Synthesis of alkyl 4-aryl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3- carboxylates

Article abstract of DOI:10.1134/S107042801402016X

Reactions of alkyl acetoacetates, aromatic aldehydes, ammonium acetate, and 1,3-cyclohexanedione afford alkyl 4-aryl-2-methyl-5-oxo-1,4,5,6,7,8- hexahydroquinoline-3-carboxylates. The structure of compounds obtained was established with the help of IR,

Full text of DOI:10.1134/S107042801402016X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 2, pp. 240−243. © Pleiades Publishing, Ltd., 2014.
Original English Text © V.L. Gein, M.I. Kazantseva, L.F. Gein, P.A. Slepukhin, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 2, pp. 247−250.
Synthesis of Alkyl 4-Aryl-2-methyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylates
V. L. Geina, M. I. Kazantsevaa, L. F. Geinb, and P. A. Slepukhinc
aPerm’State Pharmaceutical Academy, Perm,614990 Russia
bVagner Perm’State Medical Academy, Perm, Russia
cPostovskii Institute of Organic Synthesis,
Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
е-mail: geinvl48@mail.ru
Received September 11, 2013
Abstract—Reactions of alkyl acetoacetates, aromatic aldehydes, ammonium acetate, and 1,3-cyclohexanedione
afford alkyl 4-aryl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates. The structure of compounds
obtained was established with the help of IR, 1Н NMR, and mass spectra and by X-ray diffraction analysis.
DOI: 10.1134/S107042801402016X
A reaction was described of ethyl acetoacetate with
dimedone, arylaldehyde, and ammonium acetate that
led to the formation of ethyl 4-aryl-2,7,7-trimethyl-5-
oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates [1].
It was found that similar compounds exhibit antioxidant
activity [2].
acetate and various acetoacetic esters. The reaction
proceeds at heating the mixture of initial reagents at
150–160°С for 5–10 min without solvent and furnishes
alkyl 4-aryl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquin-
oline-3-carboxylates Iа–Im.
We used in the reactions isopropyl, isobutyl, and
tert-butyl acetoacetates. Compounds Iа–Im are white
light-yellow crystalline substances soluble in DMF,
DMSO, in ethanol at heating, insoluble in water. With
arylaldehydes having electron-acceptor substituents the
yield of the reaction products was higher. The yields also
In continuation of research in this field aiming at
designing new heterocycles and at elucidating the effect
of the nature of cyclic β-diketone and of ester group on
the reaction progress we investigated the reactions of
aromatic aldehyde, 1,3-cyclohexanedione, ammonium
R1
O
CHO
O
O
O
AcONH
4
COOR2
Me
+
+
Me
OR2
O
R1
N
H
_
Ia–Im
Ià Im
R1 = 4-CH3О, R2 = C(CH3)3 (а), R1 = 3-NO2, R2 = C(CH3)3 (b), R1 = 4-NO2, R2 = C(CH3)3 (c), R1 = H, R2 = CH(CH3)2 (d); R1 = 4-Cl,
R2 = CH(CH3)2 (e), R1 = 4-CH3О, R2 = CH(CH3)2 (f); R1 = 3-NO2, R2 = CH(CH3)2 (g), R1 = 4-NO2, R2 = CH(CH3)2 (h); R1 = H, R2 =
CH2CH(CH3)2 (i); R1 = 4-Cl, R2 = CH2CH(CH3)2 (j); R1 = 4-CH3О, R2 = CH2CH(CH3)2 (k), R1 = 3-NO2, R2 = CH2CH(CH3)2 (l), R1 =
4-NO2, R2 = CH2CH(CH3)2 (m).
240

SYNTHESIS OF ALKYL 4-ARYL-2-METHYL-5-OXO-1,4,5,6,7,8-...
241
increased in the reactions with isobutyl and isopropyl
acetoacetates apparently due to the reduced solubility
of compounds Id–Im in ethanol during the workup of
the reaction mixture. The replacement of dimedone [1]
by 1,3-cyclohexanedione did not significantly affect the
reaction course.
Iа belongs to a centrosymmetric space group. The bond
lengths and bond angles are close to standard values. The
dihydropyridine ring is in the pseudoboat conformation
with the axial location of the 4-MеОС6Н4 fragment. In the
crystals due to the formation of intermolecular hydrogen
bonds N–H⋯O the molecules are arranged in chains di-
rected along the 0b axis. Parameters of the intermolecular
hydrogen bonds are as follows: N1–H12 0.91(2), H12⋯О4
[x, y + 1, z] 2.00(2), N1⋯О4 [x, y + 1, z] 2.884(3) Å, angle
N1H12О4 [x, y + 1, z] 164(1)°.
IR spectra of compounds Iа–Im contain absorption
bands of the stretching vibrations of the double bond
С=С at 1608–1638 cm–1, of the С=О group in the posi-
tion 5 of the heterocycle at 1648–1688 cm–1, of the ester
carbonyl group at 1688–1704 cm–1, of the N–H bond at
3280–3296 cm–1.
EXPERIMENTAL
In the 1Н NMR spectra of obtained compounds along
with the signals of aromatic protons and the protons of
groups attached to the aromatic ring, and also of the pro-
tons of the alkyl substituent in the ester group multiplets
are observed from the protons in the positions 8, 7, and
6 of the cycle in the regions 1.81–2.25, 1.69–1.92, 2.05–
2.48 ppm respectively, and also a singlet from the proton
in the position 4 of the pyridine ring at 4.70–5.00 ppm,
the signal from the NH group proton in the position 1 of
the heterocycle at 8.85–9.23 ppm.
IR spectra were recorded on a spectrophotometer
Specord M-80 from mulls in mineral oil. 1Н NMR spec-
tra were registered on a spectrometer Bruker DRX500
(500.13 MHz) in DMSO-d6, internal reference TMS. Mass
spectrum was obtained on an instrument Finnigan MАT
INCOS-50 (ionizing electrons energy 70 eV). Melting
points were measured on an instrument Melting Point
M-565. Elemental analysis was performed on an analyzer
Perkin Elmer 2400.
X-ray diffraction analysis was carried out on an
X-ray diffractometer Xcalibur 3 with a CCD detector
along a standard procedure (MoKα-radiation, graphite
monochromator, ω-scanning). For the analysis a frag-
ment of a colorless needle crystal was used of the size
0.22 × 0.11 × 0.03 mm. Collection and processing of data
was performed applying CrysAlis software [2]. No cor-
rection for extinction was introduced. The structure was
solved by the direct method and refined applying the
SHELXTL-97 software [3] in anisotropic (isotropic for
hydrogen atoms) approximation using full-matrix least-
squares method with respect to F2. Hydrogen atoms were
included in refinement in the rider model with dependent
thermal parameters save the hydrogen atom of the NH
group which was refined independently in the isotropic
approximation. According to XRD results the crystal is
monoclinic, space group с2/c, a 31.173(3), b 7.4087(11),
c 17.3721(17) Å, β 91.251(12)°, V 4011.2(8) Å3, Z 8, dcalc
1.224, μ 0.084 mm–1. In the range 2.61° < θ < 26.37°
11245 reflections were collected, among them 4060
independent (Rint 0.0900), in particular, 1314 with I >
2σ(I). Completeness for θ 26.00° was 99.1%. The final
parameters of refinement are as follows: R1 0.0459, wR2
0.0368 for reflections with I > 2σ(I), R1 0.1922, wR2
0.0427 for all reflections at the quality factor s 0.883.
Δρ 0.181/–0.182 ē Å–3 [4].
The mass spectrum of compound Ic containing the
peak of the molecular ion [M – Н]+, m/z 384, and peaks
of fragment ions [M – Ph]+ (262), [M – NO2]+ (338),
[M – C(CH3)3]+ (206) confirms the assumed structure.
The single crystal of compound Iа obtained by slow
crystallization from ethanol was subjected to X-ray dif-
fraction (XRD) analysis in order to establish its struc-
ture. According to XRD data the crystal of compound
Structure of the molecule of tert-butyl 2-methyl-4-(4-
methoxyphenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate (Iа) according to XRD data, atoms are shown in
thermal ellipsoids of 50%-probability.
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GEIN et al.
242
The results of the XRD study were deposited in Cam-
6.82–7.15 m (5H, C6H5), 8.85 s (1Н, NH). Found, %:
С 73.67, 73.72; Н 7.46, 7.31; N 4.57, 4.34. С20Н23NO3.
Calculated, %: С 73.82; Н 7.12; N 4.30.
bridge Crystallographic Data Center (CCDC no. 982561),
and they are available free at the address www.ccdc.cam.
ac.uk/data_request/cif.
Isopropyl 2-methyl-5-oxo-4-(4-chlorophenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Ie).
Yield 75%, mp 270–272°С. IR spectrum, ν, cm–1: 3296
(NН), 1696 (С=О), 1648 (С=О), 1618 (С=С). 1Н NMR
spectrum, δ, ppm: 1.02 d, 1.16 d [7Н, СН(СН3)2],
1.87–1.92 m (2Н, С8Н2), 2.14–2.24 m (2Н, С7Н2), 2.28 s
(3Н, 2-CH3), 2.45–2.48 m (2Н, С6Н2), 4.85 s (1Н, С4Н),
7.10–7.25 m (4H, C6H5Сl), 9.15 s (1Н, NH). Found, %:
С 66.67, 66.58; Н 6.36, 6.25; N 3.57, 3.64. С20Н22ClNO3.
Calculated, %: С 66.76; Н 6.16; N 3.89.
tert-Butyl 2-methyl-4-(4-methoxyphenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Iа).
A mixture of 0.01 mol of acetoacetic ester, 0.01 mol of
aromatic aldehyde, 0.01 mol of 1,3-cyclohexanedione,
and 0.01 mol of ammonium acetate was heated at 150–
160°С for 5–10 min. The reaction mixture was cooled
to room temperature, treated with ethanol, crystals were
filtered off and recrystallized from ethanol. Yield 63%,
mp 219–221°С. IR spectrum, ν, cm–1: 3296 (NН), 1700
1
(С=О), 1686 (С=О), 1618 (С=С). Н NMR spectrum,
Isopropyl 2-methyl-4-(4-methoxyphenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (If).
Yield 63%, mp 217–219°С. IR spectrum, ν, cm–1: 3288
(NН), 1700 (С=О), 1688 (С=О), 1628 (С=С). 1Н NMR
spectrum, δ, ppm: 1.04 d, 1.16 d [7Н, СН(СН3)2,
J 6.20 Hz], 1.87–1.92 m (2Н, С8Н2), 2.13–2.22 m (2Н,
С7Н2), 2.25 s (3Н, 2-CH3), 2.45–2.48 m (2Н, С6Н2),
3.65 s (3Н, CH3О), 4.70 s (1Н, С4Н), 6.68–7.05 m (4H,
C6H4ОСН3), 9.05 s (1Н, NH). Found, %: С 70.67, 70.56;
Н 6.96, 6.85; N 3.57, 3.68. С21Н25NO4. Calculated, %:
С 70.96; Н 7.09; N 3.94.
δ, ppm: 1.30 s [9Н, С(CH3)3], 1.86–1.91 m (2Н, С8Н2),
2.15–2.22 m (2Н, С7Н2), 2.25 s (3Н, 2-CH3), 2.44–2.47 m
(2Н, С6Н2), 3.68 s (3Н, CH3О), 4.75 s (1Н, С4Н), 6.68–
7.06 m (4Н, C6H4ОСН3), 9.02 s (1Н, NH). Found, %:
С 71.67, 71.57; Н 7.56, 7.28; N 3.57, 3.52. С22Н27NO4.
Calculated, %: С 71.52; Н 7.37; N 3.79.
Compounds Ib–Im were prepared similarly.
tert-Butyl 2-methyl-4-(3-nitrophenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Ib).
Yield 66%, mp 240–242°С. IR spectrum, ν, cm–1: 3280
(NН), 1700 (С=О), 1688 (С=О), 1618 (С=С). 1Н NMR
spectrum, δ, ppm: 1.30 s [9Н, С(CH3)3], 1.88–1.92 m
(2Н, С8Н2), 2.15–2.23 m (2Н, С7Н2), 2.28 s (3Н, 2-CH3),
2.46–2.48 m (2Н, С6Н2), 4.95 s (1Н, С4Н), 7.45–7.63 m
(4H, C6H4NO2), 9.17 s (1Н, NH). Found, %: С 65.67,
65.63; Н 6.56, 6.47; N 7.57, 7.37. С21Н24N2O5. Calcu-
lated, %: С 65.61; Н 6.29; N 7.29.
Isopropyl 2-methyl-4-(3-nitrophenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Ig).
Yield 76%, mp 249–251°С. IR spectrum, ν, cm–1: 3280
(NН), 1700 (С=О), 1688 (С=О), 1638 (С=С). 1Н NMR
spectrum, δ, ppm: 0.98 d, 1.17 d [7Н, СН(СН3)2,
J 6.20 Hz], 1.75–1.80 m (2Н, С8Н2), 1.89–1.94 m (2Н,
С7Н2), 2.31 s (3Н, 2-CH3), 2.45–2.48 m (2Н, С6Н2),
4.98 s (1Н, С4Н), 7.95–8.10 m (4H, C6H4NO2), 9.25 s
(1Н, NH). Found, %: С 64.55, 64.62; Н 6.06, 6.13;
N 7.37, 7.18. С20Н22N2O5. Calculated, %: С 64.85;
Н 5.99; N 7.56.
tert-Butyl 2-methyl-4-(4-nitrophenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Ic).
Yield 71%, mp 233–235°С. IR spectrum, ν, cm–1: 3296
(NН), 1704 (С=О), 1648 (С=О), 1628 (С=С). 1Н NMR
spectrum, δ, ppm: 1.30 s [9Н, С(CH3)3], 1.87–1.92 m
(2Н, С8Н2), 2.13–2.24 m (2Н, С7Н2), 2.28 s (3Н, 2-CH3),
2.46–2.49 m (2Н, С6Н2), 4.93 s (1Н, С4Н), 7.40–7.43 m
(4H, C6H4NO2), 9.18 s (1Н, NH). Found, %: С 65.69,
65.63; Н 6.53, 6.31; N 7.55, 7.37. С21Н24N2O5. Calcu-
lated, %: С 65.61; Н 6.29; N 7.29.
Isopropyl 2-methyl-4-(4-nitrophenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Ih).
Yield 71%, mp 258–260°С. IR spectrum, ν, cm–1: 3296
(NН), 1700 (С=О), 1696 (С=О), 1628 (С=С). 1Н NMR
spectrum, δ, ppm: 0.99 d, 1.16 d [7Н, СН(СН3)2,
J 6.20 Hz], 1.72–1.77 m (2Н, С8Н2), 1.88–1.93 m (2Н,
С7Н2), 2.31 s (3Н, 2-CH3), 2.14–2.27 m (2Н, С6Н2),
4.93 s (1Н, С4Н), 7.15–7.88 m (4H, C6H4NO2), 9.20 s
(1Н, NH). Found, %: С 64.45, 64.56; Н 6.17, 6.13;
N 7.67, 7.53. С20Н22N2O5. Calculated, %: С 64.85;
Н 5.99; N 7.56.
Isopropyl 2-methyl-5-oxo-4-phenyl-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (Id). Yield 72%,
mp 232–234°С. IR spectrum, ν, cm–1: 3280 (NН), 1696
1
(С=О), 1652 (С=О), 1608 (С=С). Н NMR spectrum,
δ, ppm: 1.03 d, 1.15 d [7Н, СН(СН3)2, J 6.20 Hz],
1.85–1.92 m (2Н, С8Н2), 2.14–2.25 m (2Н, С7Н2), 2.26 s
(3Н, 2-CH3), 2.44–2.48 m (2Н, С6Н2), 4.76 s (1Н, С4Н),
Isobutyl 2-methyl-4-phenyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (Ii). Yield 64%,
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SYNTHESIS OF ALKYL 4-ARYL-2-METHYL-5-OXO-1,4,5,6,7,8-...
243
mp 193–195°С. 1Н NMR spectrum, δ, ppm: 0.73–0.82 t
[6Н, СН2СН(СН3)2], 1.05–1.17 m [1Н, СН2СН(СН3)2],
1.72–1.77 m (2Н, С8Н2), 1.88–1.93 m (2Н, С7Н2),
2.14–2.24 m (2Н, С6Н2), 2.30 s (3Н, 2-CH3), 3.68–3.76 m
[2Н, СН2СН(СН3)2], 4.92 s (1Н, С4Н), 7.04–7.20 m
(5H, C6H5), 9.20 s (1Н, NH). Found, %: С 74.45, 74.41;
Н 7.16, 7.12; N 4.37, 4.35. С21Н25NO3. Calculated, %:
С 74.31; Н 7.42; N 4.13.
Isobutyl 2-methyl-4-(3-nitrophenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Il).
Yield 82%, mp 183–185°С. 1Н NMR spectrum, δ, ppm:
0.75–0.88 t [6Н, СН2СН(СН3)2], 1.06–1.15 m [1Н,
СН2СН(СН3)2], 1.71–1.78 m (2Н, С8Н2), 1.82–1.93 m
(2Н, С7Н2), 2.13–2.24 m (2Н, С6Н2), 2.37 s (3Н, 2-CH3),
3.70–3.76 m [2Н, СН2СН(СН3)2], 4.95 s (1Н, С4Н),
7.20–7.90 m (4H, C6H4NO2), 9.12 s (1Н, NH). Found, %:
С 65.45, 65.40; Н 6.26, 6.28; N 7.37, 7.32. С21Н24N2O5.
Calculated, %: С 65.61; Н 6.29; N 7.29.
Isobutyl 2-methyl-5-oxo-4-(4-chlorophenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Ij).
Yield 73%, mp 205–207°С. 1Н NMR spectrum, δ, ppm:
0.70–0.88 t [6Н, СН2СН(СН3)2], 1.07–1.17 m [1Н,
СН2СН(СН3)2], 1.71–1.77 m (2Н, С8Н2), 1.85–1.93 m
(2Н, С7Н2), 2.14–2.24 m (2Н, С6Н2), 2.30 s (3Н, 2-CH3),
3.65–3.76 m [2Н, СН2СН(СН3)2], 4.80 s (1Н, С4Н),
6.90–7.20 m (4H, C6H4Cl), 8.96 s (1Н, NH). Found, %:
С 67.35, 67.32; Н 6.16, 6.12; N 3.47, 3.43. С21Н24ClNO3.
Calculated, %: С 67.46; Н 6.47; N 3.75.
Isobutyl 2-methyl-4-(4-nitrophenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Im).
1
Yield 85%, mp 300°С. Н NMR spectrum, δ, ppm:
0.70–0.88 t [6Н, СН2СН(СН3)2], 1.07–1.16 m [1Н,
СН2СН(СН3)2], 1.73–1.77 m (2Н, С8Н2), 1.87–1.93 m
(2Н, С7Н2), 2.14–2.24 m (2Н, С6Н2), 2.34 s (3Н, 2-CH3),
3.65–3.73 m [2Н, СН2СН(СН3)2], 4.99 s (1Н, С4Н),
7.21–7.98 m (4H, C6H4NO2), 9.23 s (1Н, NH). Found, %:
С 65.47, 65.37; Н 6.18, 6.15; N 7.35, 7.32. С21Н24N2O5.
Calculated, %: С 65.53; Н 6.19; N 7.17.
Isobutyl 2-methyl-4-(4-methoxyphenyl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Ik).
Yield 64%, mp 173–175°С. 1Н NMR spectrum, δ, ppm:
0.70–0.91 t [6Н, СН2СН(СН3)2], 1.07–1.17 m [1Н,
СН2СН(СН3)2], 1.70–1.77 m (2Н, С8Н2), 1.86–1.93 m
(2Н, С7Н2), 2.14–2.24 m (2Н, С6Н2), 2.25 s (3Н, 2-CH3),
3.63 s (3Н, ОCH3), 3.65–3.76 m [2Н, СН2СН(СН3)2],
4.75 s (1Н, С4Н ), 6.63–7.04 m (4H, C6H4ОСН3), 8.87 s
(1Н, NH). Found, %: С 71.45, 71.43; Н 7.06, 7.08; N 3.57,
3.52. С22Н27NO4. Calculated, %: С 71.52; Н 7.37; N 3.79.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 2 2014