Reaction of dialkyl 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3- dicarboxylates with aliphatic amines

Article abstract of DOI:10.1134/S1070363208120116

Benzylamine, phenethylamine, and homoveratrylamine reacted with dialkyl 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylates at the endocyclic carbonyl group with conservation of the enolic hydroxy group to give dialkyl 4-alkylamino-2-aryl-6-hydroxy-6-methylcyclohex-3-ene-1,3-dicarboxylates. The reaction of dimethyl 4-hydroxy-4-methyl-6-oxo-2-phenylcyclohexane-1,3- dicarboxylate with tryptamine was accompanied by dehydration with formation of dimethyl 4-[2-(1H-indol-3-yl)ethylamino]-6-methyl-2-phenylcyclohexa-3,5-diene-1, 3-dicarboxylate, presumably due to basic properties of the indole nitrogen atom.

Full text of DOI:10.1134/S1070363208120116

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 12, pp. 2357–2362. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.L. Gein, N.V. Nosova, A.S. Prusakova, M.I. Vakhrin, A.P. Kriven’ko, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78,
No. 12, pp. 2011–2016.
Reaction of Dialkyl 2-Aryl-4-hydroxy-4-methyl-6-oxocyclo-
hexane-1,3-dicarboxylates with Aliphatic Amines
V. L. Geina, N. V. Nosovaa, A. S. Prusakovaa, M. I. Vakhrina, and A. P. Kriven’kob
a Perm State Pharmaceutical Academy, ul. Lenina 48, Perm, 614990 Russia
e-mail: gein@permonline.ru
b Saratov State University, Saratov, Russia
Received January 11, 2008
Abstract—Benzylamine, phenethylamine, and homoveratrylamine reacted with dialkyl 2-aryl-4-hydroxy-4-
methyl-6-oxocyclohexane-1,3-dicarboxylates at the endocyclic carbonyl group with conservation of the enolic
hydroxy group to give dialkyl 4-alkylamino-2-aryl-6-hydroxy-6-methylcyclohex-3-ene-1,3-dicarboxylates. The
reaction of dimethyl 4-hydroxy-4-methyl-6-oxo-2-phenylcyclohexane-1,3-dicarboxylate with tryptamine was
accompanied by dehydration with formation of dimethyl 4-[2-(1H-indol-3-yl)ethylamino]-6-methyl-2-
phenylcyclohexa-3,5-diene-1,3-dicarboxylate, presumably due to basic properties of the indole nitrogen atom.
DOI: 10.1134/S1070363208120116
We previously described in detail reactions of
dialkyl 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-
1,3-dicarboxylates with aromatic amines in the
presence of acid catalyst (2% of acetic acid or 1% of p-
toluenesulfonic acid). It was found that nucleophile
attacks the endocyclic carbonyl carbon atom to give
the corresponding arylaminocyclohexenedicarboxylates
[1–6]. The reactions with dimethyl 6-oxocyclohexane-
1,3-dicarboxylates were accompanied by dehydration
with formation of arylaminocyclohexadienedicarbox-
ylates; the dehydration process was also favored by
increased concentration of the acid catalyst (9% of
acetic acid) [2, 7].
I–IV with benzylamine, phenethylamine, homo-
veratrylamine [2-(3,4-dimethoxyphenyl)ethanamine],
and tryptamine. It is known that some derivatives of
the above amines exhibit strong physiological activity;
furthermore, such compounds as adrenalin and
serotonin are biogenic amines.
Dialkyl oxocyclohexane-1,3-dicarboxylates I–IV
successfully reacted with benzylamine, phenethyl-
amine, and homoveratrylamine on heating for a short
time in boiling alcohol containing a catalytic amount
of acetic acid, and the products were the corresponding
dialkyl 4-alkylamino-2-aryl-6-hydroxy-6-methylcyclo-
hex-3-ene-1,3-dicarboxylates Va–Vf, Va, VIIa–VIId,
VIIg–VIIi, and VIIIa (Scheme 1, Table 1). The reac-
tions with dimethyl 4-oxocyclohexane-1,3-dicarboxy-
lates Ia–Ic required no catalyst. In both cases,
regardless of the presence or absence of acetic acid in
the reaction medium, the hydroxy group in position 4
of the cyclohexane ring remained unchanged.
There are almost no published data on reactions of
dialkyl 4-oxocyclohexane-1,3-dicarboxylates with
aliphatic amines. It was reported that bis(ethoxycar-
bonyl)-substituted cyclohexanones reacted with
benzylamine and cyclohexenylamine in the presence of
a catalytic amount of acetic acid to produce the
corresponding N-benzyl(cyclohexyl)cyclohexenamines
[8]. The reaction with benzylamine successfully oc-
curred in the absence of catalyst.
Dimethyl cyclohex-3-ene-1,3-dicarboxylate Vc was
also synthesized by independent method. While
studying three-component condensation of methyl
acetoacetate with p-nitrobenzaldehyde and benzyl-
amine, we found that the product was not the
corresponding Hantzsch dihydropyridine but dimethyl
4-benzylamino-6-hydroxy-6-methyl-2-(4-nitrophenyl)-
cyclohex-3-ene-1,3-dicarboxylate (Vc) which was
formed in a high yield (Scheme 2). Samples of Vc had
With a view to examine the reactivity of dialkyl
oxocyclohexane-1,3-dicarboxylates, as well as to
obtain new potential biologically active compounds, in
the present work we performed reactions of dimethyl,
diisopropyl,
diallyl, and di-tert-butyl 2-aryl-4-
hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylates
2357

2358
GEIN et al.
Scheme 1.
Scheme 2.
O
O
O
H
O
O
OR
NH2
H3C
HO
CH3
O
2
+
+
H3C
NH2
X
R'
O
OR
NO2
Ia_Ic, IIa, IIIa, IVa_IVd
NH
O
CH3
X
NH
O
O
H3C
HO
OR
+
H3C
HO
R'
O
O
NO2
O
OR
CH3
Vc
Va_Vf, VIa, VIIa_VIId, VIIg_VIIi, VIIIa
Va–Vc, VIa, VIIa, VIIb, X = Ph; Vd, VIIc, VIId,
VIIg, X = PhCH2; Vf, VIIh, VIIi, VIIIa, X = 3,4-
(MeO)2C6H3CH2; Ia–Ic, Va–Vd, Vf, R = Me; IIa,
VIa, R = i-Pr; IVa–IVc, VIIa–VIId, VIIg–VIIi, R =
t-Bu; IIIa, VIIIa, R = CH2=CHCH2; Ia, IIIa, IVa, Va,
Vd, Vf, VIIa, VIIc, VIIh, VIIIa, R′ = H; Ib, Vb, R′ =
4-MeO; Ic, IIa, IVb, Vc, VIa, VIIb, R′ = 4-O2N; IVc,
VIId, R′ = 3-O2N; IVd, VIIg, VIIi, R′ = 4-Cl.
similar spectral properties and showed no depression
of the melting point on mixing. Presumably, the
process involves intermediate formation of cyclic β-
hydroxy ketone, where benzylamine acts as base
catalyst. In the next step, the resulting cyclohexanone
reacts with benzylamine as nucleophile.
The reaction of dimethyl 4-hydroxy-4-methyl-6-
oxo-2-phenylcyclohexane-1,3-dicarboxylate (Ia) with
tryptamine was accompanied by dehydration of the
amination product with formation of dimethyl 4-[2-
(1H-indol-3-yl)ethylamino]-6-methyl-2-phenylcyclo-
hexa-3,5-diene-1,3-dicarboxylate (IXa). In the
reactions of diesters Id, IVd, and IVe with tryptamine
under analogous conditions, the hydroxy group
remained unchanged, and the products were dimethyl
and di-tert-butyl 2-aryl-6-hydroxy-4-[2-(1H-indol-3-
yl)ethylamino]-6-methylcyclohex-3-ene-1,3-dicarbo-
xylates Ve, VIIe, and VIIf, respectively (Scheme 3,
Table 1).
Table 1. Yields, melting points, and elemental analyses of
dialkyl 4-alkylamino-2-aryl-6-hydroxy-6-methylcyclohex-3-
ene-1,3-dicarboxylates Va–Vf, VIa, VIIa–VIIi, and VIIIa
Comp. Yield,
no.
Vа
mp,
Found
N, %
3.35
3.22
6.19
3.24
5.21
2.93
5.56
2.76
5.29
2.88
5.00
4.71
4.74
2.60
2.54
2.28
Calculated
N, %
3.42
3.18
6.16
3.31
5.36
2.95
5.48
2.84
5.20
2.76
5.07
4.82
4.85
2.58
2.51
2.32
Formula
%
43
50
54
30
35
57
30
59
85
70
31
90
40
62
68
55
°С
169–171
176–177
155–157
134–136
182–183
158–159
123–125
184–185
202–204
176–177
130–132
164–166
170–172
176–178
183–185
148–150
C24H27NO5
C25H29NO6
C24H26N2O7
C25H29NO5
C29H34N2O7
C27H33NO7
C28H34N2O7
C30H39NO5
C30H38N2O7
C31H41NO5
C31H40N2O7
C33H41ClN2O5
C34H44N2O6
C31H40ClNO5
C33H45NO7
C33H44ClNO7
Vb
Vc
Vd
Ve
Vf
Presumably, dehydration of the amination product
of compound Ia is favored by basic properties of the
indole nitrogen atom which is capable of binding
proton in position 5 of the cyclohexene ring. Di-tert-
butyl cyclohexene-1,3-dicarboxylates VIIa and VIIf
are more stable: electron-donor properties of the tert-
butyl group hamper the elimination of proton from C5 in
the cyclohexene ring, and no dehydration is observed.
VIа
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
Compounds Va–Vf, VIa, VIIa–VIIi, and VIIIa are
white, off-white, or yellow crystalline substances that
are soluble in DMSO, DMF, and acetone and insoluble
in water. The IR spectra of crystalline samples of Va–
20
131–133
2.57
C31H37NO7
2.61
VIIIa
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 12 2008

REACTION OF DIALKYL 2-ARYL-4-HYDROXY-4-METHYL-...
2359
Scheme 3.
NH
O
CH3
HN
O
R = CH3
R' = H
H3C
C6H5
CH3
NH2
O
O
O
O
OR
C6H4R'
IXa
H3C
HO
+
N
H
NH
O
O
OR
Ia, Id, IVd, IVe
HN
OR
C6H4R'
H3C
HO
O
OR
Ve, VIIe, VIIf
Ia, Id, Ve, R = Me; IVd, IVe, VIIe, VIIf, R = t-Bu; Ia, R′ = H; Id, Ve, R′ = 3,4-(MeO)2; IVd, VIIe, R′ = 4-Cl; IVe,
VIIf, R′ = 4-MeO.
2.59 and 2.44–2.70 ppm with a coupling constant J of
17 Hz were assigned to the C5H2 group, and the NH
signal was a triplet at δ 8.80–9.30 ppm (Table 2).
Compound Vd displayed in the mass spectrum the
molecular ion peak with m/z 423, ion peaks with m/z
405 [M – H2O]+, 346 [M – H2O – COOCH3]+, and 300
[M – H2O – (CH2)2C6H5]+, and other fragment ion
peaks, which were consistent with the assumed
Vf, VIa, VIIa–VIIi, and VIIIa contained absorption
bands in the regions 3490–3565 (νOH), 3240–3285
1
(νNH), and 1644–1660 cm–1 (C=C) (Table 2). In the H
NMR spectra of these compounds, the hydroxy proton
resonated as a singlet at δ 4.12–4.65 ppm, two CH
protons in positions 1 and 2 of the cyclohexene ring
gave doublets at δ 3.85–4.25 and 2.09–2.58 ppm with a
coupling constant J of 10 Hz, two doublets at δ 2.40–
Table 2. IR and 1H NMR spectra of dialkyl 4-alkylamino-2-aryl-6-hydroxy-6-methylcyclohex-3-ene-1,3-dicarboxylates Va–
Vf, VIa, VIIa–VIIi, and VIIIa
Comp.
no.
IR spectrum, ν, cm–1
1H NMR spectrum, δ, ppm
1657 (C=C), 1715
(COO), 3250 (NH),
3510 (OH)
1.13 s (3H, CH3), 2.45 d (1H, C2H, J 10 Hz), 2.58 d (1H, C5HAHB, J 17 Hz), 2.59 d (1H, C5HAHB, J 17
Hz), 3.14 s, 3.45 s (3H each, 2CH3O), 4.11 d (1H, C1H, J 10 Hz), 4.46 m (2H, CH2), 4.49 s (1H, OH), 7.07
m, 7.19 m, 7.40 m (10H, 2C6H5), 9.18 t (1H, NH)
1.12 c (3H, CH3), 2.37 d (1H, C2H, J 10 Hz), 2.48 d (1H, C5HAHB, J 17 Hz), 2.55 d (1H, C5HAHB, J 17 Hz),
3.21s, 3.43 s (3H each, 2CH3O), 3.71 c (3H, 4-CH3OC6H4), 4.02 d (1H, C1H, J 10 Hz), 4.44 m (2H, CH2),
4.23 s (1H, OH), 6.67 d, 6.93 d (4H, 4-CH3OC6H4), 7.30 m (5H, C6H5), 9.17 t (1H, NH)
1.16 s (3H, CH3), 2.51 d (H, C2H, J 10 Hz), 2.59 d (1H, C5HAHB, J 17 Hz), 2.70 d (1H, C5HAHB, J 17 Hz),
3.15 s, 3.46 s (3H each, 2CH3O), 4.25 d (1H, C1H, J 10 Hz), 4.48 m (2H, CH2), 4.65 s (1H, OH), 7.35 m
(5H, C6H5, 2H, 4-NO2C6H4), 8.09 d (2H, 4-NO2C6H4), 9.28 t (1H, NH)
1.07 s (3H, CH3), 2.32 d (1H, C2H, J 10 Hz), 2.50 d (1H, C5HAHB, J 17 Hz), 2.53 d (1H, C5HAHB, J 17 Hz),
2.79 t (2H, PhCH2), 3.06 s, 3.37 s (3H each, 2CH3O), 3.25 m (2H, CH2NH), 4.01 d (1H, C1H, J 10 Hz),
4.40 s (1H, OH), 7.10 m (10N, 2C6H5), 8.80 t (1H, NH)
1.06 c (3H, CH3), 2.34 d (1H, C2H, J 10 Hz), 2.48 d (1H, C5HAHB, J 17 Hz), 2.51 d (1H, C5HAHB, J 17
Va
1660 (C=C), 1710
(COO), 3285 (NH),
3505 (OH)
Vb
Vc
Vd
Ve
1644 (C=C), 1725
(COO), 3283 (NH),
3517 (OH)
1648 (C=C), 1720
(COO), 3255 (NH),
3565 (OH)
1650 (C=C), 1723
(COO), 3265 (NH),
Hz), 2.90 t (2H, CH2), 3.11 s, 3.41 s (3H each, 2CH3O), 3.60 s, 3.62 s [3H each, 3,4-(CH3O)2C6H4], 3.28
3400 (NH), 3540 (OH) m (2H, CH2NH), 3.95 d (1H, C1H, J 10 Hz), 4.36 s (1H, OH), 6.48 m, 6.68 d, 6.97 m, 7.15 s , 7.28 d, 7.52
d [8H, 3,4-(CH3O)2C6H3, indole], 8.82 t (1H, NH), 10.83 s [1H, NH (indole)]
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 12 2008

2360
GEIN et al.
Table 2. (Contd.)
Comp.
no.
IR spectrum, ν, cm–1
1H NMR spectrum, δ, ppm
1650 (C=C), 1710
(COO), 3250 (NH),
3540 (OH)
1.31 s (3H,CH3); 2.37 d (1H, C2H, J 10 Hz), 2.50 d (1H, C5HAHB, J 15 Hz), 2.60 d (1H,C5HAHB, J 15 Hz),
2.78 t (2H, CH2), 3.08 s, 3.27 s (3H each, 2CH3O), 3.39 m (2H,CH2NH), 3.67 s, 3.70 s (3H each, 2OCH3),
4.02 d (1H, C1H, J 10 Hz), 4.40 s (1H, OH), 6.73 m, 7.02 m [8H, C6H5, 3,4-(CH3O)2C6H3], 8.87 t (1H,
NH)
Vf
1652 (C=C), 1728
(COO), 3255 (NH),
3490 (OH)
0.69 d, 0.85 d, 0.99 d, 1.06 d [6H each, 2CH(CH3)2], 1.30 s (3H, CH3), 2.58 d (1H, C2H, J 11 Hz), 2.67 d
(1H, C5HAHB, J 17 Hz), 2.86 d (1H, C5HAHB, J 17 Hz), 3.35 d (1H, C1H, J 11 Hz), 4.13 m (2H, CH2), 4.26
s (1H, OH), 4.79 m, 4.87 m [1H each, 2CH(CH3)2], 7.41 m (5H, C6H5), 7.64 d, 8.20 d (4H, 4-NO2C6H4),
9.30 s (1H, NH)
VIa
1644 (C=C), 1700
(COO), 3250 (NH),
3500 (OH)
0.96 s, 1.22 s [9H each, 2(CH3)3C], 1.17 s (3H, CH3), 2.20 d (1H, C2H, J 10 Hz), 2.47 d (1H, C5HAHB, J
17 Hz), 2.54 d (1H, C5HAHB, J 17 Hz), 3.95 d (1H, C1H, J 10 Hz), 4.42 m (2H, CH2), 4.23 s (1H, OH),
7.20 m (10H, 2C6H5), 9.11 t (1H, NH)
0.97 s, 1.22 s [9H each, 2(CH3)3C], 1.20 s (3H, CH3), 2.25 d (1H, C2H, J 10 Hz), 2.51 d (1H, C5HAHB, J
17 Hz), 2.63 d (1H, C5HAHB, J 17 Hz), 4.11 d (1H, C1H, J 10 Hz), 4.44 m (2H, CH2), 4.42 s (1H, OH),
7.36 m (5H, C6H5, 2H, 4-NO2C6H4), 8.15 d (2H, 4-NO2C6H4), 9.27 t (1H, NH)
VIIa
VIIb
1650 (C=C), 1690
(COO), 3240 (NH),
3500 (OH)
1640 (C=C), 1690
(COO), 3250 (NH),
3508 (OH)
0.89 s, 1.16 s [9H each, 2(CH3)3C], 1.12 s (3H, CH3), 2.10 d (1H, C2H, J 10 Hz), 2.40 d (1H, C5HAHB, J
17 Hz), 2.44 d (1H, C5HAHB, J 17 Hz), 2.75 t (2H, PhCH2), 3.31 m (2H, CH2NH), 3.85 d (1H, C1H, J 10
Hz), 4.15 s (1H, OH), 7.12 m (10H, 2C6H5), 8.81 t (1H, NH)
VIIc
VIId
VIIe
1655 (C=C), 1705
(COO), 3250 (NH),
3525 (OH)
1660 (C=C), 1705
(COO), 3250 (NH),
0.95 s, 1.15 s [9H each, 2(CH3)3C], 1.10 s (3H, CH3), 2.09 d (1H, C2H, J 10 Hz), 2.44 d (1H, C5HAHB, J
17 Hz), 2.47 d (1H, C5HAHB, J 17 Hz), 2.88 t (2H, CH2), 3.38 m (2H, CH2NH), 3.86 d (1H, C1H, J 10 Hz),
3420 (NH), 3530 (OH) 4.12 s (1H, OH), 7.20 m (9H, 4-ClC6H4, indol), 8.90 t (1H, NH), 10.82 s [1H, NH (indole)]
1650 (C=C), 1720
VIIf
(COO), 3260 (NH),
3400 (NH), 3540 (OH)
1650 (C=C), 1690
(COO), 3230 (NH),
3560 (OH)
0.96 s, 1.22 s [9H each, 2(CH3)3C], 1.17 c (3H, CH3), 2.20 d (1H, C2N, J 10 Hz), 2.47 d (1H, C5HAHB, J
17 Hz), 2.54 d (1H, C5HAHB, J 17 Hz), 2.78 t (2H, PhCH2), 3.95 d (1H, C1H, J 10 Hz), 4.12 m (2H,
CH2NH), 4.23 s (1H, OH), 7.20 m (9H, C6H5, 4-ClC6H4), 9.11 t (1H, NH)
0.95 s, 1.20 s [9H each, 2(CH3)3C], 1.25 s (3H, CH3), 2.15 d (1H, C2H, J 10 Hz), 2.43 d (1H, C5HAHB, J
17 Hz), 2.65 d (1H, C5HAHB, J 17 Hz), 2.75 t (2H, CH2Ar), 3.39 m (2H, CH2NH), 3.72 s, 3.81 s (3H each,
2OCH3), 3.86 d (1H, C1H, J 10 Hz), 4.12 s (1H, OH), 6.64 m, 7.19 m [8H, C6H5, 3,4-(CH3O)2C6H3], 8.73
t (1H, NH)
VIIg
VIIh
1650 (C=C), 1710
(COO), 3280 (NH),
3550 (OH)
1650 (C=C), 1700
(COO), 3230 (NH),
3570 (OH)
0.97 s, 1.21 s [9H each, 2(CH3)3C], 1.25 s (3H, CH3), 2.11 d (1H, C2N, J 10 Hz), 2.33 d (1H, C5HAHB, J
17 Hz), 2.44 d (1H, C5HAHB, J 17 Hz), 2.75 t (2H, CH2Ar), 3.25 s, 3.82 s (3H each, 2OCH3), 3.88 d (1H,
C1H, J 10 Hz), 3.90 m (2H, CH2NH), 4.21 s (1H, OH), 6.92 m, 7.18 m [7H, 4-ClC6N4, 3,4-(CH3O)2C6H3],
8.83 t (1H, NH)
VIIi
1650 (C=C), 1710
(COO), 3280 (NH),
3520 (OH)
1.15 s (3H, CH3), 2.47 d (1H, C5HAHB, J 17 Hz), 2.56 d (1H, C5HAHB, J 17 Hz), 2.62 d (1H, C2H, J 10
Hz), 2.72 t (2H, CH2Ar), 3.67 s, 3.70 s (3H each, 2CH3O), 4.07 d (1H, C1H, J 10 Hz), 4.12 m, 4.40 m (2H
each, CH2O), 4.50 s (1H, OH), 4.74 m (2H, CH2NH), 4.87 m, 5.12 m (2H each, CH2=), 5.37 m, 5.69 m
(1H each, 2CH=), 6.81 m, 7.24 m [8H, C6H5, 3,4-(CH3O)2 · C6H3], 8.93 t (1H, NH)
VIIIa
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REACTION OF DIALKYL 2-ARYL-4-HYDROXY-4-METHYL-...
2361
structure. The mass spectrum of VIIb contained peaks
from ions with m/z 538 [M]+, 520 [M – H2O]+, and 437
[M – COOC(CH3)3]+, and other fragment ions.
precipitate was filtered off and recrystallized from
isopropyl alcohol.
Diallyl 4-hydroxy-4-methyl-6-oxo-2-phenylcyclo-
hexane-1,3-dicarboxylate (IIIa). Allyl acetoacetate,
0.05 mol, and benzaldehyde, 0.025 mol, were
dissolved in 6 ml of isopropyl alcohol, 1 ml of
piperidine was added, and the mixture was kept for 24
h at room temperature. The precipitate was filtered off
and recrystallized from isopropyl alcohol.
Cyclohexadienedicarboxylate IXa is a yellow crystal-
line substance which is soluble in DMSO, DMF, tolu-
ene, and benzene and insoluble in water. It showed in
the IR spectrum absorption bands due to stretching vibra-
tions of the N–H (3360, 3250 cm–1), C=O (1720 cm–1),
1
and C=C bonds (1675, 1645 cm–1). The H NMR
spectrum of IXa contained signals from aromatic
protons, a three-proton singlet at δ 1.69 ppm from the
6-methyl group, a doublet at δ 3.16 ppm (J = 1.3 Hz)
from 2-H, a doublet at δ 6.33 ppm (J = 1.3 Hz) from 1-
H, a singlet at δ 4.38 ppm from 5-H, a triplet at δ 8.87
ppm from the 4-NH proton, and a singlet at δ 10.83
ppm from the NH proton in the indole ring.
Di-tert-butyl 2-aryl-4-hydroxy-4-methyl-6-oxo-
cyclohexane-1,3-dicarboxylates IVa–IVe (general
procedure). tert-Butyl acetoacetate, 0.05 mol, and the
corresponding aromatic aldehyde, 0.025 mol, were
dissolved in 6 ml of isopropyl or tert-butyl alcohol (if
necessary, on heating), 1 ml of piperidine was added,
and the mixture was kept for 1–3 days at room
temperature. The precipitate was filtered off and
recrystallized from isopropyl alcohol.
The above spectral data indicate that compounds
Va–Vf, VIa, VIIa–VIIi, VIIIa, and IXa exist as
enamino tautomer which is likely to be stabilized by
intramolecular hydrogen bond N–H···O=C.
Dimethyl
2-aryl-4-benzylamino-6-hydroxy-6-
Va–Vc
methylcyclohex-3-ene-1,3-dicarboxylates
(general procedure). a. A solution of 0.005 mol of
dimethyl 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-
1,3-dicarboxylate Ia–Ic and 0.005 mol of benzylamine
in 20 ml of ethanol was heated for 1–3 h under reflux
in the absence of a catalyst or in the presence of 1 vol %
of acetic acid. The mixture was cooled, and the
precipitate was filtered off and recrystallized from
ethanol.
EXPERIMENTAL
The IR spectra were recorded from samples
dispersed in mineral oil on UR-20 and Specord M80
1
spectrometers. The H NMR spectra were measured
from solutions in DMSO-d6 on Bruker AM-300
(300 MHz) and Bruker DRX-400 (400 MHz)
instruments using hexamethyldisiloxane as internal
reference. The mass spectra (electron impact, 70 eV)
were obtained on an MKh-1320 spectrometer. The
progress of reactions and the purity of products were
monitored by TLC on Silufol UV-254 plates using
Dimethyl 4-benzylamino-6-hydroxy-6-methyl-2-
(4-nitrophenyl)cyclohex-3-ene-1,3-dicarboxylate (Vc).
b. A solution of 0.005 mol of methyl acetoacetate,
0.025 mol of 4-nitrobenzaldehyde, and 0.025 mol of
benzylamine in 10 ml of ethanol was heated for 3 h
under reflux (on a water bath). The mixture was
cooled, poured into cold water, and left overnight. The
aqueous phase was separated by decanting, and the
crystals were washed with ethanol, filtered off, and
recrystallized from ethanol. Yield 37%, mp 154–156°
C. IR spectrum (mineral oil), ν, cm–1: 3515 (OH), 3280
hexane–diethyl
ether–chloroform (2:2:1)
benzene–ethyl acetate (5:1) as eluents.
and
Dimethyl 2-aryl-4-hydroxy-4-methyl-6-oxocyclo-
hexane-1,3-dicarboxylates Ia–Id (general proce-
dure). Methyl acetoacetate, 0.05 mol, and the
corresponding aromatic aldehyde, 0.025 mol, were
dissolved in 6 ml of methanol or ethanol (if necessary,
on heating), 1 ml of piperidine was added, and the
mixture was kept for 1–3 days at room temperature.
The precipitate was filtered off and recrystallized from
ethanol.
1
(NH), 1725 (C=O), 1645 (C=C). H NMR spectrum
(DMSO-d6), δ, ppm: 1.15 s (3H, CH3), 2.51 d (1H, 2-
H, J = 10 Hz), 2.60 d and 2.70 d (1H each, 5-H, J = 17
Hz), 3.16 s and 3.46 s (3H each, CH3O), 4.25 d (1H,
1-H, J = 10 Hz), 4.47 m (2H, CH2), 4.65 s (1H, OH),
7.35 m (7H, Harom), 8.10 d (2H, C6H4), 9.29 t (1H,
NH). Found, %: C 63.50; H 5.88; N 6.82. C24H26N2O7.
Calculated, %: C 63.44; H 5.73; N 6.17.
Diisopropyl 4-hydroxy-4-methyl-2-(4-nitrophenyl)-
6-oxocyclohexane-1,3-dicarboxylate (IIa). Isopropyl
acetoacetate, 0.05 mol, and 4-nitrobenzaldehyde,
0.025 mol, were dissolved in 6 ml of isopropyl alcohol
on heating, 1 ml of piperidine was added, and the
mixture was kept for 24 h at room temperature. The
Dimethyl, diisopropyl, di-tert-butyl, and diallyl-
4-alkylamino-2-aryl-6-hydroxy-6-methylcyclohex-3-
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GEIN et al.
ene-1,3-dicarboxylates Vd–Vf, VIa, VIIa–VIIi, and
VIIIa (general procedure). A solution of 0.005 mol of
dimethyl, diisopropyl, diallyl, or di-tert-butyl 2-aryl-4-
hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylate
Ia, Id, IIa, IIIa, or IVa–IVe and 0.005 mol of the
corresponding amine in 20 ml of ethanol containing
1 vol % of acetic acid was heated for 1–3 h under
reflux. The mixture was cooled, and the precipitate
was filtered off and recrystallized from ethyl or
isopropyl alcohol.
REFERENCES
1. Sorokin, V.V., Kuz’min, M.V., Smirnova, N.S.,
Kozhevnikova, N.I., and Kriven’ko, A.P., Zh. Org. Khim.,
1994, vol. 30, no. 4, p. 528.
2. Sorokin, V.V., Grigor’ev, A.V., Ramazanov, A.K., and
Kriven’ko, A.P., Russ. J. Org. Chem., 2000, vol. 36, no. 6,
p. 781.
3. Ramazanov, A.K., Sorokin, V.V., and Kriven’ko, A.P.,
Khimiya i komp’yuternoe modelirovanie. Butlerovskie
soobshcheniya (Chemistry and Computer Modeling.
Butlerov Reports), Saratov, 2002, no. 6, p. 79.
Dimethyl 4-[2-(1H-indol-3-yl)ethylamino]-6-me-
thyl-2-phenylcyclohexa-3,5-diene-1,3-dicarboxylate
(IXa). A solution of 0.005 mol of dimethyl 4-hydroxy-
4-methyl-6-oxo-2-phenylcyclohexane-1,3-dicarboxylate
(Ia) and 0.005 mol of tryptamine in 20 ml of ethanol
containing a few drops of acetic acid was heated for
2 h under reflux. The mixture was cooled, and the
precipitate was filtered off and recrystallized from
ethanol. Yield 53%, mp 141–142°C. IR spectrum
(mineral oil), ν, cm–1: 3360, 3250 (NH); 1720 (C=O);
4. Sorokin, V.V., Kuz’min, M.V., Smirnova, N.S., Kozhev-
nikova, N.I., and Kriven’ko, A.P., Khimiya i tekhnologiya
furanovykh soedinenii (Chemistry and Technology of
Furan Compounds), Krasnodar, 1995, p. 15.
5. Sorokin, V.V., Novye dostizheniya v organicheskoi khimii
(New Advances in Organic Chemistry), Kriven’ko, A.P.,
Ed., Saratov, 1997, p. 59.
6. Gein, V.L., Nosova, N.V., Potemkin, K.D., Aliev, Z.G.,
and Kriven’ko, A.P., Russ. J. Org. Chem., 2005, vol. 41,
no. 7, p. 1016.
1
1675, 1645 (C=C). H NMR spectrum (DMSO-d6), δ,
ppm: 1.69 c (3H, CH3), 2.89 t (2H, CH2), 3.16 d (1H,
2-H, J = 1.3Hz), 3.33 s and 3.57 s (3H each, CH3O),
3.53 m (2H, CH2NH), 4.38 s (1H, 5-H), 6.33 d (1H, 1-
H, J = 1.3Hz), 7.16 m (10H, Harom), 8.87 t (1H,
CH2NH), 10.83 s (1H, NH, indole). Found, %: C
72.88; H 6.39; N 6.20. C27H28N2O4. Calculated, %: C
72.97; H 6.31; N 6.31.
7. Gein, V.L., Gein, N.V., Voronina, E.V., and Kriven’ko, A.P.,
Khim.-Farm. Zh., 2002, vol. 36, no. 3, p. 23.
8. Grigor’eva, E.A., Kriven’ko, A.P., Sorokin, V.V.,
Ramazanov, A.K., and Inozemtseva, O.A., Izv. Vyssh.
Uchebn. Zaved., Khim. Khim. Tekhnol., 2004, vol. 50, no. 5,
p. 131.
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