Reactions of 2-Acetyl-5-hydroxy-5-methyl-3-phenylcyclohexanone and Alkyl 4-Hydroxy-4-methyl-2-oxo-6-phenylcyclohexanecarboxylates with Nucleophilic Reagents

Article abstract of DOI:10.1134/S1070363219070016

A series of novel enamines, bis(enamines), benzisoxazoles, tetrahydroindazoles, benzophenone hydrazones were obtained via reactions of 2-acetyl-5-hydroxy-5-methylcyclohexanone and alkyl 4-hydroxy-4-methyl-2-oxocyclohexanecarboxylates with nucleophilic rea

Full text of DOI:10.1134/S1070363219070016

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 7, pp. 1353–1359. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 7, pp. 987–994.
Reactions of 2-Acetyl-5-hydroxy-5-methyl-
3-phenylcyclohexanone and Alkyl 4-Hydroxy-4-methyl-
2-oxo-6-phenylcyclohexanecarboxylates
with Nucleophilic Reagents
V. L. Geina*, N. V. Nosovaa, A. V. Vagapovaa, N. V. Dozmorovaa, and A. N. Yankinb
a Perm State Pharmaceutical Academy, ul. Polevaya 2, Perm, 614990 Russia
*e-mail: geinvl48@mail.ru
b St. Petersburg State University, St. Petersburg, Russia
Received February 4, 2019; revised February 4, 2019; accepted February 10, 2019
Abstract—Aseries of novel enamines, bis(enamines), benzisoxazoles, tetrahydroindazoles, benzophenone hydra-
zones were obtained via reactions of 2-acetyl-5-hydroxy-5-methylcyclohexanone and alkyl 4-hydroxy-4-methyl-
2-oxocyclohexanecarboxylates with nucleophilic reagents such as aliphatic and aromatic amines, diamines,
hydroxylamine, hydrazine, phenylhydrazine, benzophenone hydrazone. The structures of the compounds obtained
were proved by IR and 1H NMR spectroscopy methods.
Keywords: 2-acetylcyclohexanone, alkyl 2-oxocyclohexanecarboxylates, enamines, indazoles, benzisoxazoles,
hydrazones
DOI: 10.1134/S1070363219070016
Cyclohexanones and their derivatives are an important
scaffolds for the synthesis of new heterocyclic compounds
with antimicrobial [1–4], analgesic [5], anti-phage [6],
antiarrhythmic [7], hypoglycemic [8], anti-cancer [9],
anti-convulsive [10], anti-inflammatory [11] and sedative
activity [5, 10]. It is known that the products of reaction
of compounds bearing a cyclohexanone fragment with
nucleophilic reagents are good diuretics [12], enzyme
inhibitors such as cholinesterase [13], and can be used as
antiprotozoal [14], antitripanosomal [ 15] and anthelmin-
tic pharmaceuticals [16]. In addition, there are positive
results of studies of these compounds as ligand agonists
of H1 receptors of the body, which has pharmacothera-
peutic potential in the treatment of neuro-degenerative
and neuropsychiatric disorders, as well as various types
of allergies [17, 18].
aureus and E. coli [19]. Herein we reported the synthe-
sis of new enamines, bis(enamines), benzisoxazoles,
tetrahydroindazoles, and benzophenone hydrazones 2–8
based on reactions of cyclohexanones 1b–1h with some
N-nucleophilic reagents.
The reactions of 2-acetyl-cyclohexanone 1a and al-
kyl 2-oxocyclohexane-carboxylates 1b, 1d, and 1e with
mononucleophilic reagents, such as alkyl and aryl amines,
were performed when boiling equimolar amounts of the
reagents in ethyl alcohol, in some cases with the addi-
tion of a catalytic amount of acetic acid. The amination
of the carbonyl group of the alicyclic compound took
place, which led to the formation of the corresponding
enamines 2–4 (Scheme 1).
Alkyl 4-hydroxy-4-methyl-2-oxo-6-phenylcyclo-
hexane-1-carboxylates 1d and 1e reacted with aliphatic
diamines, such as ethylene diamine and 1,3-propanedi-
amine, in ethanol when heated for 2–4 h. The reactions
proceeded regioselectively with the participation of both
amino groups of the diamine and the carbonyl group of the
alicycle of two cyclohexanone molecules with the forma-
tion of new bis(enamine) derivatives 5а–5c (Scheme 1).
Recently, we have obtained 2-acetyl-5-hydroxy-
5-methyl-3-phenylcyclohexanone 1a and alkyl 4-hy-
droxy-4-methyl-2-oxo-6-phenylcyclohexanecarboxylates
1b–1h by reacting benzalacetone with acetylacetone and
acetoacetates, respectively, in the presence of potassium
hydroxide in ethanol at room temperature and stud-
ied their antimicrobial action against the strains of St.
1353

1354
GEIN et al.
Scheme 1.
R1 = Me (1a, 6); R1 = OMe (1b, 2, 3); R1 = Me, R2 = OMe (4a); R1 = OMe, R2 = OMe (4b); R1 = OMe, R2 = F (4c); R1 = OMe,
R2 = Н (4d); R1 = OMe, R2 = Cl (4e); R1 = O-iPr, R2 = Me (4f); R1 = O-iBu, R2 = Me (4g); R1 = O-iBu, R2 = Me (4h); R1 =
O-iPr, n = 2 (5a); R1 = O-iPr, n = 3 (5b); R1 = O-iBu, n = 2 (5c); R1 = OEt, R3 = Ph (7a); R1 = OEt, R3 = Н (7b); R1 = OBn
(8a); R1 = O-iPr (8b); R1 = OEt (8c).
The resulting compounds 2–5 are yellow crystalline
substances, soluble in acetone, DMSO, DMF, and when
heated, in ethyl, isopropyl, n-butyl alcohols and acetoni-
trile, insoluble in water.
In the IR spectra of enamines 3, 4a–4h and bis-
(enamines) 5а–c, there are strong absorption bands of
the NH group (3296–3266 cm–1) and the ester moiety
(1696–1740 cm–1). The absorption band of the C=C bond
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(1596–1564 cm–1) is present in the spectra of compounds
4a–4h. The 1H NMR spectra of compounds 2–5 contain
singlet signals of the methyl group at the C5 atom of
the ring (1.21–1.78 ppm), multiplets of the aromatic
protons (6.98–7.40 ppm) and doublets of the protons at
the C6 atom (1.82–2.88 ppm) with spin-spin coupling
constants within 15.8–17.0 Hz. The absence of a signal
from the C2H proton in the spectrum of compound 1a
(C1H for compounds 1b, 1d, 1e), and the presence of a
signal from the proton of the NH group (9.07–13.07 ppm)
confirms the enamine formation. The mass spectrum of
compound 4g contains a peak of a molecular ion with m/z
375, as well as peaks of fragmentary ions with с m/z 360
[М – CH3]+, 318 [М – CH2CH(CH3)2]+, 298 [М – C6H5]+
and 274 [M – COOCH2CH(CH3)2]+ that confirms the
proposed structure.
group (3312 cm–1). The 1H NMR spectra of compounds
6 and 7a–7c contain singlet signals of the methyl groups
at the C6 atom (1.21–1.32 ppm), a triplet (2.46–2.62 ppm,
J = 14.3–16.8 Hz) and a doublet of doublets of the protons
of the methylene group at the C5 atom (2.56–2.74 ppm,
J = 14.3–16.5, 1.4–1.6 Hz), as well as doublets from
the C7H proton (1.40–1.62 and 1.62–1.96 ppm) as the
AB system with spin-spin coupling constants within
11.6–13.4 Hz, and multiplet signals of aromatic protons
(7.13–7.68 ppm). In the spectra of compounds 6 and 7c,
additional singlet signals of the methyl groups at the C3
atom (1.72 and 1.48 ppm) are observed. In the case of
tetrahydroindazole 7b, a broad singlet of two protons of
the OH and NH groups was found (10.20 ppm).
Compounds 7a, 7b reacted with an alcoholic solution
of iron(III) chloride to form an intense violet-purple solu-
tion. This fact, along with literature data for analogous
compounds, whose structure was confirmed using X-ray
diffraction data [20] and the results of IR, 1H NMR spec-
troscopy, indicates enolization of the carbonyl group at
the C3 atom of heterocycle.
The formation of enamine form of compounds 2–5 is
explained by the existence of an intramolecular hydrogen
bond between the hydrogen atom of the amino group and
the oxygen atom of the ester carbonyl group. Dehydra-
tion of compounds 2–5 involving the C3H proton is due
to the presence of a catalytic amount of acetic acid in the
reaction medium.
The reaction of alkyl 4-hydroxy-4-methyl-2-oxo-
6-phenylcyclohexane-1-carboxylates 1b, 1d, and 1f with
benzophenone hydrazone led to the formation of the cor-
responding hydrazones 8a–8c (Scheme 1). Structure of
compounds 8a–8c was confirmed by the data of IR, 1H
NMR spectroscopy and mass spectrometry.
In order to obtain new bicyclic derivatives containing
biologically active isoxazole and pyrazole fragments,
we performed the reactions of cyclohexanones 1a and
1c with hydroxylamine, phenylhydrazine and hydra-
zine hydrate in ethyl alcohol when heated. During the
interaction of these reagents, nucleophilic substitution
of the oxygen atom of the carbonyl group of the ring
was observed, followed by heterocyclization and the
formation of 4,5,6,7-tetrahydrobenzo[c]isoxazole 6 and
4,5,6,7-tetrahydro-2H-indazoles 7a–7c with yield of 41
and 61–93%, respectively (Scheme 1). The yield of com-
pound 6 is lower in comparison with derivatives 7a–7c
due to the lower nucleophilicity of the reagent.
In conclusion, the reaction of 2-acetyl-5-hydroxy-
5-methylcyclohexanone and alkyl 4-hydroxy-4-methyl-
2-oxocyclohexanecarboxylates with alkyl and aryl amines
leads to the formation of the corresponding enamines
and bis(enamines). The interaction of functionalized
cyclohexanones with binucleophilic reagents, such as
hydroxylamine and hydrazine, is accompanied by cy-
clization with the formation of new benzisoxazole and
4,5,6,7-tetrahydro-2H-indazole derivatives. In the case
of the reaction of cyclohexanones with benzophenone
hydrazone, the corresponding hydrazones form.
Benzisoxazole 6 and tetrahydroindazoles 7a–7c are
colorless crystalline substances, soluble in DMF and
DMSO, poorly soluble in ethyl and n-butyl alcohols,
acetonitrile, dioxane and insoluble in water.
EXPERIMENTAL
In the IR spectra of compounds 6 and 7a–7c, there are
strongabsorptionbandsoftheOHgroup(3312–3400cm–1)
and the conjugated C=N bond (1600–1640 cm–1). There
are no bands due to stretching vibrations of the carbonyl
groups characteristic of the starting cyclohexanones in the
spectra of compounds 6, 7a–7c. In the spectrum of 7c, a
band is observed due to vibrations of the secondary NH
IR spectra were taken on a Specord M-80 instrument
from mineral oil. H NMR spectra were recorded on a
1
BrukerAM-300 spectrometer with an operating frequency
of 300 MHz from DMSO-d6 solutions, the internal stan-
dard was tetramethylsilane. Mass spectra were taken on a
Finnigan MAT INCOS-50 instrument (70 eV). Elemental
analysis was performed on a PerkinElmer 2400 instru-
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GEIN et al.
ment. Melting points were determined on a Melting Point
M-565 instrument.
mp 120–122°С. IR spectrum, ν, cm–1: 3223 (NH), 1660
(C=O), 1592(С=С). 1НNMRspectrum, δ, ppm:1.69s(3Н,
Me), 1.88s(3Н, COMe), 2.33d(1Н, C6HAHB, J=16.8Hz),
2.93 d (1Н, C6HAHB, J = 16.5 Hz), 3.77 s (3Н, OMe),
4.08 m (1Н, C1H), 5.99 s (1Н, С4Н), 6.98–7.21 m (9Н, Ph,
С6Н4), 13.07 s (1H, NH). Found, %: С 79.06; Н 7.00; N
4.02. C22H23NO2. Calculated, %: С 79.25; Н 6.95; N 4.20.
2-Acetyl-5-hydroxy-5-methyl-3-phenylcyclohexa-
none 1a and alkyl 4-hydroxy-4-methyl-2-oxo-6-phenyl-
cyclohexanecarboxylates 1b–1h were prepared according
to a known procedure [19].
Methyl 5-hydroxy-3-[(2-hydroxyethyl)amino]-
5-methyl-1,4,5,6-tetrahydro-(1,1'-biphenyl)-2-carbox-
ylate (2). To a solution of 0.01 mol of methyl 4-hydroxy-
4-methyl-2-oxo-6-phenylcyclohexane-1-carboxylate 1b in
19.6 mL of ethanol were added 0.02 mol of ethanolamine
and 0.4 mL of glacial acetic acid. The resulting mixture
was boiled for 6 h. The precipitate formed was filtered
off, dried and recrystallized from ethanol. Yield 51%,
mp 143–145°С. 1Н NMR spectrum, δ, ppm: 1.76 s (3Н,
Me), 2.22 d. d (1Н, C6HAHB, J = 16.9, 1.4 Hz), 2.71 d. d (1Н,
C6HAHB, J = 16.5, 8.1 Hz), 3.33 m (2Н, NHCH2CH2OH),
3.44 s (3Н, OMe), 3.53 m (2Н, NHCH2CH2OH), 3.98 m (1Н,
C1H), 4.76 t (1Н, NHCH2CH2OH, J = 5.5 Hz), 6.20 s (1Н,
C4H), 7.05–7.17 m (5Н, Ph), 9.13 t (1Н, NHCH2CH2OH, J =
5.8 Hz). Found, %: С 71.23; Н 7.41; N 4.68. C17H21NO3.
Calculated, %: С 71.06; Н 7.37; N 4.87.
Methyl 5-methyl-3-[(4-methoxyphenyl)amino]-1,6-
dihydro-(1,1'-biphenyl)-2-carboxylate (4b). Yield 57%,
mp 132–134°С. IR spectrum, ν, cm–1: 3240 (NH), 1664
(C=O), 1592 (С=С). 1Н NMR spectrum, δ, ppm: 1.67 s
(3Н, Me), 2.27 d (1Н, C6HAHB, J = 15.9 Hz), 2.83 d (1Н,
C6HAHB, J = 16.1 Hz), 3.51 s (3Н, OMe), 3.76 s (3Н,
OMe), 4.07 m (1Н, C1H), 5.90 s (1Н, С4Н), 6.96–7.23
m (9Н, Ph, С6Н4), 10.52 s (1H, NH). Found, %: С 75.48;
Н 6.67; N 4.19. C22H23NO3. Calculated, %: С 75.62; Н
6.63; N 4.01.
Methyl 5-methyl-3-[(4-fluorophenyl)amino]-1,6-
dihydro-(1,1'-biphenyl)-2-carboxylate (4c). Yield 44%,
mp 127–128°С. IR spectrum, ν, cm–1: 3260 (NH), 1670
(C=O), 1580 (С=С). 1Н NMR spectrum, δ, ppm: 1.70 s
(3Н, Me), 2.32 d (1Н, C6HAHB, J = 16.7 Hz), 2.78 d (1Н,
C6HAHB, J = 16.7 Hz), 3.49 s (3Н, OMe), 4.06 m (1Н,
C1H), 5.86 s (1Н, С4Н), 6.98–7.16 m (9Н, Ph, С6Н4),
10.44 s (1H, NH). Found, %: С 74.98; Н 5.92; N 4.29.
C21H20FNO2. Calculated, %: С 74.76; Н 5.97; N 4.15.
Methyl 3-(benzylamino)-5-hydroxy-5-methyl-
1,4,5,6-tetrahydro-(1,1'-biphenyl)-2-carboxylate (3).
To a solution of 0.01 mol of methyl 4-hydroxy-4-methyl-
2-oxo-6-phenylcyclohexane-1-carboxylate 1b in 10 mL
of ethanol was added 0.01 mol of benzyl amine. The
resulting mixture was boiled for 10 min, then cooled.
The formed precipitate was filtered off, dried and re-
crystallized from ethanol. Yield 24%, mp 115–117°С. IR
spectrum, ν, cm–1: 3472 (OH), 3272 (NH), 1740 (C=O),
1592 (Ar). 1Н NMR spectrum, δ, ppm: 1.21 s (3Н, Me),
1.82 d (1Н, C6HAHB, J = 15.8 Hz), 1.98 d (1Н, C6HAHB,
J = 15.9 Hz), 2.26 d (1Н, C4HAHB, J = 12.8 Hz), 2.72 d (1Н,
C4HAHB, J = 12.8 Hz), 3.38 s (3Н, OMe), 3.71 m (1Н, C1H),
4.35d(2Н, NHCH2C6H5, J=6.5Hz), 7.01–7.25m(10Н, 2Ph),
9.15 t (1H, NH, J = 6.3 Hz). Found, %: С 75.01; Н 7.14;
N 4.10. C22H25NO3. Calculated, %: С 75.19; Н 7.17; N 3.99.
Methyl 5-methyl-3-(phenylamino)-1,6-dihydro-
(1,1′-biphenyl)-2-carboxylate (4d). Yield 29%, mp
96–97°С. IR spectrum, ν, cm–1: 3240 (NH), 1668 (C=O),
1572 (С=С). 1Н NMR spectrum, δ, ppm: 1.69 s (3Н, Me),
2.29 d (1Н, C6HAHB, J = 15.9 Hz), 2.86 d (1Н, C6HAHB,
J = 16.1 Hz), 3.52 s (3Н, OMe), 4.07 m (1Н, C1H), 6.01
s (1Н, С4Н), 7.12–7.38 m (10Н, 2Ph), 10.55 s (1H, NH).
Found, %: С 78.74; Н 6.55; N 4.57. C21H21NO2. Calculated,
%: С 78.97; Н 6.63; N 4.39.
Methyl 5-methyl-3-[(4-chlorophenyl)amino]-1,6-
dihydro-(1,1'-biphenyl)-2-carboxylate (4e). Yield 37%,
mp 120–121°С. IR spectrum, ν, cm–1: 3296 (NH), 1660
(C=O), 1584 (С=С). 1Н NMR spectrum, δ, ppm: 1.70 s
(3Н, Me), 2.30 d (1Н, C6HAHB, J = 15.9 Hz), 2.86 d (1Н,
C6HAHB, J = 16.0 Hz), 3.53 s (3Н, OMe), 4.07 m (1Н, C1H),
5.99 s (1Н, С4Н), 7.14–7.40 m (9Н, Ph, С6Н4), 10.55 s (1H,
NH). Found, %: С 71.54; Н 5.63; N 4.19. C21H20ClNO2.
Calculated, %: С 71.28; Н 5.70; N 3.96.
General procedure for the synthesis of compounds
4a–4h. To a solution of 0.005 mol of 4-hydroxy-4-meth-
yl-6-phenyl-cyclohexanone 1a in 5 mL of ethyl alcohol
were added 0.005 mol of the corresponding aryl amine
and 0.1 mL of glacial acetic acid. The resulting mixture
was boiled for 3–4 h, then cooled. The precipitate was
filtered off, dried and recrystallized from ethanol.
Isopropyl 5-methyl-3-(p-tolylamino)-1,6-dihydro-
(1,1'-biphenyl)-2-carboxylate (4f). Yield 61%, mp
83–84°С. IR spectrum, ν, cm–1: 3240 (NH), 1660 (C=O),
5-Methyl-1-{3-[(4-methoxyphenyl)amino]-1,6-di-
hydro-(1,1'-biphenyl)-2-yl}ethanone (4a). Yield 60%,
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1
1564 (С=С). Н NMR spectrum, δ, ppm: 0.89 d (3Н,
СНMe2, J = 6.0 Hz), 1.17 d (3Н, ОСНMe2, J = 6.0 Hz),
1.72 s (3Н, Me), 2.28 d (1Н, C6HAHB, J = 16.2 Hz), 2.29
s (3Н, 4-Me-С6Н4), 2.85 d (1Н, C6HAHB, J = 17.0 Hz),
4.04–4.06 m (1Н, C1H), 4.82 m (1Н, ОСНMe2), 5.97 s
(1Н, С4Н), 6.99–7.22 m (9Н, Ph, С6Н4), 10.59 s (1H,
NH). Found, %: С 79.69; Н 7.55; N 3.52. C24H27NO2.
Calculated, %: С 79.74; Н 7.53; N 3.87.
16.1 Hz), 2.68 d (2Н, 2C6HAHB, J = 16.2 Hz), 3.47 m (4Н,
2СН2NH), 3.94 m (2Н, 2C1H), 4.78 m (2Н, 2ОСНMe2),
6.21 s (2Н, 2С4Н), 7.12–7.24 m (10Н, 2Ph), 9.09 s (2H,
2NH). Found, %: С 76.26; Н 7.75; N 5.19. C36H44N2O4.
Calculated, %: С 76.02; Н 7.80; N 4.93.
Diisopropyl 3,3''-[propane-1,2-diylbis(azanediyl)]bis-
[5-methyl-1,6-dihydro-(1,1'-biphenyl)-2-carboxylate]
(5b). Yield 34%, mp 103–104°С. IR spectrum, ν, cm–1:
3256 (NH), 1736 (C=O). 1Н NMR spectrum, δ, ppm: 0.86
d (6Н, 2ОСНMe2, J = 6.0 Hz), 1.13 d (6Н, 2ОСНMe2,
J= 6.0 Hz), 1.77 s (6Н, 2Me), 1.82 m [2Н, СН2(СН2NH)2],
2.25 d (2Н, 2C6HAHB, J = 17.1 Hz), 2.70 d (2Н, 2C6HAHB,
J = 16.7 Hz), 3.40 m [4Н, СН2(СН2NH)2], 3.95–3.96 m
(2Н, 2C1H), 4.77–4.78 m (2Н, 2ОСНMe2), 6.20 s (2Н,
2С4Н), 7.11–7.23 m (10Н, 2Ph), 9.07 s (2H, 2NH). Found,
%: С 76.54; Н 7.83; N 5.14. C37H46N2O4. Calculated, %:
С 76.26; Н 7.96; N 4.81.
Isobutyl 5-methyl-3-(p-tolylamino)-1,6-dihydro-
(1,1'-biphenyl)-2-carboxylate (4g). Yield 59%, mp
87–89°С. IR spectrum, ν, cm–1: 3296 (NH), 1696 (C=O),
1
1567 (С=С). Н NMR spectrum, δ, ppm: 0.69 d (3Н,
ОСН2СНMe2, J = 6.0 Hz), 0.71 d (3Н, ОСН2СНMe2,
J = 6.0 Hz), 1.67–1.68 m (3Н, ОСН2СНMe2), 1.69 s (3Н,
Me), 2.26 d (1Н, C6HAHB, J = 16.1 Hz), 2.30 s (3Н, 4-Me-
С6Н4), 2.87 d (1Н, C6HAHB, J = 16.8 Hz), 3.67–3.68 m
(1Н, ОСН2СНMe2), 3.77–3.78 m (1Н, ОСН2СНMe2),
4.11 m (1Н, C1H), 5.99 s (1Н, С4Н), 6.01–7.17 m (9Н,
Ph, С6Н4), 10.59 s (1H, NH). Mass spectrum, m/z (Irel,
%): 375 (56) [M]+. Found, %: С 79.73; Н 7.72; N 3.89.
C25H29NO2. Calculated, %: С 79.96; Н 7.78; N 3.73.
Diisobutyl 3,3"-[ethane-1,2-diylbis(azanediyl)]bis[5-
methyl-1,6-dihydro-(1,1'-biphenyl)-2-carboxylate] (5c ).
To a solution of 0.01 mol of isobutyl 4-hydroxy-4-methyl-
2-oxo-6-phenylcyclohexane-1-carboxylate 1e in 20 mL
of ethanol was added 0.01 mol of ethylenediamine. The
resulting mixture was boiled for 3 h. The solvent was evapo-
rated. The precipitate was filtered off, washed with water,
then with alcohol, dried and recrystallized from ethanol.
Yield 11%, mp 171–172°С. IR spectrum, ν, cm–1: 3408
Isobutyl 5-methyl-3-[(4-fluorophenyl)amino]-1,6-
dihydro(1,1′-biphenyl)-2-carboxylate (4h). Yield 66%,
mp 80–82°С. IR spectrum, ν, cm–1: 3240 (NH), 1664
(C=O), 1580 (С=С). 1Н NMR spectrum, δ, ppm: 0.68 d
(3Н, ОСН2СНMe2, J= 6.0 Hz), 0.70 d (3Н, ОСН2СНMe2,
J = 6.0 Hz), 1.67–1.68 m (3Н, ОСН2СНMe2), 1.69 s (3Н,
Me), 2.26 d (1Н, C6HAHB, J = 16.3 Hz), 2.88 d (1Н,
C6HAHB, J = 16.6 Hz), 3.68–3.69 m (1Н, ОСН2СНMe2),
3.78–3.79 m (1Н, ОСН2СНMe2), 4.09 m (1Н, C1H), 5.94
s (1Н, С4Н), 7.16–7.21 m (9Н, Ph, С6Н4), 10.56 s (1H,
NH). Found, %: С 79.71; Н 7.02; N 3.90. C24H26FNO2.
Calculated, %: С 75.96; Н 6.91; N 3.69.
1
(ОH), 3266 (NH), 1720 (C=O). Н NMR spectrum, δ,
ppm: 0.47 d (6Н, ОСН2СНMe2, J = 7.5 Hz), 0.57 d (6Н,
ОСН2СНMe2, J = 7.5 Hz), 1.16 s (6Н, 2Me), 1.32 m (6Н,
2ОСН2СНMe2), 1.65 d (2Н, 2C4HAHB, J = 13.2 Hz), 1.87
d (2Н, 2C4HAHB, J = 13.2 Hz), 2.22 d (2Н, 2C6HAHB,
J = 16.5 Hz), 2.45 d (2Н, 2C6HAHB, J = 16.5 Hz), 3.38
m (4Н, 2ОСН2СНMe2), 3.41 m (4Н, 2СН2NH), 3.86 m
(2Н, 2C1H), 4.78 m (2Н, 2ОСНMe2), 4.32 s (1Н, ОН),
7.02–7.11 m (10Н, 2Ph), 9.18 s (2H, 2NH). Found, %:
С 71.47; Н 8.25; N 4.17. C38H52N2O4. Calculated, %: С
71.12; Н 8.28; N 4.43.
General procedure for the synthesis of compounds
5a, 5b. To a solution of 0.01 mol of alkyl 4-hydroxy-
4-methyl-2-oxo-6-phenylcyclohexane-1-carboxylate
in 9.5 mL of ethanol were added 0.01 mol of diamine
and 0.5 mL of glacial acetic acid. The resulting mixture
was boiled for 2–4 h. The solvent was evaporated. The
precipitate was filtered off, washed with water, dried and
recrystallized from ethanol.
3,6-Dimethyl-4-phenyl-4,5,6,7-tetrahydrobenzo[c]-
isoxazole-6-ol (6). Potassium hydroxide (0.1 mol)
was added to a solution of 0.1 mol of hydroxylamine
hydrochloride in 30 mL of ethanol. The precipitate was
filtered off. 2-Acetyl-5-hydroxy-5-methyl-3-phenylcy-
clohexanone 1a (0.05 mol) was added to the filtrate. The
mixture was boiled for 2 h. The solvent was evaporated.
The precipitate was filtered off and recrystallized from
ethanol. Yield 41%, mp 134–136°С. IR spectrum, ν, cm–1:
Diisopropyl 3,3''-[ethane-1,2-diylbis(azanediyl)bis-
[5-methyl-1,6-dihydro-(1,1'-biphenyl)-2-carboxylate]
(5a). Yield 26%, mp 154–155°С. IR spectrum, ν, cm–1:
3300 (NH), 1750 (C=O). Н NMR spectrum, δ, ppm:
0.87 d (6Н, ОСНMe2, J = 6.0 Hz), 1.14 d (6Н, ОСНMe2,
J = 6.0 Hz), 1.78 s (6Н, 2Me), 2.22 d (2Н, 2C6HAHB, J =
1
1
3376 (ОH), 1640 (C=N). Н NMR spectrum, δ, ppm:
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1358
GEIN et al.
1.32s(3Н, Me), 1.62d(1Н, C7HAHB, J=13.2Hz), 1.72s(3Н,
Me), 1.94 d (1Н, C7HAHB, J= 13.4 Hz), 2.62 t (1Н, C5HAHB,
J = 16.5 Hz), 2.74 d. d (1Н, C5HAHB, J = 16.5, 1.6 Hz), 3.98
m (1Н, C4H), 4.67 s (1Н, ОН), 7.22–7.31 m (5Н, Ph). Found,
%: С 74.34; Н 7.01; N 5.93. C15H17NO2. Calculated, %:
С 74.05; Н 7.04; N 5.76.
10 mL of ethanol was boiled for 2–3 h. After removing
the solvent, the precipitate was filtered off and recrystal-
lized from ethanol.
Benzyl 2-[(diphenylmethylene)hydrazono]-4-hy-
droxy-4-methyl-6-phenylcyclohexanecarboxylate (8a).
Yield 87%, mp 195–196°С. IR spectrum, ν, cm–1: 3440
(ОH), 1728 (С=О), 1624 (C=N). 1Н NMR spectrum, δ,
ppm: 1.23 s (3Н, Me), 1.76 t (1Н, C5HAHB, J= 12.5 Hz), 1.89
d (1Н, C5HAHB, J = 13.0 Hz), 2.15 d (1Н, C3HAHB, J = 14.2
Hz), 3.34 d (1Н, C3HAHB, J = 14.2 Hz), 3.60–3.61 m (1Н,
C6H), 3.75 d (1Н, C1H, J= 12.1 Hz), 4.48 s (2Н, СН2Ph), 4.78
s (1Н, ОН), 7.18–7.57 m (20Н, 4Ph). Found, %: С 78.71;
Н 6.29; N 5.73. C34H32N2O3. Calculated, %: С 79.04; Н
6.24; N 5.42.
6-Methyl-2,4-diphenyl-4,5,6,7-tetrahydro-2H-
indazole-3,6-diol (7a). To a solution of 0.01 mol of ethyl
4-hydroxy-4-methyl-2-oxo-6-phenylcyclohexane-1-car-
boxylate 1b in 20 mL of ethanol was added 0.01 mol of
phenylhydrazine. The mixture was boiled for 6 h. After
removing the solvent, the precipitate was filtered off,
treated with acetone and recrystallized from ethanol. Yield
74%, mp 217–219°С. IR spectrum, ν, cm–1: 3312 (ОH),
3200 (ОH), 1680 (C=N). 1Н NMR spectrum, δ, ppm: 1.26
s (3Н, Me), 1.47 d (1Н, C7HAHB, J = 12.2 Hz), 1.96 d (1Н,
C7HAHB, J = 13.2 Hz), 2.46 t (1Н, C5HAHB, J = 14.3 Hz),
2.63 d. d (1Н, C5HAHB, J = 14.3, 1.6 Hz), 3.76 q (1Н, C4H,
J= 14.1 Hz), 4.67 s (1Н, ОН), 7.15–7.68 m (10Н, 2Ph), 10.68
s (OH). Found, %: С 74.61; Н 6.31; N 8.96. C20H20N2O2.
Calculated, %: С 74.98; Н 6.29; N 8.74.
Isobutyl 2-[(diphenylmethylene)hydrazono]-
4-hydroxy-4-methyl-6-phenylcyclohexanecarboxylate
(8b). Yield 88%, mp 165–166°С. IR spectrum, ν, cm–1:
1
3424 (ОH), 1728 (С=О), 1624 (C=N). Н NMR spec-
trum, δ, ppm: 0.50 d (3Н, ОCH2CHMe2, J= 6.0 Hz), 0.51
d (3Н, ОCH2CHMe2, J = 6.0 Hz), 1.23 s (3Н, Me), 1.32
m (1Н, ОCH2CHMe2), 1.75 t (1Н, C5HAHB, J = 12.3 Hz),
1.85 d (1Н, C5HAHB, J = 13.0 Hz), 2.14 d (1Н, C3HAHB, J =
14.2 Hz), 3.16 m (2Н, ОCH2CHMe2), 3.32 d (1Н, C3HAHB,
J = 14.2 Hz), 3.56–3.57 m (1Н, C6H), 3.67 d (1Н, C1H, J =
12.1 Hz), 4.68 s (1Н, ОН), 7.16–7.56 m (15Н, 3Ph). Found,
%: С 77.26; Н 7.17; N 5.61. C31H34N2O3. Calculated, %:
С 77.15; Н 7.10; N 5.80.
6-Methyl-4-phenyl-4,5,6,7-tetrahydro-2H-inda-
zole-3,6-diol (7b). Amixture of 0.005 mol of 4-hydroxy-
4-methyl-6-phenylcyclohexanone, 10 mL of ethanol and
0.005 mol of hydrazine hydrate was boiled for 30 min.
The precipitate was filtered off and washed with ethanol.
Yield 61%, mp 261–263°С. IR spectrum, ν, cm–1: 3360
1
(ОH), 3280 (NH), 1600 (C=N). Н NMR spectrum, δ,
Ethyl 2-[(diphenylmethylene)hydrazono]-4-hyd-
roxy-4-methyl-6-phenylcyclohexanecarboxylate (8c).
Yield 63%, mp 178–179°С. IR spectrum, ν, cm–1: 3496
(ОH), 1728 (С=О), 1624 (C=N). 1Н NMR spectrum, δ,
ppm: 0.66 t (3Н, ОCH2Me2, J = 7.5 Hz), 1.23 s (3Н, Me),
1.32m(1Н, ОCH2CHMe2), 1.73t(1Н, C5HAHB, J=13.0Hz),
1.87 d (1Н, C5HAHB, J = 12.8 Hz), 2.13 d (1Н, C3HAHB,
J = 14.1 Hz), 3.31 d (1Н, C3HAHB, J = 14.1 Hz), 3.43 q (2Н,
ОCH2Me2, J = 7.5 Hz), 3.55–3.56 m (1Н, C6H), 3.61 d (1Н,
C1H, J = 12.1 Hz), 4.67 s (1Н, ОН), 7.17–7.56 m (15Н, 3Ph).
Found, %: С 76.92; Н 6.73; N 6.38. C29H30N2O3. Calcu-
lated, %: С 76.63; Н 6.65; N 6.16.
ppm: 1.21 s (3Н, Me), 1.40 d (1Н, C7HAHB, J = 13.2 Hz),
1.89 d (1Н, C7HAHB, J = 13.2 Hz), 2.47 t (1Н, C5HAHB, J =
16.8 Hz), 2.56 d. d (1Н, C5HAHB, J = 16.5, 1.4 Hz), 3.82 q
(1Н, C4H, J = 16.1 Hz), 4.45 s (1Н, ОН), 7.13–7.23 m (5Н,
Ph), 10.20 br. s (2Н, NH, OH). Found, %: С 68.60; Н 6.66;
N 11.73. C14H16N2O2. Calculated, %: С 68.83; Н 6.60;
N 11.47.
3,6-Dimethyl-4-phenyl-4,5,6,7-tetrahydro-2H-
indazole-6-ol (7c) was prepared analogously. Yield 93%,
mp 226–228°С. IR spectrum, ν, cm–1: 3400 (ОH), 3312
(NH), 1600 (C=N). 1Н NMR spectrum, δ, ppm: 1.24s(3Н,
Me), 1.48 s (3Н, Me), 1.62 d (1Н, C7HAHB, J= 11.6 Hz), 1.85
d (1Н, C7HAHB, J= 12.0 Hz), 2.57 m (2Н, C5H2), 3.87 q (1Н,
C4H, J = 16.0 Hz), 4.37 s (1Н, ОН), 7.14–7.26 m (5Н, Ph),
11.76 s (1Н, NH). Found, %: С 74.61; Н 7.56; N 11.77.
C15H18N2O. Calculated, %: С 74.35; Н 7.49; N 11.56.
ACKNOWLEDGMENTS
The studies were performed with use of the equipment
of the Resource Educational “Center Chemistry” of the
Science Park of St. Petersburg State University.
General procedure for the synthesis of compounds
8a–8c. Amixture of 0.005 mol of the corresponding cyclo-
ketol, 0.005 mol of benzophenone hydrazone and
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 7 2019

REACTIONS OF 2-ACETYL-5-HYDROXY-5-METHYL-3-PHENYLCYCLOHEXANONE
1359
11. RU Patent 2428410, 2011.
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