Synthesis and structure of diisopropyl 6-hydroxy-6-methyl-4-oxocyclohexane- 1,3-dicarboxylates and their reactions with nucleophilic reagents

Article abstract of DOI:10.1007/s11178-005-0287-7

Base-catalyzed reactions of isopropyl acetoacetate with aromatic and heterocyclic aldehydes afforded the corresponding diisopropyl 6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxylates which were brought into reactions with mono- and difunctional nitrogen-containing nucleophiles. According to the X-ray diffraction data, diisopropyl 4-oxocyclohexane-1,3- dicarboxylates in crystal exist in the ketone form.

Full text of DOI:10.1007/s11178-005-0287-7

Russian Journal of Organic Chemistry, Vol. 41, No. 7, 2005, pp. 1016–1022. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 7, 2005,
pp. 1039–1045.
Original Russian Text Copyright © 2005 by Gein, Nosova, Potemkin, Aliev, Kriven’ko.
Synthesis and Structure of Diisopropyl 6-Hydroxy-6-methyl-
4-oxocyclohexane-1,3-dicarboxylates and Their Reactions
with Nucleophilic Reagents
V. L. Gein1, N. V. Nosova1, K. D. Potemkin1, Z. G. Aliev2, and A. P. Kriven’ko3
1 Perm State Pharmaceutical Academy, ul. Lenina 48, Perm, 614990 Russia
e-mail: perm@pfa.ru
2 Institute of Chemical Physics Problems, Russian Academy of Sciences, Chernogolovka, Moscow oblast, Russia
3 Saratov State University, Saratov, Russia
Received July 20, 2004
Abstract—Base-catalyzed reactions of isopropyl acetoacetate with aromatic and heterocyclic aldehydes
afforded the corresponding diisopropyl 6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxylates which were
brought into reactions with mono- and difunctional nitrogen-containing nucleophiles. According to the X-ray
diffraction data, diisopropyl 4-oxocyclohexane-1,3-dicarboxylates in crystal exist in the ketone form.
With the goal of elucidating the effect of alkyl
radical in the alkoxycarbonyl group on the reactivity
of 1,3-bis(alkoxycarbonyl)-substituted cyclohexanones
(cyclic β-hydroxy ketones) [1–6] we synthesized
2-substituted diisopropyl 6-hydroxy-6-methyl-4-oxo-
cyclohexane-1,3-dicarboxylates and studied their
structure and reactions with mono- and difunctional
nitrogen-containing nucleophiles. Compounds Ia–If
were obtained by the known method, namely by
diketone condensation of isopropyl acetoacetate with
aromatic and heterocyclic aldehydes under conditions
of base catalysis [1] (in the presence of piperidine;
Scheme 1).
ester (1722–1735 and 1737–1745 cm–1) and ketone
carbonyl groups (1700–1710 cm–1) and hydroxy group
(3450–3504 cm–1). In the 1H NMR spectra of Ia–If we
observed a singlet at δ 1.18–1.30 ppm from protons of
the methyl group on C6, a singlet at δ 4.58–4.91 ppm
from the hydroxy proton, doublet signals at δ 3.15–
3.42 and 3.67–4.05 ppm (J = 12 Hz) from protons
in positions 1 and 3 of the cyclohexane ring, a triplet
at δ 3.73–4.04 ppm from the 2-H proton, and two
doublets (AB system) from the C5H2 methylene group
at δ 2.25–2.40 and 2.82–3.02 ppm (J = 14 Hz).
Compounds Ia–If can exist as ketone (A) and enol
1
tautomers (B). The H NMR spectra of Ia–If contain
Cyclohexanedicarboxylates Ia–If were isolated as
colorless crystalline substances which are soluble in
dimethyl sulfoxide, dimethylformamide, and acetone
and insoluble in water. Their IR spectra contained
absorption bands due to stretching vibrations of the
a signal at δ 12 ppm, which may be attributed to proton
of the hydroxy group in the enol tautomer. The fraction
of the enol form depends on the substituent R in
position 2 of the cyclohexane ring. Electron-acceptor
groups in the aryl substituent, e.g., nitro group, favor
Scheme 1.
O
O
Me
OH
O
Me
NH
O
Me
O
Me
O
O
Me
2
+
RCHO
Me
HO
Me
HO
R
R
Me
O
Me
Me
Me
Me
Me
O
O
O
O
A
Ia–If
B
R = Ph (a), 4-CH3OC6H4 (b), 4-BrC6H4 (c), 4-O2NC6H4 (d), 3-O2NC6H4 (e), 2-pyridyl (f).
1070-4280/05/4107-1016 © 2005 Pleiades Publishing, Inc.

SYNTHESIS AND STRUCTURE OF DIISOPROPYL 6-HYDROXY-6-METHYL-...
H5b
1017
C7
H5a
C6
enolization, and the fraction of the enol tautomer
attains 5%; the fractions of the enol form in com-
pounds Ia and If are 3.7 and 3.3%, respectively.
C5
C4
O4
H3
C3
H1a
C1
O1
Compounds Ia–If turn dark yellow on treatment
with iron(III) chloride; on storage, the solution grad-
ually darkens and acquires dark red color, presumably
as a result of displacement of the tautomeric equilib-
rium toward the enol form. Thus the color test with
iron(III) chloride and the H NMR data suggest that
compounds Ia–If in solution exist as mixtures of
ketone (A) and enol tautomers (B).
H1
O2
C20
C17
O6
O5
C10
C2
C8
H18
C18
N
H2
O3
1
C12
C13
C16
9 C9
H
C19
C11
C15
C14
The structure of compound If in crystal was studied
by the X-ray diffraction method. A single crystal of If
suitable for X-ray analysis was obtained by slow crys-
tallization from an alcoholic solution. The structure of
molecule If is shown in figure; for the sake of sim-
plicity, some hydrogen atoms are not shown. It is seen
that compound If in crystal exists exclusively as
ketone form A. The cyclohexane ring adopts a chair
conformation. The three bulky substituents (two alkoxy-
carbonyl groups and benzene ring) occupy equatorial
positions. The bond lengths and bond angles in mole-
cule If have their usual values and require no com-
ments. Probably, molecules If in crystal are linked
through a very weak hydrogen bond O1–N1 ···O3
[d(O1 · · · O3) = 3.146 Å, d(H1 · · · O3) = 2.331 Å,
∠O1N1O3 = 165.58°] to give centrosymmetric dimers.
Structure of the molecule of diisopropyl 6-hydroxy-6-
methyl-4-oxo-2-(2-pyridyl)cyclohexane-1,3-dicarboxylate
(If) according to the X-ray diffraction data.
ments showed that compounds Id and Ie successfully
reacted with aromatic amines on heating in boiling
isopropyl alcohol in the presence of acetic acid. As
a result, we isolated the corresponding 2-substituted
diisopropyl 4-arylamino-6-hydroxy-6-methyl-3-cyclo-
hexene-1,3-dicarboxylates IId and IIe in high yields
(Scheme 2). Isopropyl alcohol was selected as solvent
in order to avoid transesterification of initial com-
pounds I.
Compounds IId and IIe are yellow crystalline sub-
stances which are soluble in DMSO, DMF, acetone,
toluene, and benzene and insoluble in water. The IR
spectra of crystalline samples of IId and IIe contained
absorption bands due to stretching vibrations of the
N–H (3150–3210 cm–1), O–H (3450–3520 cm–1), and
C=C bonds (1650–1665 cm–1). Compounds IId and IIe
contained a singlet from the hydroxy proton (δ 4.58–
4.60 ppm), doublets from two CH protons in positions
1 and 2 of the cyclohexane ring (δ 4.16–4.23 and 2.48–
2.52 ppm, respectively, J = 11 Hz), and a singlet from
the NH proton (δ 10.72–10.78 ppm). The spectral data
indicate that compounds IId and IIe exist in the
enamino form.
We examined reactions of diisopropyl cyclo-
hexanedicarboxylates Ia–If with aromatic amines, hy-
drazines, phenylhydrazine, and hydroxylamine in order
to elucidate how the nature of the alkoxycarbonyl
group affects the reactivity of these compounds. We
previously showed [2] that dimethyl 4-oxocyclo-
hexane-1,3-dicarboxylates react with aromatic amines
on heating in boiling benzene in the presence of
a catalytic amount of acetic acid. The reaction is
accompanied by elimination of water with formation
of arylaminocyclohexadienes [2]. Under analogous
conditions, diethyl 6-hydroxy-4-oxocyclohexane-1,3-
dicarboxylates give rise to the corresponding aryl-
aminocyclohexenes, and the hydroxy group on C6
remains intact [3, 4].
Reactions of cyclic hydroxy ketones containing
methoxy- or ethoxycarbonyl groups in positions 1 and
3 of the cyclohexane ring are known to react with
hydrazine hydrate at the 1,3-dioxo fragment; the
subsequent heterocyclization gives the corresponding
tetrahydroindazoles [5, 6]. Under similar conditions,
bis(tert-butoxycarbonyl)-substituted analogs are con-
verted into 6-hydrazones [5]. Diisopropyl 6-hydroxy-
6-methyl-4-oxocyclohexane-1,3-dicarboxylates Ic–Ie
reacted with hydrazine hydrate at a ratio of 1 : 1 in
Diisopropyl 6-hydroxy-4-oxocyclohexane-1,3-di-
carboxylates were brought into reactions with p-tolu-
idine and p-anisidine. However, the procedures
reported in [2, 3] turned out to be inapplicable. When
the reactions were performed by heating of the reac-
tants in boiling benzene or toluene, the process was
accompanied by strong tarring, and we failed to isolate
the desired amination products. Our further experi-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 7 2005

GEIN et al.
1018
Scheme 2.
Ar
PhNH
NH
O
N
O
OPr-i
OPr-i
ArNH2
PhNHNH2
Me
HO
Me
HO
R
R
O
O
O
OPr-i
O
OPr-i
OPr-i
IId, IIe
IVa, IVc, IVd
Me
HO
R
HO
NH
N
O
N
O
OPr-i
OH
OPr-i
Ia–If
NH2NH2
NH2OH
Me
HO
Me
HO
R
R
O
OPr-i
O
OPr-i
IIIc–IIIe
Va, Vb, Ve
IVa, Va, R = Ph; Vb, R = 4-CH3OC6H4; IIIc, IVc, R = 4-BrC6H4; IId, IIId, IVd, R = 4-O2NC6H4; IIe, IIIe, Ve, 3-O2NC6H4;
IId, Ar = 4-CH3OC6H4; IIe, Ar = 4-CH3C6H4.
alcohol on heating on a water bath in the absence of
a catalyst. As with dimethyl and diethyl esters, the
products were isopropyl 3,6-dihydroxy-6-methyl-
4,5,6,7-tetrahydro-2H-indazole-5-carboxylates IIIc–
IIIe (Scheme 2) but their formation required a longer
time (by a factor of 3–4), presumably due to stronger
electron-donor effect of the isopropyl group as com-
pared to ethyl. When the reaction time was shorter, we
isolated mixtures of initial hydroxy ketones, inter-
mediate hydrazones, and cyclization products, but we
failed to terminate the process at the stage of formation
of the corresponding hydrazones.
The reactions of compounds Ia–Ie with phenyl-
hydrazine and hydroxylamine afforded the correspond-
ing diisopropyl 6-hydroxy-6-methyl-4-phenylhydra-
zonocyclohexane-1,3-dicarboxylates IVa, IVc, and
IVd and diisopropyl 6-hydroxy-4-hydroxyimino-6-
methylcyclohexane-1,3-dicarboxylates Va, Vb, and Ve
(Scheme 2). No subsequent cyclization occurred, re-
gardless of the reaction time. Presumably, the nucleo-
philicity of the nitrogen atom in the phenylhydrazine
residue and of the oxygen atom in the hydroxylamine
residue is insufficient to ensure heterocyclization.
Phenylhydrazones IVa, IVc, and IVd are colorless
crystalline substances which are soluble in DMSO,
poorly soluble in alcohols, and insoluble in water.
Their IR spectra contained absorption bands due to
stretching vibrations of the O–H (3442–3505 cm–1),
N–H (3370–3380 cm–1), and C=N bonds (1689–
1700 cm–1). Phenylhydrazones IVa, IVc, and IVd dis-
Indazoles IIIc–IIIe are colorless crystalline sub-
stances readily soluble in DMS and DMF, poorly
soluble in dioxane and alcohol, and insoluble in water.
Compounds IIIc–IIIe give rise to an intense cherry
color on treatment with a solution of iron(III) chloride.
The IR spectra of crystalline indazoles IIIc–IIIe con-
tained absorption bands due to stretching vibrations of
the 6-OH (3435–3500 cm–1) and NH groups (3255–
1
played in the H NMR spectra doublets from protons
in positions 1 and 3 of the cyclohexane ring (δ 3.04–
3.15 and 3.64–3.75 ppm, respectively, J = 12 Hz),
a triplet from the 2-H proton at δ 3.66–3.83 ppm, and
a singlet from the NH proton at δ 9.05–9.09 ppm.
1
3280 cm–1). In the H NMR spectra of IIIc–IIIe,
doublets from the 4-H and 5-H protons were located
at δ 2.48–2.58 and 3.95–4.18 ppm, respectively (J =
11 Hz), and the NH and 3-OH protons gave a broaden-
ed singlet in the δ region 8–12 ppm with an intensity of
2H. The IR and 1H NMR data, in combination with the
color test with iron(III) chloride, suggest that com-
pounds IIIc–IIIe in crystal and in solution exist in the
enol form, in keeping with published data for struc-
turally related indazoles [7] which were studied by
X-ray analysis.
Oximes Va, Vb, and Ve are colorless crystalline
substances which are readily soluble in DMSO and
DMF, poorly soluble in alcohol, and insoluble in water.
Their IR spectra contained absorption bands at 3480–
3540, 3280–3284, and 1690–1695 cm–1, which were
assigned to stretching vibrations of the 6-hydroxy
group, N-OH group, and C=N bond, respectively. In
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 7 2005

SYNTHESIS AND STRUCTURE OF DIISOPROPYL 6-HYDROXY-6-METHYL-...
1019
1
the H NMR spectra of Va, Vb, and Ve we observed
Diisopropyl 2-(4-bromophenyl)-6-hydroxy-6-
methyl-4-oxocyclohexane-1,3-dicarboxylate (Ic).
Yield 76%, mp 173–174°C. IR spectrum, ν, cm–1: 1710
(CO, ketone); 1732, 1745 (CO, ester); 3490 (OH).
1H NMR spectrum, δ, ppm: 0.70 d, 0.83 d, 0.94 d, and
0.97 d [3H each, CH(CH3)2]; 1.18 s (3H, CH3); 2.27 d
(1H, 5-HA or 5-HB, J = 14 Hz); 2.83 d (1H, 5-HB or
5-HA, J = 14 Hz); 3.20 d (1H, 1-H, J = 12 Hz); 3.73 t
(1H, 2-H); 3.86 d (1H, 3-H; J = 12 Hz); 4.56 m and
4.65 m [1H each, CH(CH3)2]; 4.82 s (1H, OH); 7.20 d
and 7.42 d (2H each, 4-BrC6H4). Found, %: C 53.62;
H 5.75. C21H27BrO6. Calculated, %: C 53.74; H 5.80.
doublets from protons in positions 1 and 3 of the
cyclohexane ring (δ 2.95–3.18 and 3.50–3.70 ppm,
respectively, J = 12 Hz), a triplet from the 2-H proton
at δ 3.56–3.80 ppm, and a singlet from the oxime
hydroxy proton at δ 10.62–10.74 ppm.
EXPERIMENTAL
The IR spectra were recorded from samples
dispersed in mineral oil on UR-20 and Specord 80
spectrometers. The H NMR spectra were measured
on Bruker AM-300 (300 MHz) and Bruker DRX-400
(400 MHz) instruments from solutions in DMSO-d6
using HMDS as internal reference. The progress of
reactions and the purity of products were monitored
by TLC on Silufol UV-254 plates using benzene–ethyl
acetate (5:1) as eluent.
1
Diisopropyl 6-hydroxy-6-methyl-2-(4-nitrophe-
nyl)-4-oxocyclohexane-1,3-dicarboxylate (Id). Yield
83%, mp 186–188°C. IR spectrum, ν, cm–1: 1695 (CO,
ketone); 1727, 1732 (CO, ester); 3510 (OH). 1H NMR
spectrum, δ, ppm: 0.77 d, 0.92 d, 1.05 d, and 1.08 d
[3H each, CH(CH3)2]; 1.27 s (3H, CH3); 2.38 d (1H,
5-HA or 5-HB, J = 14 Hz); 2.83 d (1H, 5-HB or 5-HA,
J = 14 Hz); 3.30 d (1H, 1-H, J = 12 Hz); 4.02 t (1H,
2-H); 3.97 d (1H, 3-H, J = 12 Hz); 4.67 m and 4.75 m
[1H each, CH(CH3)2]; 4.58 s (1H, OH); 7.60 d and
8.12 d (2H each, 4-O2NC6H4). Found, %: C 59.77;
H 6.64; N 3.29. C21H27NO8. Calculated, %: C 59.85;
H 6.46; N 3.32.
Diisopropyl 6-hydroxy-6-methyl-4-oxo-2-phenyl-
cyclohexane-1,3-dicarboxylate (Ia). Isopropyl aceto-
acetate, 0.046 mol, and benzaldehyde, 0.023 mol, were
dissolved in 6 ml of isopropyl alcohol (on heating if
necessary). Piperidine, 1 ml, was added to the solution,
and the mixture was kept for 1–3 days at room tem-
perature. The precipitate was filtered off and recrys-
tallized from isopropyl alcohol. Yield 70%, mp 180–
181°C. IR spectrum, ν, cm–1: 1700 (CO, ketone); 1722,
Diisopropyl 6-hydroxy-6-methyl-2-(3-nitrophe-
nyl)-4-oxocyclohexane-1,3-dicarboxylate (Ie). Yield
81%, mp 174–176°C. IR spectrum, ν, cm–1: 1712 (CO,
ketone); 1731, 1738 (CO, ester); 3523 (OH). 1H NMR
spectrum, δ, ppm: 0.75 d, 0.90 d, 1.00 d, and 1.04 d
[3H each, CH(CH3)2]; 1.30 s (3H, CH3); 2.40 d (1H,
5-HA or 5-HB, J = 14 Hz); 2.94 d (1H, 5-HB or 5-HA,
J = 14 Hz); 3.42 d (1H, 1-H, J = 12 Hz); 3.98 t (1H,
2-H); 4.05 d (1H, 3-H, J = 12 Hz); 4.63 m and 4.75 m
[1H each, CH(CH3)2]; 4.90 s (1H, OH); 7.60 t, 7.79 d,
8.11 d, and 8.22 s (1H each, 3-O2NC6H4). Found, %:
C 59.91; H 6.39; N 3.27. C21H27NO8. Calculated, %:
C 59.85; H 6.46; N 3.32.
1
1737 (CO, ester); 3450 (OH). H NMR spectrum, δ,
ppm: 0.70 d, 0.88 d, 1.00 d, and 1.02 d [3H each,
CH(CH3)2]; 1.25 s (3H, CH3); 2.32 d (1H, 5-HB or
5-HA, J = 14 Hz); 2.86 d (1H, 5-HA or 5-HB, J =
14 Hz); 3.24 d (1H, 1-H, J = 12 Hz); 3.79 t (1H, 2-H);
3.85 d (1H, 3-H, J = 12 Hz); 4.66 m and 4.72 m [1H
each, CH(CH3)2]; 4.77 s (1H, OH); 7.20 m (5H, C6H5).
Found, %: C 67.19; H 7.54. C21H28O6. Calculated, %:
C 67.00; H 7.49.
Compounds Ib–If were synthesized according to
a similar procedure.
Diisopropyl 6-hydroxy-2-(4-methoxyphenyl)-6-
methyl-4-oxocyclohexane-1,3-dicarboxylate (Ib).
Yield 72%, mp 164–166°C. IR spectrum, ν, cm–1: 1715
(CO, ketone); 1737, 1742 (CO, ester); 3532 (OH).
1H NMR spectrum, δ, ppm: 0.68 d, 0.83 d, 0.94 d, and
0.97 d [3H each, CH(CH3)2]; 1.18 s (3H, CH3); 2.25 d
(1H, 5-HA or 5-HB, J = 14 Hz); 2.82 d (1H, 5-HB or
5-HA, J = 14 Hz); 3.15 d (1H, 1-H, J = 12 Hz), 3.78 t
(1H, 2-H); 3.67 d (1H, 3-H, J = 12 Hz); 3.63 s
(3H, 4-CH3OC6H4); 4.58 m and 4.65 m [1H each,
CH(CH3)2]; 4.70 s (1H, OH); 6.75 d and 7.14 d
(2H each, 4-CH3OC6H4). Found, %: C 65.09; H 7.29.
C22H30O7. Calculated, %: C 65.01; H 7.44.
Diisopropyl 6-hydroxy-6-methyl-4-oxo-2-(2-pyr-
idyl)cyclohexane-1,3-dicarboxylate (If). Yield 37%,
mp 122–124°C. IR spectrum, ν, cm–1: 1704 (CO,
ketone); 1734, 1742 (CO, ester); 3504 (OH). 1H NMR
spectrum, δ, ppm: 0.76 d, 0.89 d, 0.99 d, and 1.01 d
[3H each, CH(CH3)2]; 1.27 s (3H, CH3); 2.32 d (1H,
5-HA or 5-HB, J = 14 Hz); 3.02 d (1H, 5-HB or 5-HA,
J = 14 Hz); 3.32 d (1H, 1-H, J = 12 Hz); 4.04 t (1H,
2-H); 4.00 d (1H, 3-H, J = 12 Hz); 4.65 m and 4.72 m
[1H each, CH(CH3)2]; 4.91 s (1H, OH); 7.12 d, 7.22 t,
7.68 t, and 8.51 d (1H each, 2-pyridyl). Found, %:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 7 2005

GEIN et al.
1020
OH), 4.73 m [1H, CH(CH3)2], 6.98 d and 7.34 d (2H
each, 4-BrC6H4), 8–12 br.s (2H, NH, OH). Found, %:
C 52.65; H 5.03; N 6.73. C18H21BrN2O4. Calculated,
%: C 52.82; H 5.17; N 6.84.
C 63.44; H 7.31; N 3.84. C20H27NO6. Calculated, %:
C 63.65; H 7.21; N 3.71.
Diisopropyl 6-hydroxy-4-(4-methoxyphenyl-
amino)-6-methyl-2-(4-nitrophenyl)-3-cyclohexene-
1,3-dicarboxylate (IId). A solution of 0.005 mol of
compound Id, 0.005 mol of p-anisidine, and 0.4 ml of
acetic acid (2% by volume) in 20 ml of 2-propanol was
heated for 9–16 h under reflux. The mixture was
cooled and evaporated, and the residue was recrys-
tallized from isopropyl alcohol. Yield 49%, mp 148–
150°C. IR spectrum, ν, cm–1: 1665 (C=C), 1710 (CO),
Isopropyl 3,6-dihydroxy-6-methyl-4-(4-nitro-
phenyl)-4,5,6,7-tetrahydro-2H-indazole-5-carbox-
ylate (IIId) was synthesized in a similar way. Yield
56%, mp 272–274°C. IR spectrum, ν, cm–1: 1720
1
(CO), 3280 (NH), 3500 (OH). H NMR spectrum, δ,
ppm: 0.80 d and 1.09 d [3H each, CH(CH3)2], 1.26 s
(3H, CH3), 2.49 d (1H, 7-HA or 7-HB, J = 15 Hz),
2.80 d (1H, 7-HB or 7-HA, J = 15 Hz), 2.58 d (1H, 4-H,
J = 11 Hz), 4.18 d (1H, 5-H, J = 11 Hz), 4.56 s (1H,
OH), 4.76 m [1H, CH(CH3)2], 7.39 d and 8.12 d (2H
each, 4-O2NC6H4), 8–12 br.s (2H, NH, OH). Found,
%: C 57.70; H 5.56; N 11.25. C18H21N3O6. Calculated,
%: C 57.59; H 5.64; N 11.19.
1
3210 (NH), 3450 (OH). H NMR spectrum, δ, ppm:
0.39 d, 0.74 d, 0.88 d, and 1.00 d [3H each, CH(CH3)2];
1.10 s (3H, CH3); 2.20 d (1H, 5-HA or 5-HB, J =
17 Hz); 2.90 d (1H, 5-HB or 5-HA, J = 17 Hz); 2.48 d
(1H, 2-H, J = 11 Hz); 4.23 d (1H, 1-H, J = 11 Hz);
3.77 s (3H, 4-CH3OC6H4); 4.58 s (1H, OH); 4.65 m
and 4.78 m [1H each, CH(CH3)2]; 6.97 d and 7.12 d
(2H each, 4-CH3OC6H4); 7.62 d and 8.17 d (2H each,
4-NO2C6H4); 10.72 s (1H, NH). Found, %: C 63.72;
H 6.39; N 5.41. C28H34N2O8. Calculated, %: C 63.87;
H 6.51; N 5.32.
Isopropyl 3,6-dihydroxy-6-methyl-4-(3-nitro-
phenyl)-4,5,6,7-tetrahydro-2H-indazole-5-carbox-
ylate (IIIe) was synthesized in a similar way. Yield
85%, mp 289–291°C. IR spectrum, ν, cm–1: 1732
1
(CO), 3255 (NH), 3440 (OH). H NMR spectrum, δ,
Diisopropyl 6-hydroxy-6-methyl-4-(4-methyl-
phenylamino)-2-(3-nitrophenyl)-3-cyclohexene-1,3-
dicarboxylate (IIe) was synthesized in a similar way.
Yield 60%, mp 127–129°C. IR spectrum, ν, cm–1: 1650
ppm: 0.73 d and 1.02 d [3H each, CH(CH3)2]; 1.20 s
(3H, CH3); 2.53 d (1H, 7-HA or 7-HB, J = 15 Hz);
2.76 d (1H, 7-HB or 7-HA, J = 15 Hz); 2.56 d (1H, 4-H,
J = 11 Hz); 4.14 d (1H, 5-H, J = 11 Hz); 4.49 s (1H,
OH); 4.73 m [1H, CH(CH3)2]; 7.51 t, 7.49 d, 7.87 s,
and 8.00 d (1H each, 3-O2NC6H4); 8–12 br.s (2H,
NH, OH). Found, %: C 57.73; H 5.75; N 11.27.
C18H21N3O6. Calculated, %: C 57.59; H 5.64; N 11.19.
1
(C=C), 1700 (CO), 3150 (NH), 3520 (OH). H NMR
spectrum, δ, ppm: 0.31 d, 0.77 d, 0.98 d, and 1.03 d
[3H each, CH(CH3)2]; 1.09 s (3H, CH3); 2.19 d (1H,
5-HA or 5-HB, J = 17 Hz); 2.97 d (1H, 5-HB or 5-HA,
J = 17 Hz); 2.25 s (3H, 4-CH3C6H4); 2.52 d (1H, 2-H,
J = 11 Hz); 4.16 d (1H, 1-H, J = 11 Hz); 4.57 s (1H,
OH); 4.59 m and 4.73 m [1H each, CH(CH3)2]; 7.00 d
and 7.14 d (2H each, 4-CH3C6H4); 7.50 t, 7.59 d,
7.91 s, and 7.99 d (1H each, 3-O2NC6H4); 10.78 s (1H,
NH). Found, %: C 65.96; H 6.62; N 5.42. C28H34N2O7.
Calculated, %: C 65.87; H 6.71; N 5.49.
Diisopropyl 6-hydroxy-6-methyl-2-phenyl-4-
phenylhydrazonocyclohexane-1,3-dicarboxylate
(IVa). Phenylhydrazine, 0.005 mol, was added to
0.005 mol of compound Ia in 20 ml of 2-propanol, the
mixture was heated for 1 h on a boiling water bath and
cooled, and the precipitate was filtered off and recrys-
tallized from isopropyl alcohol. Yield 59%, mp 210–
212°C. IR spectrum, ν, cm–1: 1689 (C=N), 1725 (CO),
Isopropyl 4-(4-bromophenyl)-3,6-dihydroxy-6-
methyl-4,5,6,7-tetrahydro-2H-indazole-5-carbox-
ylate (IIIc). Hydrazine hydrate, 0.005 mol, was added
to a mixture of 0.005 mol of compound Ic and 20 ml
of 2-propanol. The mixture was heated for 3–5 h on
a boiling water bath and cooled, and the precipitate
was filtered off and recrystallized from 2-propanol.
Yield 88%, mp 290–291°C. IR spectrum, ν, cm–1: 1731
1
3370 (NH), 3442 (OH). H NMR spectrum, δ, ppm:
0.66 d, 0.93 d, 1.00 d, and 1.02 d [3H each, CH(CH3)2];
1.30 s (3H, CH3); 2.17 d (1H, 5-HA or 5-HB, J =
15 Hz); 3.17 d (1H, 5-HB or 5-HA, J = 15 Hz); 3.03 d
(1H, 1-H, J = 12 Hz); 3.66 t (1H, 2-H); 3.64 d
(1H, 3-H, J = 12 Hz); 4.59 m and 4.74 m [1H each,
CH(CH3)2]; 4.41 s (1H, OH); 7.96 m (10H, C6H5);
9.05 s (1H, NH). Found, %: C 69.44; H 7.49; N 6.08.
C27H34N2O5. Calculated, %: C 69.51; H 7.34; N 6.00.
1
(CO), 3260 (NH), 3435 (OH). H NMR spectrum, δ,
ppm: 0.77 d and 1.03 d [3H each, CH(CH3)2], 1.18 s
(3H, CH3), 2.42 d (1H, 7-HA or 7-HB, J = 15 Hz),
2.69 d (1H, 7-HB or HA, J = 15 Hz), 2.48 d (1H, 4-H,
J = 11 Hz), 3.95 d (1H, 5-H, J = 11 Hz), 4.38 s (1H,
Diisopropyl 2-(4-bromophenyl)-6-hydroxy-6-
methyl-4-phenylhydrazonocyclohexane-1,3-dicar-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 7 2005

SYNTHESIS AND STRUCTURE OF DIISOPROPYL 6-HYDROXY-6-METHYL-...
1021
boxylate (IVc) was synthesized in a similar way. Yield
75%, mp 216–218°C. IR spectrum, ν, cm–1: 1700
(C=N), 1735 (CO), 3380 (NH), 3505 (OH). H NMR
boxylate (Vb) was synthesized in a similar way. Yield
82%, mp 211–212°C. IR spectrum, ν, cm–1: 1690
(C=N), 1725 (CO), 3280 (NOH), 3500 (OH). 1H NMR
spectrum, δ, ppm: 0.71 d, 0.81 d, 0.97 d, and 0.99 d
[3H each, CH(CH3)2]; 1.22 s (3H, CH3); 1.95 d (1H,
5-HA or 5-HB, J = 14 Hz); 3.28 d (1H, 5-HB or 5-HA,
J = 14 Hz); 2.95 d (1H, 1-H, J = 12 Hz); 3.56 t (1H,
2-H); 3.50 d (1H, 3-H, J = 12 Hz); 3.68 s (3H,
4-CH3OC6H4); 4.60 m and 4.65 m [1H each,
CH(CH3)2]; 4.30 s (1H, 4-OH); 6.80 d and 7.16 d
(2H each, 4-CH3OC6H4); 10.62 s (1H, NOH). Found,
%: C 62.77; H 7.30; N 3.42. C22H31NO7. Calculated,
%: C 62.69; H 7.41; N 3.32.
1
spectrum, δ, ppm: 0.73 d, 0.95 d, 1.00 d, and 1.04 d
[3H each, CH(CH3)2]; 1.30 s (3H, CH3); 2.16 d (1H,
5-HA or 5-HB, J = 14 Hz); 3.17 d (1H, 5-HB or 5-HA,
J = 15 Hz); 3.04 d (1H, 1-H, J = 12 Hz); 3.66 t (1H,
2-H); 3.64 d (1H, 3-H, J = 12 Hz); 4.60 m and 4.76 m
[1H each, CH(CH3)2]; 4.48 s (1H, OH); 7.28 d and
7.49 d (2H each, 4-BrC6H4); 6.86 m (5H, C6H5);
9.06 s (1H, NH). Found, %: C 59.58; H 5.98; N 5.09.
C27H33BrN2O5. Calculated, %: C 59.45; H 6.10; N 5.13.
Diisopropyl 6-hydroxy-6-methyl-2-(4-nitrophe-
nyl)-4-phenylhydrazonocyclohexane-1,3-dicarbox-
ylate (IVd) was synthesized in a similar way. Yield
66%, mp 209–211°C. IR spectrum, ν, cm–1: 1690
Diisopropyl 6-hydroxy-4-hydroxyimino-6-
methyl-2-(3-nitrophenyl)cyclohexane-1,3-dicarbox-
ylate (Ve) was synthesized in a similar way. Yield
71%, mp 215–216°C. IR spectrum, ν, cm–1: 1695
(C=N), 1735 (CO), 3280 (NOH), 3540 (OH). 1H NMR
spectrum, δ, ppm: 0.71 d, 0.80 d, 0.94 d, and 0.96 d
[3H each, CH(CH3)2]; 1.27 s (3H, CH3); 2.04 d (1H,
5-HA or 5-HB, J = 14 Hz); 3.32 d (1H, 5-HB or 5-HA,
J = 14 Hz); 3.18 d (1H, 1-H, J = 12 Hz); 3.80 t (1H,
2-H); 3.70 d (1H, 3-H, J = 12 Hz); 4.58 m and 4.66 m
[1H each, CH(CH3)2]; 4.56 s (1H, 4-OH); 7.60 t,
7.77 d, 8.10 d, and 8.20 s (1H each, 3-O2NC6H4);
10.74 s (1H, NOH). Found, %: C 57.86; H 6.32;
N 6.33. C21H28N2O8. Calculated, %: C 57.79; H 6.47;
N 6.42.
1
(C=N), 1722 (CO), 3375 (NH), 3500 (OH). H NMR
spectrum, δ, ppm: 0.71 d, 0.93 d, 0.99 d, and 1.03 d
[3H each, CH(CH3)2]; 1.32 s (3H, CH3); 2.21 d (1H,
5-HA or 5-HB, J = 15 Hz); 3.20 d (1H, 5-HB or 5-HA,
J = 15 Hz); 3.15 d (1H, 1-H, J = 12 Hz); 3.83 t (1H,
2-H); 3.75 d (1H, 3-H, J = 12 Hz); 4.60 m and 4.74 m
[1H each, CH(CH3)2]; 4.62 s (1H, OH); 7.60 d and
8.18 d (2H each, 4-O2NC6H4); 6.96 m (5H, C6H5);
9.09 s (1H, NH). Found, %: C 63.49; H 6.34; N 8.15.
C27H33N3O7. Calculated, %: C 63.39; H 6.50; N 8.21.
Diisopropyl 6-hydroxy-4-hydroxyimino-6-
methyl-2-phenylcyclohexane-1,3-dicarboxylate
(Va). A solution of 0.006 mol of potassium hydroxide
in 5 ml of 2-propanol was added to a solution of
0.006 mol of hydroxylamine hydrochloride in 6 ml
of 2-propanol. The precipitate was filtered off, and
0.004 mol of compound Ia was added to the filtrate.
The mixture was heated for 1 h on a boiling water bath
and cooled, and the precipitate was filtered off and
recrystallized from 2-propanol. Yield 61%, mp 225–
226°C. IR spectrum, ν, cm–1: 1690 (C=N), 1719 (CO),
X-Ray analysis of diisopropyl 6-hydroxy-6-
methyl-4-oxo-2-(2-pyridyl)cyclohexane-1,3-dicar-
boxylate (If). Unit cell parameters: a = 9.838(2), b =
18.578(4), c = 5.976(1) Å; α = 86.21(3), β = 74.85(3),
γ = 76.04(3)°; V = 1023.1(3) Å3; M 377.43; dcalc
=
1.225 g/cm3; Z = 2; space group P-1. A set of experi-
mental reflections was acquired on a KM-4 (KUMA
Diffraction) automatic four-circle diffractometer with
a χ-geometry (ω/2Θ scanning, monochromatic MoKα
irradiation, 2Θ ≤ 52.1°). Total of 3171 independent
reflections were measured. No correction for absorp-
tion was introduced (μ 0.090 mm–1). The structure was
solved by the direct method using SIR92 program [8],
followed by calculation of the electron density maps.
The positions of hydrogen atoms in the methyl and
aromatic groups were set from the geometry considera-
tions, and the positions of the other hydrogen atoms
were determined from difference synthesis of electron
density. The structure was refined by the least-squares
procedure in full-matrix anisotropic approximation for
non-hydrogen atoms using SHELXL-97 program [9]
until R1 = 0.0787, wR2 = 0.2410 [from 2040 reflections
1
3284 (NOH), 3480 (OH). H NMR spectrum, δ, ppm:
0.66 d, 0.77 d, 0.95 d, and 0.97 d [3H each, CH(CH3)2];
1.23 s (3H, CH3); 1.98 d (1H, 5-HA or 5-HB, J =
14 Hz); 3.29 d (1H, 5-HB or 5-HA, J = 14 Hz); 3.00 d
(1H, 1-H, J = 12 Hz); 3.62 t (1H, 2-H); 3.58 d
(1H, 3-H, J = 12 Hz); 4.57 m and 4.62 m [1H each,
CH(CH3)2]; 4.36 s (1H, 4-OH); 7.18 m (5H, C6H5);
10.65 s (1H, NOH). Found, %: C 64.35; H 7.58;
N 3.65. C21H29NO6. Calculated, %: C 64.43; H 7.47;
N 3.58.
Diisopropyl 6-hydroxy-4-hydroxyimino-2-(4-
methoxyphenyl)-6-methylcyclohexane-1,3-dicar-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 7 2005

GEIN et al.
1022
4. Kriven’ko, A.P. and Sorokin, V.V., Russ. J. Org. Chem.,
with I ≥ 2σ(I)] and R1 = 0.1144, wR2 = 0.2653 (from all
3171 reflections); GooF = 1.113.
1999, vol. 35, p. 1097.
5. Gein, V.L., Gein, N.V., Potemkin, K.D., and Kriven’-
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 04-03-96042).
ko, A.P., Russ. J. Gen. Chem., 2004, vol. 74, p. 1564.
6. Sorokin, V.V., Grigor’ev, A.V., Ramazanov, A.K., and
Kriven’ko, A.P., Khim. Geterotsikl. Soedin., 1999, p. 757.
7. Usova, E.B., Lysenko, L.I., Krapivin, G.D., Zavod-
nik, V.E., and Kul’nevich, V.G., Khim. Geterotsikl.
Soedin., 1997, p. 1459.
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1. Finar, I.L., J. Chem. Soc., 1961, p. 674.
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2. Gein, V.L., Gein, N.V., Voronina, E.V., and Kriven’-
Gualardi, A., J. Appl. Crystallogr., 1993, vol. 26, p. 343.
ko, A.P., Khim.-Farm. Zh., 2002, vol. 36, no. 3, p. 23.
3. Sorokin, V.V., Kuz’min, M.V., Smirnova, N.S., Kozhev-
nikova, N.I., and Kriven’ko, A.P., Zh. Org. Khim., 1994,
vol. 30, p. 528.
9. Sheldrick, G.M., SHELX97. Programs for Crystal Struc-
ture Analysis, Gottingen: Univ. of Gottingen, Germany,
1998, p. 2332.
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