Synthesis and Analgesic Activity of N,6-Diaryl-4-hydroxy-4-methyl-2-oxocyclohexane-1-carboxamides and Their Dehydration Products

Article abstract of DOI:10.1134/S1070363220090017

Abstract: A series of new N,6-diaryl-4-hydroxy-4-methyl-2-oxocyclohexane-1-carboxamides was obtained through the reaction of N-arylamides of acetoacetic acid with benzalacetone and 4-chlorobenzalacetone under basic conditions (KOH) in methanol at room tem

Full text of DOI:10.1134/S1070363220090017

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 9, pp. 1581–1590. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 9, pp. 1315–1325.
Synthesis and Analgesic Activity of N,6-Diaryl-4-hydroxy-
4-methyl-2-oxocyclohexane-1-carboxamides
and Their Dehydration Products
N. V. Nosovaa, A. A. Sokolova, O. N. Geina, V. L. Geina,*,
A. N. Yankinb, S. E. Danilovс, and M. V. Dmitrievd
a Perm State Pharmaceutical Academy, Perm, 614990 Russia
b National Research University ITMO, St. Petersburg, 197101 Russia
с St. Petersburg State University, St. Petersburg, 199034 Russia
d Perm State National Research University, Perm, 614990 Russia
*e-mail: geinvl48@mail.ru
Received April 23, 2020; revised April 23, 2020; accepted April 30, 2020
Abstract—A series of new N,6-diaryl-4-hydroxy-4-methyl-2-oxocyclohexane-1-carboxamides was obtained
through the reaction of N-arylamides of acetoacetic acid with benzalacetone and 4-chlorobenzalacetone under
basic conditions (KOH) in methanol at room temperature. Increasing of the amount of potassium hydroxide
used in the reaction led to the formation of dehydration products, namely N,6-diaryl-4-methyl-2-oxocyclohex-
3-ene-1-carboxamides. The latter were also formed by using unsubstituted acetoacetamide and N-methylace-
toacetamide. The synthesized compounds were tested for analgesic activity.
Keywords: acetoacetic acid N-arylamides, benzalacetone, 4-chlorobenzalacetone, N,6-diaryl-4-hydroxy-
4-methyl-2-oxocyclohexane-1-carboxamides, analgesic activity
DOI: 10.1134/S1070363220090017
The synthesis of cyclohexanones attracts the attention
of researchers both in theoretical and practical aspects.
This is due to the fact that the cyclohexanone fragment
is the main structural unit of a number of widely used
natural and synthetic drugs [1, 2]. The best-known
representative of this class is camphor (Scheme 1),
a structural terpenoid found in camphor laurel oil
(Cinnamomum camphora) and used as an analeptic drug
[3]. Functionalized cyclohexanone derivatives are used
as fluorescent agents [4] and have anthelmintic [5], anti-
inflammatory [6], antibacterial [7–9], anticonvulsant [10],
antitumor [11, 12], antiviral [13] and herbicidal activity
[14]. Some of them are phosphodiesterase inhibitors
and can be used as anti-inflammatory agents for the
treatment of chronic obstructive pulmonary disease [15,
16]. There are a number of well-known drugs containing
a cyclohexanone fragment in their structure (Scheme
1). For example, ketamine and methoxetamine are non-
inhalation anesthetics that exhibit analgesic activity [17,
18], while naloxone and naltrexone are opioid receptor
antagonists [19, 20]. Tetracycline is a broad-spectrum
antibiotic [21], and cyclovalon is a synthetic choleretic
drug, which in addition to the main effect (bile formation)
also has an anti-inflammatory effect [22].
Earlier, we have obtained derivatives of 2-acetyl-4-
hydroxy-5-methyl-3-phenyl-1-cyclohexanone and alkyl
4-hydroxy-4-methyl-2-oxo-6-phenylcyclohexane-1-
carboxylates [23] through the reaction of benzalacetone
withacetylacetoneandacetoaceticacidesters, respectively,
under basic catalysis. In addition, their reactions with
N-nucleophilic reagents have been performed [24] and
antimicrobial action against St. aureus and E. coli have
been studied [23].
Continuing research in the field of the chemistry
of cyclohexanones [23–26] and aiming to obtain new
potentially biologically active compounds, we for the first
time carried out the synthesis of N,6-diaryl-4-hydroxy-
4-methyl-2-oxocyclohexane-1-carboxamides 3а–3k by
reacting benzalacetone 2а and 4-chlorobenzalacetone
2b with acetoacetic acid arylamides 1 in ethanol at room
temperature in the presence of potassium hydroxide as
the catalyst (Scheme 2).
1581

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NOSOVA et al.
Scheme 1.
Scheme 2.
Compounds 3а–3k contain a hydroxyl group at
dehydration, 3-cyclohexene-1-carboxamides 4c and 4d,
position 4 of the alicycle. Under similar conditions, N,6-
diaryl-4-methyl-2-oxo-3-cyclohexene-1-carboxamides
4а and 4b were obtained when increasing the
concentration of potassium hydroxide to 20 mol %.
In the case of unsubstituted acetoacetic acid amide
5а and N-methylacetoacetamide 5b, regardless of the
concentration of potassium hydroxide, the products of
were obtained (Scheme 3).
When N,N-dimethyl- and N,N-diethylacetoacetamides
were used, the reaction products were not isolated due to
resinification of the reaction mixture.
The obtained cyclohexanones 3а–3k are colorless
crystalline substances, soluble in DMSO and DMF, with
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Scheme 3.
heating in ethanol, isopropanol, and acetone, insoluble in
ethyl acetate, diethyl ether and water.
H3∙∙∙O2 [1 – x, 1 – y, 2 – z], due to which the molecules
in the crystal are bound into centrosymmetric dimers.
The IR spectra of compounds 4b and 4c contain
strong absorption bands of the amide carbonyl group
(1660–1688 cm–1), the ketone (1704–1712 cm–1), and
NH groups (3302–3408 cm–1). In the 1Н NMR spectra of
compounds 4а–4d, in addition to the signals of aromatic
protons (6.80–7.48 ppm), there is a singlet of methyl
group protons at the C4 atom of the ring (1.95–2.01 ppm),
a doublet and a doublet of doublets of two protons at the
С5 atom in the form of an AB system (2.42–2.68 ppm,
J = 8.0–12.0 Hz), a doublet of triplets of the C6H moiety
(3.58–3.70 ppm, J = 8.0–12.0 Hz), a doublet of the C1H
group (3.51–3.82 ppm, J = 12.0 Hz), a singlet of the =CH
group (5.81–5.98 ppm) and a singlet of the NH protons
of the amide residue (6.75–10.04 ppm). The 13C NMR
spectra of compounds 4а–4d contain signals from the
carbonyl groups of the alicycle (194.66–194.99 ppm),
the amide (167.39–168.75 ppm), and methyl groups at
the C4 atom of the alicycle (23.52–23.72 ppm).
The IR spectra of compounds 3а–3k contain strong
absorption bands of the amide carbonyl group (1660–
688 cm–1), ketone group (1704–1712 cm–1), NH (3302–
3408 cm–1), and hydroxyl groups (3432–3538 cm–1). In
the 1H NMR spectra of compounds 3а–3k, in addition to
the signals of aromatic protons (6.80–7.93 ppm), there is
a singlet of methyl group protons at the C4 atom of the
ring (1.23–1.28 ppm), a doublet of doublets and a triplet
of two protons at the С5 atom in the form of anAB system
(1.83–2.12 ppm, J = 11.13–14.7 Hz), two doublets of
protons at the C3 atom (2.33–2.71 ppm, J = 13.0–14.8 Hz),
a doublet of triplet of the С6H proton (3.54–3.80 ppm,
J = 11.1–14.7 Hz), a doublet of the C1H proton (3.60–
4.15 ppm, J = 12.0–12.1 Hz), singlets of the OH (4.72–
4.85 ppm) and NH groups (8.79–9.92 ppm). The 13C
NMR spectra of compounds 3а–3k contain signals from
the carbonyl groups of the alicycle (205.35–206.02 ppm),
the amide (166.48–167.18 ppm), and methyl groups at
the C4 atom of the alicycle (30.20–30.33 ppm).
To establish the spatial structure of compounds
4а–4d, an X-ray diffraction analysis of a single crystal of
compound 4d was performed. The independent part of the
The mass spectrum of compound 3e contains a
molecular ion peak with m/z 353 [M]+, as well as
peaks of fragment ions with m/z 335 [M – H2O]+,
203 [M – CONHC6H4OCH3]+, and 185 [M – H2O –
CONHC6H4OCH3]+, confirming the proposed structure.
To establish the spatial structure, including the relative
configuration of chiral centers, an X-ray diffraction
study of a single crystal of compound 3e was performed.
According to X-ray diffraction data (Fig. 1), the studied
crystal consists of molecules of one pair of enantiomers
with the configuration S*, R*, and S* for C1, C4, and
C5 atoms, respectively. The cyclohexanone ring adopts
the chair conformation. The phenyl and arylcarbamoyl
substituents lie in equatorial positions in a trans position
relative to each other. The hydroxyl group located in the
axial position forms intermolecular hydrogen bonds O3–
Fig. 1. General view of the molecule of compound 3e in the
crystal.
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NOSOVA et al.
Scheme 4.
unit cell contains two crystallographically independent
molecules with similar geometry, which are enantiomers
with the S* and R* configurations of the C2 and C3 atoms.
Fig. 2 shows one of the molecules. The cyclohexenone
ring of both independent molecules takes on a half-chair
conformation. The C4, C5, C6, and C1 atoms or the C4A,
C5A, C6A, and C1A atoms for the second independent
molecule lie in the same plane. The C2 and C3 atoms are
deflected on opposite sides of the plane of the other four
atoms of the ring by 0.34 and –0.38 Å, the C2 and C3
atoms are deflected by 0.33 and –0.38 Å, respectively. The
phenyl and methylcarbamoyl substituents are expected
to be in more favorable equatorial positions in the trans
position relative to each other. In a crystal, independent
molecules of enantiomers, alternating with each other, are
linked into infinite chains along the a direction of the unit
cell due to intermolecular hydrogen bonds N1A–H1A∙∙∙O2
and N1–H1∙∙∙O2A [–1 + x, y, z].
does not contradict early studies [27, 28]. Based on the
data of IR, 1H NMR spectroscopy, a qualitative reaction
with an alcoholic solution of iron(III) chloride, as well as
X-ray diffraction data, it can be concluded that N,6-diaryl-
4-hydroxy-4-methyl-2-oxocyclohexane-1-carboxamides
3a–3k in the crystalline state and in solution exist mainly
in the ketone form 3A.
A plausible mechanism for the formation of
N,6-diaryl-4-hydroxy-4-methyl-2-oxocyclohexane-
1carboxamides 3а–3k is shown in Scheme 5. Initially,
the Michael addition of enolized acetoacetamide 1A
to the unsaturated benzalacetone molecule 2 with the
formation of intermediate A takes place. In the basic
medium, enol B is formed, followed by intramolecular
aldol condensation and the formation of a six-membered
ring of cyclohexanone derivatives 3a–3k. In the case
of a potassium hydroxide concentration of 20 mol %,
dehydration occurs with the participation of the proton
at the C3 atom and the formation of compounds 4а–4d.
In solution, the obtained compounds 3a–3k can
exist in ketone (3A) and enol (3B) forms due to proton
migration between the C1 atom of the cyclohexane ring
and the carbonyl oxygen atom at the C2 atom of the ring
(Scheme 4). The presence of two isomeric forms 3A and
3B with a predominance of the ketone form in the solution
The acute toxicity and analgesic activity of compounds
3e and 3f was investigated. The results are presented in
Tables 1, 2. Studies have shown that compounds 3e and 3f
can be attributed to the fourth hazard class (low toxicity)
according to the classification of K.K. Sidorov [30], since
the LD50 value of these compounds is in doses greater
than 2000 mg/kg when administered intraperitoneally.
As you can see from Table 1, compounds 3e and 3f
exhibit analgesic activity at a dose of 50 mg/kg when
administered intraperitoneally in the hot plate test. The
investigated compounds increased the duration of the stay
of the animals on the heated surface before the onset of
the defensive reaction compared to the control. However,
the increase in the duration of the latent period with the
introduction of these compounds is less pronounced in
comparison with the reference drug, metamizole sodium,
which was injected intraperitoneally at the same dose.
Fig. 2. General view of the molecule of compound 4d in the
crystal.
Compounds 3e and 3f also exhibit analgesic activity
in the acetic acid-induced writhing test (Table 2). It
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Table 1. Acute toxicity and analgesic activity of cyclohexaneone derivatives 3e and 3f in the hot plate testa
Compound
Control
Metamizole sodium
LD50, mg/kg
–
2900b (2160–3340)
> 2000 (n = 8)
>2000 (n = 8)
Latent period, sec
11.52 ± 0.92 (n = 9)
17.79 ± 1.86 (n = 6)
16.35 ± 1.23 (n = 9)
16.97 ± 1.18 (n = 9)
р compared to control
–
< 0.05
< 0.05
< 0.01
3e
3f
a The results are presented as mean and its standard error (M ± m); (n) number of animals.
b Literature data [29].
Table 2. Analgesic activity of cyclohexaneone derivatives 3e and 3f in the acetic acid-induced writhing test
Decrease in writhing compared
Compound
Control
Number of cramps
р compared to control
to control, %
–
28.55 ± 2.4 5
(n = 11)
–
Metamizole sodium
16.38 ± 3.13
(n = 8)
14.50 ± 4.31
(n = 9)
0.50 ± 0.22
(n = 10)
42.63
49.21
98.25
< 0.02
< 0.05
< 0.001
3e
3f
a The results are presented as mean and its standard error (M ± m); (n) number of animals.
was found that when the animals were administered
compounds 3e and 3f, the number of writhing decreased
compared to the control group. The most pronounced
decrease in the number of writhing was observed in the
group of animals that were administered compound 3f:
the decrease in writhing was more than 90% compared
to the control. The effect of reducing writhing against
when using compound 3f was also more pronounced in
comparison with the reference drug, metamizole sodium
(p <0.001).
In conclusion, the reaction of N-arylacetoacetamides
with benzalacetone and 4-chlorobenzalacetone under
basic catalysis conditions furnished new cyclohexanone
derivatives, among which substances exhibiting
pronounced analgesic activity were found. It was shown
that with a two-fold increase in the concentration of the
Scheme 5.
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NOSOVA et al.
basic catalyst, as well as in the case of unsubstituted
acetoacetamide and N-methylacetoacetamide, 2-oxo-
3-cyclohexene-1-carboxamides are formed under
similar conditions due to dehydration of the obtained
cyclohexanones.
0.9 Hz), 7.34–7.25 m (4Н, Н-Ar), 7.22 d. d (2Н, H-Ar, J =
10.8, 5.1 Hz), 7.18–7.13 m (1Н, Н-Ar), 6.98 t (1Н, Н-Ar, J =
7.4 Hz), 4.82 s (1Н, ОН), 3.87–3.77 m (2Н, C6H, C1H),
2.69 d (1Н, C3HAHB, J = 13.6 Hz), 2.36 d. d (1Н, C3HAHB,
J = 13.7, 2.3 Hz), 2.09 d. d (1Н, C5HAHB, J = 18.1, 7.2 Hz),
1.85 d. d (1Н, C5HAHB, J = 9.4, 6.8 Hz), 1.28 s (3Н, Me).
13C NMR spectrum, δС, ppm: 206.0 (CO), 166.7 (CON),
143.5, 139.0, 128.5, 128.3, 127.2, 126.3, 123.0, 118.9,
71.7, 62.4, 53.4, 45.6, 41.0, 30.3 (C4Me). Found, %: C
74.53; H 6.58; N 4.09. C20H21NO3. Calculated, %: C
74.28; H 6.55; N 4.33.
EXPERIMENTAL
IR spectra were obtained on a Shimadzu IRAffinity-1
instrument in the range of 4000–400 cm–1 from KBr
1
pellets. H and 13C NMR spectra were recorded on a
Bruker AVANCE 400SX instrument with an operating
frequency of 400 and 100 MHz, respectively, using
DMSO-d6 as the solvent. Mass spectrum of compound 3e
was recorded on a Finnigan MAT INCOS-50 instrument
(70 eV). High resolution mass spectra were recorded on a
Bruker maXis instrument with ESI ionization. Elemental
analysis was performed on an elemental analyzer Euro
EA3028-NT for the simultaneous determination of C, H,
N. Melting points were determined on a Melting Point
M-565 instrument.
Compounds 3b–3k were prepared similarly.
4-Hydroxy-4-methyl-2-oxo-6-phenyl-N-(o-tolyl)-
cyclohexanecarboxamide (3b). Yield 51%, mp 200–
202°С. IR spectrum, ν, cm–1: 3512 (OH), 3304 (NH),
1712 (СО), 1660 (CONHAr). 1Н NMR spectrum, δ, ppm:
9.06 s (1Н, NH), 7.36–7.28 m (4Н, H-Ar), 7.22–7.17 m (1Н,
Н-Ar), 7.12–6.97 m (4Н, H-Ar), 4.77 s (1Н, ОН), 3.89 d. d
(1Н, C1H, J = 12.6, 5.3 Hz), 3.80 t. d (1Н, C6H, J = 12.3,
3.8 Hz), 2.68 d (1Н, C3HAHB, J = 13.8 Hz), 2.37 d. d (1Н,
C3HAHB, J = 13.9, 2.3 Hz), 2.09 d. d (1Н, C5HAHB, J = 25.2,
12.4 Hz), 1.91–1.85 m (1Н, C5HAHB), 1.88 s (3H, Me), 1.28 s
(3Н, Me). 13C NMR spectrum, δС, ppm: 205.9 (CO),
166.7 (CON), 143.4, 136.1, 131.9, 130.0, 128.2, 127.5,
127.4, 126.3, 125.6, 125.2, 125.1, 71.6, 61.9, 53.5, 40.2,
30.3 (C4Me), 17.39 (Me). Mass spectrum (ESI), m/z:
360.2570 [M + Na]+ (calcd. for C21H23NO3Na: 360.1579).
Single crystal X-ray diffraction analysis was performed
on an Xcalibur Ruby diffractometer with a CCD detector
according to the standard method [MoKα radiation,
295(2) K, ω-scanning with a step of 1°]. Absorption
was taken into account empirically using the SCALE3
ABSPACK algorithm [31]. Structures were solved using
the SHELXS program [32] and refined by full-matrix least
squares in F2 in the anisotropic approximation for all non-
hydrogen atoms using the SHELXLprogram [33] with the
OLEX2 graphical interface [34]. Hydrogen atoms were
included into the refinement in the rider model (except
for the hydrogen atoms of the OH and NH groups, refined
independently in the isotropic approximation). The
X-ray diffraction data were deposited at the Cambridge
Crystallographic Data Center [CCDC 1994223 (3e) and
1994224 (4e)].
N-(4-Chlorophenyl)-4-hydroxy-4-methyl-2-oxo-
6-phenylcyclohexanecarboxamide (3c). Yield 89%,
mp 175–176°С. IR spectrum, ν, cm–1: 3488 (OH), 3304
(NH), 1712 (СО), 1688 (CONHAr). 1Н NMR spectrum, δ,
ppm: 9.84 s (1Н, NH), 7.48–7.43 m (2Н, H-Ar), 7.36–7.33 m
(2Н, Н-Ar), 7.31–7.26 m (4Н, Н-Ar), 7.21–7.16 m (1Н,
H-Ar), 4.78 s (1Н, ОН), 3.73–3.65 m (2Н, C6H, C1H), 2.70 d
(1Н, C3HAHB,J = 13.7 Hz), 2.36 d. d (1Н, C3HAHB,J = 13.7,
2.1 Hz), 2.09 d. d (1Н, C5HAHB,J = 14.8, 10.3 Hz), 1.89–1.82
m (1Н, C5HAHB), 1.27 s (3Н, Me). Mass spectrum (ESI),
m/z: 380.1024 [M + Na]+ (calcd. for C20H20ClNO3Na:
380.1029).
4-Hydroxy-4-methyl-2-oxo-N,6-diphenylcyclo-
hexanecarboxamide (3a). To a solution of 0.020 mol of
acetoacetanilide 1in 10 mLof ethanol was added 10 mol %
of potassium hydroxide. The resulting mixture was
stirred for 5 min, then 0.025 mol of benzalacetone 2 was
added. The resulting mixture was stirred until the reagents
were completely dissolved and kept for 1–2 days until
a precipitate was formed. The resulting precipitate was
filtered off and recrystallized from ethanol. Yield 47%,
mp 184–186°С. IR spectrum, ν, cm–1: 3520 (OH), 3328
(NH), 1712 (СО), 1660 (CONHAr). 1Н NMR spectrum,
δ, ppm: 9.75 s (1Н, NH), 7.44 d. d (2Н, H-Ar, J = 8.5,
4-Hydroxy-4-methyl-N-(2,4-dimethylphenyl)-2-
oxo-6-phenylcyclohexanecarboxamide (3d). Yield
54%, mp 203–205°С. IR spectrum, ν, cm–1: 3430 (OH),
1
3397 (NH), 1704 (СО), 1680 (CONHAr). Н NMR
spectrum, δ, ppm: 9.03 s (1Н, NH), 7.35–7.28 m (4Н, H-Ar),
7.22–7.17 m (1Н, Н-Ar), 6.96–6.84 (3Н, H-Ar), 4.81 s (1Н,
ОН), 3.86 d (1Н, C1H, J = 12.3 Hz), 3.80 t. d (1Н, C6H, J =
12.1, 3.6 Hz), 2.67 d (1Н, C3HAHB, J = 13.8 Hz), 2.36 d. d
(1Н, C3HAHB, J = 13.8, 2.2 Hz), 2.19 s (3Н, Ме), 2.08 t (1Н,
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C5HAHB, J = 12.8 Hz), 1.90–1.84 m (1Н, C5HAHB), 1.81 s
(3H, Me), 1.28 s (3Н, Me). 13C NMR spectrum, δС, ppm:
206.5 (CO), 167.1 (CON), 143.9, 134.6, 134.0, 132.4,
128.7, 127.9, 126.7, 126.6, 125.8, 72.2, 62.4, 53.9, 46.0,
30.8 (C4Me), 20.9 (Ме), 17.39 (Me). Mass spectrum
(ESI), m/z: 380.1735 [M + Na]+ (calcd. for C22H25NO3Na:
374.1727).
143.8, 135.2, 129.8, 128.8, 127.8, 127.6, 126.8, 126.1,
125.6, 125.5, 72.2, 62.2, 53.9, 46.3, 41.7, 30.8 (C4Me).
Mass spectrum (ESI), m/z: 358.1159 [M + H]+ (calcd. for
C20H21ClNO3: 358.1204).
6-(4-Chlorophenyl)-4-hydroxy-4-methyl-2-oxo-
N-phenylcyclohexanecarboxamide (3g). Yield 52%,
mp 218–220°С. IR spectrum, ν, cm–1: 3526 (OH), 3315
(NH), 1716 (СО), 1671 (CONHAr). 1Н NMR spectrum,
δ, ppm: 9.90 s (1Н, NH), 7.44 d (2Н, H-Ar, J = 7.6 Hz),
7.40–7.33 m (4Н, H-Ar), 7.26–7.20 m (2Н, H-Ar),
7.00 q. d (1Н, H-Ar, J=2.3, 1.1Hz), 4.80 s (1Н, ОН), 3.79 d
(1Н, C1H, J = 12.7 Hz), 3.76–3.67 m (1Н, C6H), 2.69 d
(1Н, C3HAHB, J = 13.8 Hz), 2.37 d (1Н, C3HAHB, J =
13.7, 2.3 Hz), 2.10 t (1Н, C5HAHB, J = 13.2 Hz), 1.88–
1.82m(1Н,C5HAHB),1.28s(3Н,Me). Massspectrum(ESI),
m/z: 380.1037 [M + Na]+ (calcd. for C20H20ClNO3Na:
380.1024).
4-Hydroxy-4-methyl-N-(2-methoxyphenyl)-2-oxo-
6-phenylcyclohexanecarboxamide (3e). Yield 78%, mp
186–188°С. IR spectrum, ν, cm–1: 3450 (OH), 3409 (NH),
1705 (СО), 1679 (CONHAr). 1Н NMR spectrum, δ, ppm:
8.92 s (1Н, NH), 7.93 d (1Н, H-Ar, J = 12.3 Hz), 7.33–7.25 m
(4Н, H-Ar), 7.18–7.13 m (1Н, Н-Ar), 7.01–6.94 m (2Н,
H-Ar), 6.80 d. d. d (1Н, H-Ar, J = 8.6, 6.3, 2.5 Hz), 4.81 s
(1Н, ОН), 4.20 d (1Н, C1H, J = 12.2 Hz), 3.81–3.73 m (1Н,
C6H), 3.78 s (3Н, ОМе), 2.62 d (1Н, C3HAHB, J = 13.5 Hz),
2.34 d. d (1Н, C3HAHB, J = 13.6, 2.1 Hz), 2.19 s (3Н, Ме),
1.99t(1Н, C5HAHB,J=13.2Hz), 1.89–1.83m(1Н, C5HAHB),
1.27 s (3Н, Me). 13C NMR spectrum, δС, ppm: 206.6
(CO), 167.5 (CON), 148.9, 144.1, 128.7, 127.8, 126.7,
124.1, 121.0, 120.6, 111.5, 72.1, 62.5, 56.1, 54.0, 46.4
(OMe), 41.6, 30.8 (C4Me). Mass spectrum, m/z (Irel, %):
335 (56) [М – H2O]+, 203 (24) [M – CONHC6H4OCH3]+,
185 (36) [М – H2O – CONHC6H4OCH3]+. Mass spectrum
(ESI), m/z: 376.1531 [M+Na]+ (calcd. for C21H23NO4Na:
376.1519).
N-(2-Chlorophenyl)-6-(4-chlorophenyl)-4-
hydroxy-4-methyl-2-oxocyclohexanecarboxamide
(3h). Yield 63%, mp 203–205°С. IR spectrum, ν, cm–1:
3512 (OH), 3317 (NH), 1705 (СО), 1668 (CONHAr). 1Н
NMR spectrum, δ, ppm: 9.25 s (1Н, NH), 7.60 d (1Н, H-Ar,
J = 7.3 Hz), 7.40 d. d (1Н, H-Ar, J = 8.0, 1.4 Hz), 7.38–7.32 m
(4Н, H-Ar), 7.27–7.21 m (1Н, Н-Ar), 7.13–7.08 m (1Н,
H-Ar), 4.81 s (1Н, ОН), 4.07 d (1Н, C1H, J = 12.3 Hz),
3.78 t. d (1Н, C6H, J = 12.6, 3.9 Hz), 2.66 d (1Н, C3HAHB,
J = 13.7 Hz), 2.37 d. d (1Н, C3HAHB, J = 13.7, 2.3 Hz),
2.06 t (1Н, C5HAHB, J = 13.2 Hz), 1.90–1.83 m (1Н,
C5HAHB), 1.28 s (3Н, Me). 13C NMR spectrum, δС, ppm:
205.4 (CO), 167.2 (CON), 142.3, 134.7, 130.9, 129.3,
129.2, 128.2, 127.2, 125.8, 125.3, 125.2, 71.6, 61.7, 53.4,
40.7, 40.0, 30.3 (C4Me). Found, %: C 67.45; H 4.72; N
3.78. C20H19Cl2NO3. Calculated, %: C 67.37; H 4.86;
N 3.58.
Crystals of compound 3e are triclinic, space group P-1,
C21H23NO4, M 353.40, a = 5.6959(19), b = 12.519(2),
c = 13.128(4) Å, α = 89.692(20)°, β = 79.57(3)°, γ =
81.71(2)°, V = 910.8(4) Å3, Z = 2, dcalc = 1.289 g/cm3,
μ = 0.089 mm–1. The crystal was refined using a data file
with the reflection intensities of the HKLF 5 format as a
twin with two components. Final refinement parameters
are: R1 = 0.1223 [for 2688 reflections with I > 2σ(I)], wR2 =
0.3172 (for all 5601 independent reflections), S = 1.034,
ratio of twinning components is 0.605(3) : 0.395(3).
N,6-Di-(4-chlorophenyl)-4-hydroxy-4-methyl-
2-oxocyclohexanecarboxamide (3i). Yield 42%, mp
220–224°С. IR spectrum, ν, cm–1: 3523 (OH), 3302 (NH),
1709 (СО), 1665 (CONHAr). 1Н NMR spectrum, δ, ppm:
9.90 s (1Н, NH), 7.47 d (2Н, H-Ar, J = 8.9 Hz), 7.37–7.32 m
(4H, H-Ar), 7.28 d. d (2Н, H-Ar, J = 9.4, 2.4 Hz), 4.85 s (1Н,
ОН), 3.87–3.78 m (1Н, C6H), 3.76 d (1Н, C1H, J = 12.2 Hz),
2.71 d (1Н, C3HAHB, J = 13.6 Hz), 2.36 d. d (1Н, C3HAHB,
J = 13.6, 1.9 Hz), 2.12 t (1Н, C5HAHB, J = 12.8 Hz), 1.87–
1.80 m (1Н, C5HAHB), 1.27 s (3Н, Me). 13C NMR spec-
trum, δС, ppm: 205.6 (CO), 166.8 (CON), 142.4, 137.7,
130.9, 129.2, 128.5, 128.3, 126.7, 120.5, 71.7, 62.4, 53.4,
45.6, 40.5, 30.2 (C4Me). Found, %: C 67.54; H 4.98; N
N-(2-Chlorophenyl)-4-hydroxy-4-methyl-2-oxo-6-
phenylcyclohexanecarboxamide (3f). Yield 69%, mp
192–194°С. IR spectrum, ν, cm–1: 3487 (OH), 3379 (NH),
1711 (СО), 1665 (CONHAr). 1Н NMR spectrum, δ, ppm:
9.28 s (1Н, NH), 7.60 d (1Н, H-Ar, J = 7.3 Hz), 7.39 d. d (1Н,
H-Ar, J = 8.0, 1.4 Hz), 7.35–7.27 m (4Н, H-Ar), 7.26–7.15 m
(2Н, Н-Ar), 7.09 t. d (1Н, H-Ar, J = 7.8, 1.5 Hz), 4.83 s (1Н,
ОН), 4.13 d (1Н, C1H, J = 12.3 Hz), 3.78 t. d (1Н, C6H,
J = 12.6, 3.9 Hz), 2.66 d (1Н, C3HAHB, J = 13.6 Hz),
2.36d. d(1Н, C3HAHB,J=13.6, 2.2Hz), 2.04t(1Н, C5HAHB,
J = 13.2 Hz), 1.90–1.83 m (1Н, C5HAHB), 1.28 s (3Н, Me).
13C NMR spectrum, δС, ppm: 206.3 (CO), 167.8 (CON),
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1588
NOSOVA et al.
3.74. C20H19Cl2NO3. Calculated, %: C 67.37; H 4.86;
N 3.58.
(1Н, C3HAHB, J = 18.6, 11.5 Hz), 2.36 d. d. d (1Н, C3HAHB,
J = 8.8, 8.2, 4.7 Hz), 2.01 s (3Н, Me). 13C NMR spectrum,
δС, ppm: 194.9 (CO), 167.4 (CON), 163.2, 142.2, 138.8,
128.6, 128.3, 127.3, 126.7, 124.9, 123.2, 119.0, 59.3, 42.8,
38.5, 23.7 (C4Me). Mass spectrum (ESI), m/z: 328.1320
[M + Na]+ (calcd. for C20H19NO2Na: 328.1308).
6-(4-Chlorophenyl)-4-hydroxy-N-(2-methoxy-
phenyl)-4-methyl-2-oxocyclohexanecarboxamide
(3j). Yield 49%, mp 180–182°С. IR spectrum, ν, cm–1:
3530 (OH), 3331 (NH), 1712 (СО), 1662 (CONHAr).
1Н NMR spectrum, δ, ppm: 8.89 s (1Н, NH), 7.92 d (1Н,
H-Ar, J = 7.5 Hz), 7.42–7.30 m (4H, H-Ar), 7.02–6.94 m (2Н,
H-Ar), 6.81 d. d. d (1Н, H-Ar, J = 14.6, 8.5, 5.0 Hz), 4.77 s
(1Н, ОН), 4.15 d (1Н, C1H, J = 12.2 Hz), 3.82–3.74 m (1Н,
C6H), 3.78 s (3H, OMe), 2.62 d (1Н, C3HAHB, J = 13.6 Hz),
2.35 d. d (1Н, C3HAHB, J = 13.6, 2.3 Hz), 2.01 d. d (1Н,
C5HAHB, J = 15.3, 11.0 Hz), 1.88–1.82 m (1Н, C5HAHB),
1.27 s (3Н, Me). 13C NMR spectrum, δС, ppm: 205.6
(CO), 166.8 (CON), 148.6, 142.6, 130.8, 129.4, 129.2,
128.2, 127.4, 123.8, 120.7, 120.2, 111.1, 71.6, 62.0, 55.7,
53.5 (OMe), 40.7, 30.3 (C4Me). Found, %: C 65.32; H
5.81; N 3.50. C21H22ClNO4. Calculated, %: C 65.10; H
5.68; N 3.62.
N-(4-Chlorophenyl)-4-methyl-2-oxo-6-phenyl-3-
cyclohexenecarboxamide (4b) was prepared similarly.
Yield 58%, mp 168–170°С. IR spectrum (mineral oil),
1
ν, cm–1: 3314 (NH), 1673 (СО), 1664 (CONHAr). Н
NMR spectrum, δ, ppm: 10.04 s (1Н, NH), 7.48–7.45 m
(2Н, H-Ar), 7.37–7.33 m (2H, H-Ar), 7.31–7.36 m (4Н,
H-Ar), 7.21–7.16 m (1H, H-Ar), 5.98 s (1Н, =С3Н), 3.80 d
(1Н, C1H, J = 12.8 Hz), 3.74–3.66 m (1Н, C6H), 2.68 d. d
(1Н, C3HAHB, J = 17.2, 11.7 Hz), 2.52 d. d. d (1Н, C3HAHB,
J = 8.8, 5.9, 3.5 Hz), 2.01 s (3Н, Me). 13C NMR spectrum,
δС, ppm: 194.7 (CO), 167.6 (CON), 163.3, 142.1, 137.7,
128.5, 128.3, 127.8, 126.7, 124.8, 120.6, 59.5, 42.8,
38.5, 23.7 (C4Me). Found, %: C 70.51; H 5.38; N 4.34.
C20H18ClNO2. Calculated, %: C 70.69; H 5.30; N 4.12.
6-(4-Chlorophenyl)-4-hydroxy-4-methyl-N-(2,4-
dimethylphenyl)-2-oxocyclohexanecarboxamide (3k).
Yield 57%, mp 220–222°С. IR spectrum, ν, cm–1: 3538
(OH), 3368 (NH), 1708 (СО), 1680 (CONHAr). 1Н NMR
spectrum, δ, ppm: 9.01 s (1Н, NH), 7.41–7.32 m (4H, H-Ar),
6.97–6.85 m (3Н, H-Ar), 4.78 s (1Н, ОН), 3.85–3.73 m (2Н,
C1H, C6H), 2.66 d (1Н, C3HAHB, J = 13.8 Hz), 2.36 d. d
(1Н, C3HAHB, J = 13.9, 2.2 Hz), 2.18 s (3Н, OMe), 2.13–
2.04 m (1Н, C5HAHB), 1.88–1.83 m (1Н, C5HAHB), 1.84 s
(3Н, OMe), 1.28 s (3Н, Me). 13C NMR spectrum, δС, ppm:
205.5 (CO), 166.5 (CON), 142.5, 134.2, 133.5, 131.9,
130.8, 130.6, 129.3, 128.1, 126.2, 125.3, 71.6, 61.8, 53.4,
44.8, 40.2, 30.3 (C4Me), 20.4 (Me), 17.3 (Me). Found,
%: C 68.27; H 6.41; N 3.48. C22H24ClNO3. Calculated,
%: C 68.55; H 6.23; N 3.64.
4-Methyl-2-oxo-6-phenyl-3-cyclohexene-
carboxamide (4c). To a solution of 0.020 mol of
acetoacetanilide 1 in 10 mL of ethanol was added 10 or
20 mol % of potassium hydroxide. The resulting mixture
was stirred for 5 min, then 0.025 mol of benzalacetone
2 was added. The mixture was stirred until the reagents
were completely dissolved and kept for 1–2 days until
a precipitate was formed. The precipitate was filtered
off and recrystallized from ethanol. Yield 26%, mp
116–118°С. IR spectrum (mineral oil), ν, cm–1: 3429
1
(NH), 1662 (СО), 1610 (CON). Н NMR spectrum, δ,
ppm: 7.35–7.27 m (5H, H-Ar, NHAHB), 7.24–7.19 m (1H,
H-Ar), 6.80 s (1H, H-Ar, NHAHB), 5.91 s (1Н, =С3Н), 3.61–
3.50 m (2Н, C1H, C6H), 2.61–2.53 m (1Н, C3HAHB),
2.49–2.42 m (1Н, C3HAHB), 1.97 s (3Н, Me). 13C NMR
spectrum, δС, ppm: 195.5 (CO), 170.8 (CON), 163.0,
143.0, 128.7, 127.9, 127.0, 125.5, 58.6, 43.3, 24.1
(C4Me). Mass spectrum (ESI), m/z: 252.0995 [M + Na]+
(calcd. for C14H15NO2Na: 252.1004).
4-Methyl-2-oxo-N,6-diphenyl-3-cyclohexene-
carboxamide (4a). To a solution of 0.020 mol of
acetoacetanilide 1 in 10 mL of ethanol was added 20
mol % of potassium hydroxide. The resulting mixture
was stirred for 5 min, then 0.025 mol of benzalacetone
2 was added. The mixture was stirred until the reagents
were completely dissolved and kept for 1–2 days until
a precipitate was formed. The precipitate was filtered
off and recrystallized from ethanol. Yield 62%, mp
206–208°С. 1Н NMR spectrum, δ, ppm: 9.83 s (1Н, NH),
7.44 d. d (2Н, H-Ar, J = 8.5, 1.0 Hz), 7.38–7.34 m (2H, H-Ar),
7.29 t (2Н, H-Ar, J = 7.6 Hz), 7.25–7.16 m (3H, H-Ar),
6.99 d. d (1Н, H-Ar, J = 10.6, 4.2 Hz), 5.99 s (1Н, =С3Н), 3.83
d (1Н, C1H, J = 12.9 Hz), 3.76–3.65 m (1Н, C6H), 2.67 d. d
N,4-Dimethyl-2-oxo-6-phenyl-3-cyclohexene-
carboxamide (4d) was prepared similarly. Yield 32%,
mp 168–170°С. 1Н NMR spectrum, δ, ppm: 7.75 d. d (1Н,
NH, J = 8.6, 4.1 Hz), 7.30–7.27 m (4Н, H-Ar), 7.24–7.17 m
(1Н, H-Ar), 5.91 s (1Н, =С3Н), 3.58 d. d. d (1Н, C6H, J =
12.6, 10.8, 4.7 Hz), 3.51 d (1Н, C1H, J = 12.5 Hz), 2.59 d. d
(1Н, C3HAHB, J = 18.3, 10.7 Hz), 2.47 d (1Н, C3HAHB, J =
4.7 Hz), 2.47 d (3Н, NMe, J = 4.6 Hz), 1.97 s (3Н, Me).
13C NMR spectrum, δС, ppm: 195.0 (CO), 168.8 (CON),
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SYNTHESIS AND ANALGESIC ACTIVITY OF N,6-DIARYL-4-HYDROXY-...
1589
and the Chemistry Educational Center of the Research Park of
St. Petersburg State University.
162.6, 142.5, 128.2, 127.3, 126.5, 125.0, 55.4, 42.7, 38.3,
25.3 (NMe), 23.7 (C4Me).Found, %: C 74.29; H 6.78; N
5.83. C15H17NO2. Calculated, %: C 74.03; H 6.99; N 5.76.
CONFLICT OF INTEREST
Crystals of compound 4d are triclinic, space group P-1,
C15H17NO2, M 243.29, a = 9.4105(13), b = 11.5562(15),
c = 12.882(2) Å, α = 75.761(13), β = 87.700(12), γ =
89.897(11)°, V = 1356.8(4) Å3, Z = 4, dcalc = 1.191 g/cm3,
μ = 0.079 mm–1. Final refinement parameters are: R1 =
0.0727 [for 3344 reflections with I>2σ(I)], wR2 = 0.2477
(for all 6286 independent reflections), S = 1.019.
No conflict of interest was declared by the authors.
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FUNDING
This work was supported by the St. Petersburg State
University (Application for the development of the material
and technical base of St. Petersburg State University no.
33402376) using the equipment of the Resource Centers
“Chemical Analysis and Materials Research Center,” “SPbU
Computing Center,” “Magnetic Resonance Research Center,”
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