH3), 2.21 (1 Н, m, HC=O), 2.43 (1 Н,
m, HC=O), 2.63 (1 Н, m, CH), 3.23 (4 Н, m, CH2),
3.31 (4 Н, m, CH2), 3.49 (4 Н, m, CH2), 4.39 (1 Н, m,
13
NCH), 5.88 (2 H, m, HC=CH); C NMR: 20.51,
21.32, 25.71, 27.04, 27.13, 39.94, 41.36, 41.47, 41.68,
42.12, 52.23, 53.35, 134.13, 135.48, 167.24, 174.47,
175.70; MS, m/z: found [M + H]+ 321.162. Calculated
for С17H24N2O4: 321.174.
4-(3-Methyl-1-(morpholin-4-yl)-1-oxobytan-2-yl]-
4-azatricyclo[5,2,1,0]dec-8-en-3,5-dione
2-(3,5-Dioxo-4-azatricyclo[5.2.1.0]dec-8-en-4-
yl)-4-methyl-N-(4-nitrophenyl)pentanamide (XVIII).
Yield 70%; mp 93–95°С; IR: 3480, 3360 (NH), 1750
(C=O, imide), 1714 (C=O, I amide), 1630 (C=C),
1600 (Ar), 1549, 1325 (NO2); 1H NMR: 0.85 (6 H, m,
CH3), 1.35 (2 H, m, CH), 1.54 (2 H, m, CH2 bridge),
1.74 (1 H, m, CH), 3.33 (2 H, m, HC=O), 3.45 (1 H,
m, NCH), 4.1 (2 H, m, CH2), 6.11 (2 H, m,
HC=CH), 6.76 (1 H, d, Ar, J 7.8), 6.93 (2 H, d, Ar, J
8.8), 7.78 (1 H, d, Ar, J 8.6), 9.82 (1 H, s, NH);
13C NMR: 20.34, 21.72, 22.88, 24.23, 26.05, 39.75,
40.18, 40.68, 41.79, 46.34, 53.35, 120.27, 125.46,
128.19, 128.28, 143.13, 145.48, 168.49, 180.44, 180.68 ;
MS, m/z: found [M + H]+ 397.172. Calculated for
С21H23N3O5: 397.164.
(XIV).
Yield 80%; mp 83–87°С; IR: 1770, 1708, 1701, 1692
(C=O, imide); 1655 (C=O, amide); 1625 (С=С); 1113
(–О–); 1Н NMR: 1.09 (2 H, m, CH2 bridge), 1.58 (3
H, m, CH3), 2.49 (3 H, m, CH3), 3.26 (2 H, m,
HC=O), 3.42 (4 H, m, CH2), 3.47 (2 H, m, CH), 3.56
(4 H, m, CH2), 3.31 (1 H, m, CH), ), 4.10 (1 H, m,
13
NCH), 6.04 (2 H, m, HC=CH); C NMR: 20.41,
20.62, 24.71, 28.04, 28.13, 39.91, 41.05, 41.47, 42.22,
46.21, 52.23, 53.37, 134.15, 135.53, 167.27, 174.49,
175.80; MS, m/z: found [M + H]+ 333.162. Calculated
for С17H24N2O4: 333.174.
2-(1-Benzyl-2-morpholin-2-oxo-ethyl)-4-azatri-
cyclo[5,2,1,0]dec-8-en-3,5-dione (XV). Yield 76%;
mp 172–175°С; IR: 3445, 3350, 3288, 3137, 3064
(NH); 1766, 1698 (C=O, imide); 1653 (C=O, amide);
1604 (Ar); 1115 (–O–); 741 (mono substitution Ar);
1Н NMR: 1.45 (2 H, m, CH2 bridge), 3.11 (4 H, m,
CH2), 3.20 (2 H, m, HC=O), 3.31 (2 H, m, CH2), 3.41
(2 H, m, CH2), 3.53 (4 H, m, CH2), 4,99 (1 H, m,
NCH), 5.57 (1 H, m, HC=CH), 5.76 (1 H, m,
HC=CH), 7.13 (2 H, d, Ar, J 6.8), 7.18 (2 H, d, Ar, J
7.3), 7.26 (1 H, t, Ar, J 16.4); 13C NMR: 34.13, 52.06,
52.40, 52.43, 66.73, 127.10, 127.12, 128.66, 128.68,
129.99, 130.01, 134.68, 134.70, 135.21, 135.23, 137.74,
137.77, 166.49, 166.51, 177.13, 177.15, 177.35; MS, m/z:
found [M + H]+ 381.181. Calculated for С22H24N2O4:
381.174.
2-(1,3-Dioxo-1,3,3a,4,7,7a-hexahydro-2H-isoindol-
2-yl)-4-methyl-N-(4-nitrophenyl)pentanamide (XIX).
Yield 76%; mp 138–143°С; IR: 3330 (NH); 1720,
1688 (C=O, imide);1615 (I amide, С=О); 1549 (II
amide, С=О, NO2), 1344 (NO2); 1599, 1509 (Ar); 852
(1,4-disubstitution Ar); 1H NMR: 0.83 (6 H, m, CH3),
1.81 (1 H, m, CH), 2.05 (2 H, m, CH2), 2.22 (1 H, m,
HC=O), 2.42 (1 H, m, HC=O), 3.22 (4 H, m, CH2),
4.75 (1 H, m, NCH), 5.86 (2 H, m, HC=CH), 7.82 (2
H, d, J 9.2), 8.22 (2 H, d, Ar, J 9.2), 10.32 (1 H, s,
NH); 13C NMR: 21.34, 23.72, 23.88, 24.04, 25.03,
39.74, 40.16, 40.37, 40.58, 40.79, 53.35, 120.27,
125.46, 128.19, 128.28, 143.13, 145.48, 168.49, 180.44,
180.68; MS, m/z: found [M + H]+ 386.172. Calculated
for С20H23N3O5: 386.164.
2-(4-Methyl-1-(morpholin-4-yl)-1-oxopentan-2-yl]-
3a,4,7,7a-tetrahydro-1H-isoindol-1,3(2H)-dione (XVI).
Yield 68%; mp 101–104°С; IR: 1778, 1699 (C=O,
imide); 1657 (С=С); 1663 (C=O, amide); 1113, 1021
2-(3,5-Dioxo-4-azatricyclo[5,2,1,0]dec-8-en-4-yl)-
N-(2-hydroxyphenyl)acetamide (XX). Yield 70%; mp
177–180°С; IR: 3408 (OH); 3161 (NH), 1776, 1707
(C=O, imide); 1679 (I amide, C=O); 1610 (С=С);
1596 (Ar); 1545 (II amide, С=О); 1183 (С–О), 776
(1,2-disubstitution Ar); 1H NMR: 1.58 (2 H, m, CH2
bridge), 3.27 (2 H, m, HC=O), 3.44 (2 H, m, CH2),
4.12 (2 H, m, NCH2), 6.07 (2 H, m, HC=CH), 6.75 (1
H, t, Ar, J 15.8), 6.86 (1 H, d, Ar, J 6.8), 6.94 (1 H, t,
Ar, J 15.7), 7.77 (1 H, d, Ar, J 8.1),9.34 (1 H, s, OH),
1
(–O–); Н NMR: 0.9 (6 H, m, CH3). 1.32 (2 H, m,
CH2), 1.97 (1 H, m, CH), 2.19 (1 H, m, HC=O), 2.38
(1 H, m, HC=O), 2.50 (4 H, m, CH2), 3.21 (4 H, m,
CH2), 3.57 (4 H, m, CH2), 4.78 (1 H, m, NCH), 5.87
13
(2 H, m, HC=CH); C NMR: 20.23, 21.45, 24.54,
39.01, 39.26, 39.67, 40.09, 40.19, 40.30, 40.41, 40.61,
42.12, 45.13, 66.12, 67.12, 128.97, 175.31, 180.14; MS,
m/z: found [M + H]+ 335.196. Calculated for
С18H26N2O4: 335.189.
13
9.81 (1 H, s, NH); C NMR: 25.04, 25.20, 40.18,
40.37, 40.68, 46.79, 54.35, 120.27, 121.46, 124.27,
125.19, 126.28, 143.13, 145.48, 168.49, 180.54, 180.78;
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SYNTHESIS OF AMIDES OF CARBOXYLIC ACIDS
211
MS, m/z: found [M + H]+ 313.119. Calculated for
(2 H, m, CH2 bridge), 2.54 (1 H, m, HC=O), 3.09
(4 H, m, CH2), 3.22 (1 H, m, HC=O), 3.28 (1 H, m,
CH), 3.47 (1 H, m, CH), 4.99 (1 H, m, NCH), 5.21
(2 H, m, HC=CH), 5.5 (1 H, m, HC=CH), 7.12 (2 H,
d, Ar, J = 8.1), 7.22 (1 Н, d, Ar, J 7.0), 7.18 (2 Н, d, Ar,
J 7.6), 7.28 (2 H, d, Ar, J 7.5), 7.41 (2 H, d, Ar, J 8.3),
9.70 (1 H, s, NH); MS, m/z: found [M + H]+ 401.173.
Calculated for С25H24N2O3: 401.187.
2-(1,3-Dioxo-1,3,3a,4,7,7a-hexahydro-2H-isoin-
dol-2-yl)-4-methyl-N-p)-tolyl pentanamide (XXV).
Yield 83%; mp 173–175°С; IR: 3259 (NH); 1772, 1701
(C=O, imide); 1664 (C=C, I amide, С=О); 1603
(Ar); 1545 (II amide, С=О), 815 (1,4-disubstitution
Ar); 1H NMR: 0.81 (6 H, m, CH3). 1.29 (1 H, m, CH),
1.77 (2 H, m, CH2), 2.21 (1 H, m, HC=O), 2.21 (1 H,
m, HC=O), 2.42 (4 H, m, CH2), 3.2 (3 H, m, CH3),
С17H16N2O4: 313.111.
2-(3,5-Dioxo-4-azatricyclo[5,2,1,0]dec-8-en-4-
yl)-N-(2-hydroxyphenyl)-3-methyl butanamide (XXI).
Yield 70%; mp 82–85°С; IR: 3460 (OH); 3389, 3355
(NH); 1766, 1693 (C=O, imide); 1678 (I amide,
1
C=O); 1599 (Ar); 1546 (II amide, С=О); H NMR:
1.43 (2 H, m, CH2), 2.50 (2 H, m, CH2) 3.18 (1 H, m,
HC=O), 3.20 (1 H, m, HC=O), 3.27 (1 H, m, CH),
3.42 (1 H, m, CH), 5.08 (1 H, m, NCH), 5.41 (1 H,
m, HC=CH), 5.59 (1 H, m, HC=CH), 6.76 (1 H, t,
Ar, J 15.4), 6.88 (1 H, d, Ar, J 7.1), 6.97 (1 H, t, Ar, J
15.9), 7.17 (3 H, dd, Ar, J 19.7), 7.29 (2 H, t, Ar, J
14.5), 7.74 (1 H, d, Ar, J 7.7), 8.92 (1 H, s, OH), 9.78
13
(1 H, s, NH); C NMR: 15.05, 20.04, 21.45, 40.28,
40.57, 40.79, 46.79, 48.12, 52.39, 54.36, 120.25,
121.47, 124.28, 125.29, 126.38, 143.33, 145.58, 168.79, 4.66 (1 H, m, NCH), 5.86 (2 H, m, HC=CH), 7.11 (2
180.55, 180.77; MS, m/z: found [M + H]+ 354.133.
Calculated for С20H22N2O4: 354.127.
H, d, J 8.4), 7.38 (2 H, d, J 8.4), 9.61 (1 H, s, NH);
13C NMR: 21.10, 21.24, 23.76, 23.96, 24.07, 25.08,
36.85, 39.05, 39.34, 39.97, 40.18, 40.39, 40.60, 40.81,
53.27, 128.22, 128.29, 129.63, 133.32, 136.61, 167.34;
MS, m/z: found [M + H]+ 355.203. Calculated for
С21H26N2O3: 355.194.
2-(1,3-Dioxo-3а,4-dihydro-1Н-isoindol-2(3Н,7Н,
7аН)-yl)-N-(2-hydroxyphenyl)-4-methyl pentanamide
(XXII). Yield 86%; mp 177–178°С; IR: 3390. 3295
(NH), 1769, 1693 (C=O, imide, “I amide”), 1615
(С=С), 1601 (Ar), 1537 (C=O, “II amide”), 1202 (C–
O), 753 (1,2-disubstitution Ar); 1H NMR: 1.4 (3 H, m,
CH3), 1.6 (3 H, m, CH3), 1.81 (1 H, m, CH), 1.90 (1
H, m, CH), 2.19 (1 H, m, HC=O), 3.21 (1 H, m,
HC=O), 3.45 (4 H, m, CH2), 4.48 (2 H, m CH2), 4.64
(1 H, m, NCH), 6.04 (2 H, m, HC=CH), 6.7 (1 Н, t,
Ar, J 15.3), 6.8 (1 Н, d, Ar, J 8.6), 6.9 (1 Н, t, Ar, J
2-(3,5-Dioxo-4-azatricyclo[5,2,1,0]dec-8-en-4-yl)-
N-cyclohexyl)acetamide (XXVI). Yield 60%; mp 120–
121°С; IR: 3307, 3266 (NH), 1769, 1699 (C=O,
imide); 1658 (I amide, C=O); 1610 (С=С); 1551 (II
1
amide, С=О); H NMR: 1.26–1.11 (6 H, m, CH2),
1.35 (2 H, m, CH2 bridge), 1.71 (1 H, m, HC=O), 1.84
(1 H, m, HC=O), 1.97 (2 H, m, CH2), 2.26 (1 H, m,
16.3), 7.62 (1 H, d, Ar, J 8.2), 8.79 (1 H, s, OH), 9.65 CH), 2.42 (2 H, m, CH2), 3.27 (2 H, m, CH2), 4.75 (2
13
(1 H, s, NH); C NMR: 22.50, 23.25, 24.76, 24.98, H, m, NCH2), 5.84 (2 H, m, HC=CH), 9.32 (1 H, s,
NH); 13C NMR: 24.10, 24.73, 25.76, 31.32, 32.47,
45.85, 45.95, 46.05, 46.34, 52.27, 135.22, 135.29,
167.34, 169.30, 170.34, 175.12, 175.35; MS, m/z: found
[M + H]+ 303.70. Calculated for С17H22N2O3:
303.163.
25.07, 25.09, 36.95, 40.05, 40.40, 40.18, 40.39, 40.60,
40.81, 53.27, 128.22, 128.29, 129.63, 133.32, 136.61,
167.34; MS, m/z: found [M + H]+ 357.183. Calculated
for С20H24N2O4: 357.173.
2-(3,5-Dioxo-4-azatricyclo[5,2,1,0]dec-8-en-4-yl)-
N-(2-hydroxyphenyl)-4-methylpentanamide (XXIII).
2-(3,5-Dioxo-4-azatricyclo[5,2,1,0]dec-8-en-4-
Yield 80%; mp 84–85°С; IR: 3408 (OH); 3148 (NH), yl)-N-cyclohexyl)pentanamide (XXVII). Yield 73%; mp
1773, 1706 (C=O, imide); 1679 (I amide, C=O); 1610 110–111°С; IR: 3327, 3136 (NH), 1769, 1703 (C=O,
(С=С); 1596 (Ar); 1544 (II amide, С=О); 1183 (С– imide); 1664 (I amide, C=O); 1605 (С=С); 1538 (II
1
1
О), 776 (1,2-disubstitution Ar); H NMR: 0.92 (6 H, amide, С=О); H NMR: 1.11 (6 H, m, CH3). 1.37 (2
m, CH3), 1.43 (2 H, m, CH2 bridge), 1.9 (2 H, m,
CH2), 2.4 (1 H, m, HC=O), 2.6 (1 H, m, HC=O),
2.92 (1 H, m, CH), 3.21 (1 H, m, CH), 3.45 (1 H, m,
CH), 4.88 (1 H, m, NCH), 6.05 (2 H, m,
HC=CH),6.7 (1 Н, t, Ar, J 15.3), 6.8 (1 Н, d, Ar, J
8.2), 6.9 (1Н, t, Ar, J 15.3), 7.60 (1 H, d, Ar, J 8.3),
8.80 (1 H, s, OH), 9.75 (1 H, s, NH); MS, m/z: found
[M + H]+ 369.183. Calculated for С21H24N2O4:
369.181.
H, m, CH2 bridge), 1.56 (4 H, m, CH2), 1.82–1.55 (10
H, m, CH2), 2.03 (1 H, m, HC=O), 3.35 (1 H, m,
HC=O), 3.57 (2 H, m, CH), 4.25 (1 H, m, NCH),
6.02 (2 H, m, HC=CH), 7.52 (1 H, d, NH, J 8.1); MS,
m/z: found [M + H]+ 359.270. Calculated for
С21H30N2O3: 359.233.
2-(1,3-Dioxo-3а,4-dihydro-1Н-isoindol-2(3Н,7Н,
7аН)-yl)-N-cyclohexyl)acetamide (XXVIII). Yield
75%; mp 110–114°С; IR: 3287 (NH), 1779, 1708
(C=O, imide); 1658 (I amide, C=O); 1605 (С=С);
2-(3,5-Dioxo-4-azatricyclo[5,2,1,0]dec-8-en-4-
yl)-3-phenyl-N-р-tolyl propanamide (XXIV). Yield 1560 (II amide, С=О); 1H NMR: 1.26–1.11 (5 H, m,
80%; mp 149–151°С; IR: 3296, 3274 (NH); 1766, CH2), 1.57 (2 H, m, CH2), 1.71 (4 H, m, CH2), 3.25 (2
1686 (C=O, imide, I amide); 1648 (C=C), 1601 (Ar);
H, m, HC=O), 3.48 (3 H, m, CH), 3.77 (2 H, m,
1
1541 (II amide, С=О), 1171 (C–O); H NMR: 1.43 CH), 6.04 (2 H, m, HC=CH), 7.83 (1 H, m, CH),
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FIRSTOVA et al.
8.32 (1 H, s, NH); MS, m/z: found [M + H]+ 291.180.
recorded. Then, the mitotic index was calculated, i.e.,
the ratio of the number of cells in mitosis to the total
number of cells in a sample, and statistical processing
of the results was performed [41].
Calculated for С16H22N2O3: 291.171.
2-(3,5-Dioxo-4-azatricyclo[5,2,1,0]dec-8-en-4-
yl)-N-cyclohexyl)methyl butanamide (XXIX). Yield
80%; mp 115–119°С; IR: 3261 (NH), 1773, 1706
(C=O, imide); 1645 (I amide, C=O); 1605 (С=С);
1544 (II amide, С=О); 1H NMR: 0.75 (6 H, m, CH3),
1.35 (2 H, m, CH2 bridge), 1.55 (2 H, m, CH2), 1.82–
1.53 (10 H, m, CH2), 2.02 (1 H, m, HC=O), 3.37
(1 H, m, HC=O), 3.47 (2 H, m, CH),4.27 (1 H, m,
NCH), 6.04 (2 H, m, HC=CH), 7.44 (1 H, d, NH,
J 8.1); MS, m/z: found [M + H]+ 345.220. Calculated
for С20H28N2O3: 345.217.
COMPLIANCE WITH ETHICAL STANDARDS
The authors declare that they have no conflict of
interest. This article does not contain any studies
involving animals or human participants performed by
any of the authors.
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