Condensation of 2-alkylcyclohexane-1,3-diones with cyclic azomethines

Article abstract of DOI:10.1023/B:RUJO.0000045903.18108.84

Reaction of 2-acylcyclohexane-1,3-diones with 5- and 6-membered cyclic azomethines (3,4-dihydro-2H-pyrrole and 2,3,4,5-tetrahydropyridine) furnished derivatives of 2,3,3a;,4,8,9-hexahydropyrrolo[1,2-a]quinoline-5,6(1H,5aH)-dione and 3,4,4a,5,9,10-hexahydro-1H-pyrido[1,2-a]quinoline-6,7(2H,8H)-dione respectively. In reaction with 7-membered 3,4,5,6-tetrahydro-2H-azepine we failed to isolate polycyclic nitrogen-containing products.

Full text of DOI:10.1023/B:RUJO.0000045903.18108.84

Russian Journal of Organic Chemistry, Vol. 40, No. 8, 2004, pp. 1187-1189. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 8, 2004,
pp. 1234-1236.
Original Russian Text Copyright Ó 2004 by Rubinov, Rubinova.
Condensation of 2-Alkylcyclohexane-1,3-diones
with Cyclic Azomethines
D.B. Rubinov and I.L. Rubinova
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, 220141 Belarus
å-mail: rubinov@iboch.bas-net.by
Received January 8, 2004
Abstract—Reaction of 2-acylcyclohexane-1,3-diones with 5- and 6-membered cyclic azomethines (3,4-dihydro-
2Í-pyrrole and 2,3,4,5-tetrahydropyridine) furnished derivatives of 2,3,3à,4,8,9-hexahydropyrrolo[1,2-
a]quinoline-5,6(1H,5àH)-dione and 3,4,4a,5,9,10-hexahydro-1H-pyrido[1,2-a]quinoline-6,7(2H,8H)-dione
respectively. In reaction with 7-membered 3,4,5,6-tetrahydro-2Í-azepine we failed to isolate polycyclic nitrogen-
containing products.
2-Acylcyclohexane-1,3-diones (cyclic b-triketones)
I are widely used in organic synthesis [1] and exhibit a
versatile biological activity [2]. á-Methylene moiety in
the side chain of the b-tricarbonyl fragment can be
regioselectively involved into aldol-crotonic condensa-
tion with aromatic aldehydes; this reaction is applied,
e.g., to the synthesis of naturally occurring compounds
[2] and prostaglandin analogs [3]. In b-triketones fusion
with 3,4-dihydroisoquinolines á-methylene group of the
acyl chain also takes part. The latter reaction os often
used in the synthesis of steroid heteroanalogs and of other
polycyclic nitrogen-containing heterocycles [4–6].
1
2
2
2
2
5
5
,,
5
5
1
2
5
5
,D H
9D G
1
2
2
1
5
,,,
5
5
We carried out an investigation of 2-acylcycloalkane-
1,3-diones cyclocondensation with simple cyclic
azomethines: 3,4-dihydro-2Í-pyrrole (II), 2,3,4,5-tetra-
hydropyridine (III), and 3,4,5,6-tetrahydro-2Í-azepine
(IV).The azomethines were used as Schiff bases. These
compounds in contrast to 3,4-dihydroisoquinoline
derivatives are readily obtained from the corresponding
N-containing heterocycles, but they are very unstable,
easily polymerizable, and cannot be isolated in an
individual state [7–8]. Therefore we brought into the
condensation with the cyclohexane b-triketones Ià–e
freshly prepared solutions of Schiff bases II–IV.
Reactions of 2-acylcyclohexane-1,3-diones Ià–d with
dihydropyrrole (II) gave rise to pyrroloquinolinediones
Và–d in moderate yields (50–65%). In condensation of
b-triketones Ià–e with tetrahydropyridine (III)
pyridoquinolinedione derivatives VIà–e were obtained
in lower yields (40–50%).
9,D H
I, V, VI, R1 = R2 = Me, R3 = H (a); R1 =R2 = R3 = Me (b);
R1 = R2 = Me, R3 = Ph (c); R1 = H, R2 = Ph, R3 = Me (d);
I, VI, R1 = R2 = Me, R3 = Et (e).
The reaction proceeded in toluene for 2–3 days at
room temperature or for 8–10 h at boiling. The condens-
ation usually did not go to completion, and further
addition of excess azomethine or longer heating resulted
only in accumulation of side products (TLC monitoring).
The cleaner course of the process was observed at room
temperature. Reaction products were isolated by column
chromatography on silica gel with subsequent
crystallization.
The assumed structure of compounds Và–d and VIà–
e was unambiguously confirmed by the sum of spectral
data. In the IR spectra of all pyrroloquinolinediones V
1070-4280/04/4008-1187Ó2004 MAIK “Nauka/Interperiodica”

1188
RUBINOV, RUBINOVA
dihydropyrrole (II) was stored in a freezer and was used
for condensation considering the yield of azomethine to
be quantitative. Likewise were prepared methanol
solutions of 2,3,4,5-tetrahydropyridine (III) and 3,4,5,6-
tetrahydro-2H-azepine (IV) from piperidine and
hexamethyleneamine respectively.
and pyridoquinolinediones VI appeared in the region
1670–1690 cm a strong absorption band characteristic
of an s-cis-conjugated carbonyl group of an
–1
enaminodicarbonyl moiety [9], and a very strong band
–1
in the region 1540–1565 cm corresponding to a
conjugated olefin bond and an s-trans-conjugated
carbonyl group. In the proton magnetic resonance spectra
of tricyclic compounds V and VI the protons of the
introduced cyclic fragments give rise to signals in
appropriate regions and with expected multiplicity and
integral intensity. Therewith only for pyrido-quino-
linedione VId we observed under conditions of spectrum
recording (in CDCl3 solution) the presence of a diastereo-
mers mixture. Mass spectra of compounds obtained
contained molecular ion peaks, and the elemental
analyses were consistent with the assumed structures.
Condensation of 2-acylcyclohexane-1,3-diones Ia-
e with azomethines II–IV. To a solution of 0.01 mol of
triketone in 50 ml of toluene was added 20 ml of
azomethine methanol solution prepared as described
above. The reaction mixture was kept for 48–72 h at room
temperature with addition after 24 h of 5 ml more of
azomethine solution. Alternatively the reaction mixture
was heated at boiling for 8–10 h adding every 2–2.5 h 5
ml of azomethine solution. The solvent was distilled off
in a vacuum, the residue was dissolved in 100 ml of
chloroform, the solution was once washed with 5%
Na2CO3 solution, then with a small quantity (10 ml) of
1% hydrochloric acid, and dried on Na2SO4. Chloroform
was removed on a rotary evaporator, and the reaction
product was subjected to column chromatography on
silica gel with gradient elution by ethyl acetate–ethanol
mixture (gradient from 0 to 10%). The fractions giving
red spots at spraying TLC plates with iron(III) chloride
solution were collected. The combined fractions
containing the target product were evaporated in a
vacuum, and the residue was crystallized from
chloroform–ethyl ether mixture.
The formation of condensation products from cyclo-
hexane b-triketones with the seven-membered cyclic
azomethine, tetrahydroazepine IV, was observed by
means of TLC, but these compounds turned out to be
very unstable under workup conditions, and we failed to
characterize them.
EXPERIMENTAL
IR spectra were recorded on spectrophotometer UR-
1
20 fromsamples in KBr pellets. H NMR spectra were
registered on spectrometer BrukerAT-200 from solutions
in CDCl3 with TMS as internal reference. Mass spectra
were taken on MKh-1320 instrument. Melting points
were measured on Bo¸tius heating block. The progress
of reactions and purity of compounds was monitored by
TLC on Silufol UV-254 plates (Merck), development
under UV irradiation followed by spraying with alcoholic
solution of iron(III) chloride. The column
chromatography was carried out on silica gel 5/40 mesh
(Merck , eluriated from dust).
8,8-Dimethyl-2,3,3a,4,8,9-hexahydropyrrolo-[1,2-
a]quinoline-5,6(1H,5aH)-dione (Va). Yield 1.20 g
–1
(52%), mp 178–180°C. IR spectrum, n, cm : 1670, 1605,
1
1560, 1540. H NMR spectrum, d, ppm: 1.05 s, 1.10 s
(6H, CH3CCH3), 1.60–2.00 m (2H, NCH2CH2CH2),
2.20–2.40 m (2H, NCH2CH2), 2.24 s [2H,
COCH2C(CH3)2], 2.36 d (1H, COCHAHB, J 15.0 Hz),
2.46 s (2H, CH2C=C), 2.58 d.d (1H, COCHAHB, J1 15.0,
J2 4.5 Hz), 3.5–3.9 m (3H, CHNCH2). Found, %: C 72.15;
H 8.31; N 6.12. [M]+ 233. C14H19NO2. Calculated, %:
C 72.07; H 8.21; N 6.00.
3,4-Dihydro-2H-pyrrole (II) (methanol solution).
To a solution of 0.1 mol of freshly distilled pyrrolidine
in 100 ml of anhydrous ether at cooling to 0°C was added
dropwise while stirring within 5–7 min 0.1 mol of tert-
butyl hypochlorite in 20 ml of ether. The reaction mixture
was stirred for 0.5 h at room temperature, then evaporated
to 50 ml, and the solution was added dropwise to a
solution of sodium methylate prepared by dissolving 2.4
g of sodium metal in 100 ml of anhydrous methanol.
The reaction temperature was maintained at 0...5°C by
cooling the flask with ice-salt mixture. The stirring was
continued for 14–16 h at room temperature, the formed
precipitate was filtered off, washed on the filter with a
little methanol cooled to 0°C. The filtrate containing
4,8,8-Trimethyl-2,3,3a,4,8,9-hexahydropyrrolo-
[1,2-a]quinoline-5,6(1H,5aH)-dione (Vb). Yield
–1
1.30 g (53%), mp 174–175°C. IR spectrum, n, cm : 1685,
1
1610, 1560, 1545. H NMR spectrum, d, ppm: 1.05 s,
1.10 s (6H, CH3CCH3), 1.14 d (3H, CH3, J 7.0 Hz),
1.60–2.00 m (2H, NCH2CH2CH2), 2.20 m (2H,
NCH2CH2CH2), 2.24 s (2H, COCH2), 2.30–2.45 m (1H,
COCHCH3), 2.45 s (2H, CH2C=C), 3.38 m (1H, NCH),
3.55–3.80 m (2H, NCH2). Found, %: C 72.22; H 8.31;
N 6.12. [M]+ 247. C15H21NO2. Calculated, %: C 72.84;
H 8.56; N 5.66.
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1189
CONDENSATION OF 2-ALKYLCYCLOHEXANE-1,3-DIONES
8,8-Dimethyl-4-phenyl-2,3,3a,4,8,9-hexahydro-
1.52–2.04 m [(6H, NCH2(CH2)3], 2.25 s, 2.40 s [4H,
CH2(CMe2)CH2], 3.23 m (1H, NCHAHB), 3.45 d (1H,
COCHPh, J 2.0 Hz), 3.85 d.t (1H, NCH, J1 11.0, J2
2.0 Hz), 4.20 m (1H, NCHAHB), 7.18–7.30 m (5H, C6H5).
Found, %: C 78.11; H 7.73; N 4.01. [M]+ 323.
C21H25NO2. Calculated, %: C 77.98; H 7.79; N 4.33.
pyrrolo[1,2-a]quinoline-5,6(1H,5aH)-dione (Vc). Yield
–1
2.00 g (65%), mp 234–236°C. IR spectrum, n, cm :
1
1675, 1605, 1560, 1540. H NMR spectrum (CDCl3),
d, ppm: 1.14 s, 1.18 s (6H, CH3CCH3), 1.54 m (1H,
NCH2CH2CHAHB),
1.85–2.15
m
(3H,
NCH2CH2CHAHB), 2.34 s, 2.55 s [4H, CH2(CMe2)CH2],
3.43 m (1H, NCHAHB), 3.58 d (1H, COCHPh, J 5.5 Hz),
3.72 m (1H, NCHAHB), 4.15 m (1H, NCH), 7.00–7.30 m
(5H, C6H5). Found, %: C 77.56; H 7.55; N 4.37. [M]+
309. C20H23NO2. Calculated, %: C 77.64; H 7.49; N 4.53.
(4aS,5S)-5-Methyl-9-phenyl-3,4,4a,5,9,10-
hexahydro-1H-pyrido[1,2-a]quinoline-6,7(2H,8H)-
dione (VId). Yield 1.33 g (43%), mp 166–168°C. IR
–1
spectrum, n, cm : 1690, 1620, 1525. Diastereomers
1
mixture. H NMR spectrum (CDCl3), d, ppm: 1.10 d,
4-Methyl-8-phenyl-2,3,3a,4,8,9-hexahydro-
pyrrolo[1,2-a]quinoline-5,6(1H,5aH)-dione (Vd).
Yield 1.71 g (58%), mp 241–242°C. IR spectrum, n,
1.26 d (1:2, 3H, COCHCH3, J 7.0 Hz), 1.40–2.00 m [6H,
NCH2(CH2)3], 2.44–2.70 m (3H, COCH2, COCH), 2.86–
3.00 m (2H, CH2CHPh), 3.10–3.40 m (3H, CHPh,
NCH2), 4.10 br.t (1H, NCH, J 11.0 Hz), 7.20–7.40 m
(5H, C6H5). Found, %: C 77.71; H 7.45; N 4.67. [M]+
309. C20H23NO2. Calculated, %: C 77.64; H 7.49; N 4.53.
–1
1
cm : 1670, 1600, 1565, 1545. H NMR spectrum
(CDCl3), d, ppm: 1.08 d (3H, CH3, J 7.0 Hz), 1.60–
2.0 m (4H, NCH2CH2CH2), 2.20 m (2H, NCH2CH2CH2),
2.38 m (1H, COCHCH3), 2.60–3.0 m [4H,
CH2(CHPh)CH2], 3.20–3.46 m (3H, CHPh, NCH2),
3.64 m (1H, NCH), 7.20–7.40 m (5H, C6H5). Found, %:
C 77.39; H 7.25; N 4.60. [M]+ 295. C19H21NO2.
Calculated, %: C 77.26; H 7.17; N 4.74.
9,9-Dimethyl-5-ethyl-3,4,4a,5,9,10-hexahydro-1H-
pyrido[1,2-a]quinoline-6,7(2H,8H)-dione (VIe). Yield
–1
1.13 g (41%), mp 162–163°C. IR spectrum, n, cm :
1
1685, 1620, 1545, 1525 (R = C2H5). H NMR spectrum
(CDCl3), d, ppm: 0.95 t (3H, CH3CH2), 1.06 s, 1.10 s
(6H, CH3CCH3), 1.4–2.0 m [8H,CH3CH2, NCH2(CH2)3],
2.04 br.t (1H, COCHCH2, J 7.5 Hz), 2.26 s, 2.37 br.s
[4H, CH2(CH3)2CH2], 3.16 t.d (1H, NCHACHB, J1 13.5,
J2 2.0 Hz), 3.42 br.d (1H, NCH, J 11.0 Hz), 4.14 d.d
(1H, NCHACHB, J1 13.5, J2 2.0 Hz). Found, %: C 74.30;
H 9.11; N 5.17. [M]+ 275. C17H25NO2. Calculated, %:
C 74.14; H 9.15; N 5.09.
9,9-Dimethyl-3,4,4a,5,9,10-hexahydro-1H-pyrido-
[1,2-a]quinoline-6,7(2H,8H)-dione (VIa). Yield 1.04 g
(42%), mp 184–185°C. IR spectrum, n, cm : 1680, 1620,
–1
1535, 1510 (R = H). 1H NMR spectrum (CDCl3), d,
ppm: 1.07 s, 1.08 s (6H, CH3CCH3), 1.50–1.65 m (2H,
NCH2CH2CH2), 1.75–1.80 m (4H, NCH2CH2CH2CH2),
2.25 s, 2.42 s [4H, CH2C(CH3)2CH2], 2.36 d.d (1H,
COCHACH , J1 15.5, J2 6.5 Hz), 2.80 d.d (1H, COCHB,
J1 15.5, J2 6.5 Hz), 3.09 t.d (1H, NCHAHB, J1 13.0, J2
3.0 Hz), 3.58 m (1H, NCHAHB), 4.17 br.d (1H, NCH,
J 13.0 Hz). Found, %: C 72.79; H 8.65; N 5.60. [M]+
247. C15H21NO2. Calculated, %: C 72.84; H 8.56; N 5.66.
REFERENCES
1. Rubinov, D.B., Rubinova, I.L., and Akhrem, A.A., Chem.
Rev., 1999, vol. 99, p. 1047.
2. Rubinov, D.B., Rubinova, I.L., and Akhrem, A.A., Khim.
Polim. Soed., 1995, p. 635.
3. Lakhvich, F.A., Pashkovskii, F.S., and Lis, L.G., Zh. Org.
Khim., 1992, vol. 28, p. 1626.
4. Gulyakevich, O.V., Mikhal’chuk, A.L., Verenich, A.I.,
Rubinov, D.B., Zenyuk, A.A., and Akhrem, A.A., Enaminy
v organicheskom sinteze (Enamines in Organic Synthesis),
Ural. Otd. Akad Nauk, 1996, p. 111.
5. Budnikova, M.V., Rubinov, D.B., Lis, L.G., and
Mikhal’chuk, A.L., Mendeleev Commun., 1999, p. 208.
6. Budnikova, M.V., Zheldakova, T.A., Rubinov, D.B., and
Mikhal’chuk,A.L., Zh. Obshch. Khim., 2002, vol. 72, p. 1053.
7. Quick, J. and Oterson, R., Synthesis, 1976, p. 745.
8. Bachmann, W.E., Cava, M.P., and Dreiding, A.S., J. Am.
Chem. Soc., 1954, vol. 76, p. 5554.
9. Lakhvich, F.A., Lis, L.G., Rubinov, D.B., Rubinova, I.L.,
Kurbako, V.Z., and Bykhovets,A.I., Vestsi Akad. Nauk BSSR,
Ser. Khim., 1989, no. 1, p. 51.
5,9,9-Trimethyl-3,4,4a,5,9,10-hexahydro-1H-
pyrido[1,2-a]quinoline-6,7(2H,8H)-dione (VIb). Yield
–1
1.18 g (45%), mp 135–136°C. IR spectrum, n, cm : 1690,
1
1620, 1540, 1525 (R=CH3). H NMR spectrum (CDCl3),
d, ppm: 1.07 s, 1.10 s (6H, CH3CCH3), 1.18 d (3H, CH3CH,
J 7.5 Hz), 1.5–2.0 m [(6H, NCH2(CH2)3], 2.2–2.3m (1H,
COCHCH3), 2.27 C, 2.40 br.s [4H, CH2(CH3)2CH2],
3.13 t.d (1H, NCHACHB, J1 13.0, J2 2.0 Hz), 3.27 d.t
(1H, NCH, J1 11.0, J2 3.0 Hz), 4.17 br.d (1H, NCHACHB,
J 13.0 Hz). Found, %: C 73.77; H 8.95; N 5.55. [M]+
261. C16H23NO2. Calculated, %: C 73.53; H 8.87; N 5.36.
(4aR,5R)-9,9-Dimethyl-5-phenyl-3,4,4a,5,9,10-
hexahydro-1H-pyrido[1,2-a]quinoline-6,7(2H,8H)-
dione (VIc). Yield 1.62 g (50%), mp 179–180°C. IR
–1
1
spectrum, n, cm : 1695, 1610, 1540, 1505. H NMR
spectrum (CDCl3), d, ppm: 0.93 s, 1.09 s (6H, CH3CCH3),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 8 2004