Synthesis of tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione derivatives

Article abstract of DOI:10.1023/A:1016027204806

Tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-diones have been obtained by the cyclization of N-alkoxyphenyl-N-(2-carboxyethyl)-β-alanines. Fission of the ester bond occurs on cyclization of N-(4-ethoxyphenyl)-N-(2-carboxyethyl)-β-alanine, but the cyclization of the 3,4-dialkoxyphenyl derivative leads to the formation of 9-alkoxy-8-hydroxy-2,3,5,7-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-diones. The corresponding dioximes and diphenylhydrazones were obtained.

Full text of DOI:10.1023/A:1016027204806

Chemistry of Heterocyclic Compounds, Vol. 38, No. 4, 2002
SYNTHESIS OF TETRAHYDRO-
ij
1H,7H-BENZO[ ]QUINOLIZINE-
1,7-DIONE DERIVATIVES
K. Kantminene1, G. Mikul'skene2, O. Hormi3, and Z. I. Beresnevicius1
Tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-diones have been obtained by the cyclization of
N-alkoxyphenyl-N-(2-carboxyethyl)-β-alanines. Fission of the ester bond occurs on cyclization of
N-(4-ethoxyphenyl)-N-(2-carboxyethyl)-β-alanine, but the cyclization of the 3,4-dialkoxyphenyl
derivative leads to the formation of 9-alkoxy-8-hydroxy-2,3,5,7-tetrahydro-1H,7H-benzo[ij]quinolizine-
1,7-diones. The corresponding dioximes and diphenylhydrazones were obtained.
Keywords:
N-alkoxyphenyl-N-(2-carboxyethyl)-β-alanines,
dioximes,
diphenylhydrazones,
2,3,5,7-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-diones, cyclization.
The quinolizine system is contained in several alkaloids [1]. Derivatives of benzo[ij]quinolizine are used
as antibacterial preparations [2]. The preparation of dioxoyulolidines [3-5] by the interaction of acrylic acid or
its nitrile with aromatic amines at high temperature in polyphosphoric acid is accompanied by the formation of
many side products. A more convenient method of synthesizing benzoquinolizidinediones includes the
cyclization of N-aryl-N-carboxyethyl-β-alanines [6].
It seemed of interest to us to obtain benzoquinolizinediones containing alkylenedioxy and alkoxy
groups. N-Substituted phenyl-N-(2-carboxyethyl)-β-alanines 2 were obtained by the addition of amines 1 to
acrylic acid at a reactant ratio of 1:2. The addition reaction goes at room temperature or on initial heating, and
the resulting diacids 2 crystallized out from the reaction mixture. The presence of acetal and ester bonds in 2
caused auxiety that the cyclization of the latter might be accompanied by fission of these bonds. On studying the
conditions of forming yulolidine derivatives from the 4-alkoxyphenyl derivatives 2a,b, it was established that
cyclization occurs at 160°C in polyphosphoric acid, and 9-methoxy-2,3,5,7-tetrahydro-1H,7H-
benzo[ij]quinolizine-1,7-dione (3a) is formed in 11.4% yield. Under the same conditions the ethoxy derivative
2b undergoes fission of the ether bond and the hydroxy derivative 3b is isolated from the reaction mixture in
13.5% yield with a method of rapid chromatographic column.
1
The H NMR spectra of compounds 3a,b show two triplets for the four CH2 groups of the two
heterocycles and also singlets for the two aromatic protons. The signal for the methyl group was missing from
the spectrum of 3b but there was a singlet for the hydroxyl group proton at 9.28 ppm.
Due to the symmetry of compounds 3a,b relative to the hydroxy or methoxy groups the corresponding
lines in the 13C NMR spectra coincided. The signals of both carbon atoms for the carbonyl groups were
registered at low field at 192 ppm, and the signal for the methyl group of compound 3a was observed at
__________________________________________________________________________________________
1
Kaunas
University
of
Technology,
LT-3028
Kaunas,
Lithuania;
e-mail:
2
3
zigmuntas.beresnevicius@ctf.ktu.lt. Institute of Biochemistry, LT-2600 Vilnius, Lithuania. University of
Oulu, Linnanmaa POB 3336 FIN-90571 Oulu, Finland. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 4, pp. 487-493, April, 2002. Original article submitted January 26, 2001.
422
0009-3122/02/3804-0422$27.00©2002 Plenum Publishing Corporation

55.8 ppm. The chemical shifts of the C(8), C(8a), C(10), and C(10a) atoms differed by 1 ppm from the corresponding
signals for compound 3b.
It was established by us that the amount of reacting substance proves to have a large effect on the
reaction yield. In the cyclization process the yields of 4c and 4d were 57 and 47% respectively from 5 mmol of
N-(3,4-dimethoxyphenyl)- (2c) and N-(3,4-diethoxyphenyl)-N-(2-carboxyethyl)-β-alanines (2d) in
polyphosphoric acid at 100°C. An increase in the amount of reacting substances or the cyclization temperature
did not lead to an increase in yield, at 200°C it did not reach 15%. On refluxing 2c in POCl3 the yield of 4c did
not exceed 11%.
OR
R1
R2
R1
R2
9
8
HO
10
O
8a
10a
11
O
O
N
O
OH
NH2
7
1
1a–f
6
2
N
54c,d
3
HO
2a–f
OR
OR
O
O
HO
N
3a,b
N
N
HN
NH
OR
N
HO
6c,d
N
N
HO
OH
N
5c,d
Dihydrochloride
7c,d
1, 2 a R1 = OMe, R2 = H; b R1 = OEt, R2 = H; c R1 = R2 = OMe; d R1 = R2 = OEt;
e R1 + R2 = O–CH2–O; f R1 + R2 = O–CH2–CH2–O; 3 a R = Me, b R = H;
4-6 c R = Me, d R = Et
It is characteristic that in the cyclization process fission of only one ether bond close to a keto group
occurs .
Cyclization of N-(3,4-methylenedioxyphenyl)- and N-(3,4-ethylenedioxyphenyl)-N-(2-carboxyethyl)-β-
alanines 2e,f was unsuccessful. Both in polyphosphoric acid and in POCl3 blackening of the reaction mass
occurs even after a few minutes and no products were successfully isolated from it.
The structures of compounds 4 were confirmed by data of elemental analysis and spectral
investigations. The 1H NMR spectra taken in DMSO-d6 show two triplets and a quartet for the two overlapping
triplets of CH2 groups, and in the spectra taken in C6D6 all four triplets were observed. As a result of fission of
one ether bond the hydroxyl group formed was identified as a singlet at 13.5 ppm with a rather high intensity.
According to the data of NOESY spectra of compound 4c the methoxy group was assigned to position 9, since
an interaction was observed for its protons with the H(10) proton of the aromatic ring. This was also confirmed
by 13C NMR spectra. Due to the shielding γ-effect of the hydroxyl group the chemical shift of the 7-keto group
carbon atom was at 189 ppm, while the signal of the C(1) atom was at lower field at 200 ppm. In the spectrum of
compound 4d deshielding was observed for the C(10) atom, the signal of which was shifted by 1 ppm towards
low field. Characteristic lines in the INEPT spectra also confirmed the structure of the benzoquinolizinediones.
423

TABLE 1. 1H NMR Spectra of Compounds 2c-f in DMSO-d6
Com-
Chemical shifts, δ, ppm
J
HH, Hz
pound
H(5), d
H(2), d
H(6), dd
α-CН2, t
β-CН2, t
COOH, s
Other groups
26
56
6.42
6.79
6.80
6.39
6.22
6.21
2.43
2.42
3.48
3.47
12.08
12.04
3.66 (3H, s, 3-CH3O); 3.74 (3H, s, 4-CH3O)
2.8
8.7
8.8
2c
2d
1.26 (3H, t, 3-CH3CH2O);
1.34 (3H, t, 4-CH3CH2O);
3.91 (2H, q, 3-CH3CH2O);
4.01 (2H, q, 4-CH3CH2O)
6.74
6.68
6.46
6.14
2.41
2.40
3.45
3.43
12.08
12.07
5.87 (2H, s, OCH2O)
2.8
2.5
8.5
8.9
2e
2f
6.22-6.27
4.13 (2H, 2 t, OCH2CH2O);
4.18 (2H, 2 t, OCH2CH2O)
TABLE 2. 13C NMR Spectra of Compounds 2a-f in DMSO-d6
Chemical shifts, δ, ppm
Com-
pound
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
CO
C(α)
C(β)
C(7); C(8) / C(7'); C(8')
141.74
142.01
142.58
142.76
143.33
142.23
114.94
114.61
100.42
101.75
96.67
115.26
115.70
150.13
149.85
148.31
143.92
151.71
150.41
141.26
140.41
139.00
135.28
115.26
115.70
114.71
117.10
108.54
117.39
114.94
114.61
105.23
105.48
105.61
106.82
173.20
174.01
173.26
173.25
173.16
173.16
32.22
33.14
32.29
32.29
32.16
32.21
47.27
47.51
47.11
47.06
47.37
47.02
55.42
63.49; 14.86
55.64; 55.67
2a
2b
2c
2d
2e
2f
64.02; 65.24 / 14.87; 15.07
100.38
102.27
63.42; 64.42

Numerous attempts to obtain the 8,9-dimethoxy derivative of benzoquinolizine by alkylation of 4c with
dimethyl sulfate in DMF, with iodomethane in acetone or methyl ethyl ketone in the presence of K2CO3, and
with iodomethane in methanol in the presence of CH3ONa did not lead to an appreciable yield of the desired
product. Traces of the dimethoxy derivative were detected only by mass spectrometry.
By heating quinolizinediones 4 with hydroxylamine hydrochloride in the presence of pyridine or with
phenylhydrazine the dioximes 5 and diphenylhydrazones 6 were obtained. Compounds 5 and 6 were isolated
from the reaction mixture in high yield only in those cases when the reaction mixture did not darken initially. In
individual cases they began to decompose and darken also when purifying them chromatographically. The
hydrochlorides of diphenylhydrazones 7 were obtained by the usual method and were stable substances.
In addition to the signals of to the benzoquinolizinediones the 1H NMR spectra of oximes 5 show proton
signals of the N–OH group at low field at 10.5 and 11.4 ppm. In the 13C NMR spectra the same structural
regularities were observed as for compound 4. Due to the γ-influence of the hydroxyl group at C(8) the signal of
the C(7) atom was observed at 150 ppm and of the C(1) atom at 156 ppm. As a result of the deshielding effect of
the ethoxy group of compound 5d the signal for the C(10) atom was shifted by 2 ppm towards low field compared
with the analogous atom of compound 5c.
The molecular weights found for the diphenylhydrazones 6 corresponded to calculated values and the
NMR spectra show signals for the two phenyl groups in addition to those characteristic of
benzoquinolizinediones.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker Avance DPX 400 (400 MHz) spectrometer at 46°C.
The internal standard for DMSO-d6 was the residue of DMSO-d5 (δH 2.50 ppm), and for C6D6 the residue of
C6D5H (δH 7.16 ppm). The 13C and INEPT NMR spectra were recorded on a Bruker Avance DPX 400
(100.61 MHz) spectrometer. The NOESY spectrum was recorded on Bruker DRX 500 (500 MHz) apparatus.
The mass spectra were obtained on a Kratos MS 80 apparatus. Accurate molecular masses were obtained by
HRMS. The progress of reactions was followed by TLC using Silufol 254, Silufol UV 254, and Kieselgel 60
F254 (Merck 0.25 mm) plates. The 1H and 13C NMR spectra of compounds 2a-f are given in Tables 1 and 2.
N-(2-Carboxyethyl)-N-(4-methoxyphenyl)-β-alanine (2a). A mixture of p-anisidine 1a (61.5 g,
0.5 mol) and acrylic acid (72 g, 1 mol) was heated at 50°C for 4 h and left at room temperature for 2 weeks. The
resulting crystals were filtered off, and crystallized from ethanol–ether, 1:5. Yield 63.1 g (47.2%);
1
mp 119-120°C. H NMR spectrum (DMSO-d6), δ, ppm: 2.40 (4H, t, α-CH2); 3.46 (4H, t, β-CH2); 3.67 (3H, s,
CH3O); 6.71 (2H, d, HB arom.); 6.81 (2H, d, HA arom.). Found, %: C 58.44; H 6.41; N 5.24. C13H17NO5.
Calculated, %: C 58.42; H 6.41; N 5.24. HRMS (EI): found 267.1076, calculated 267.1107.
N-(2-Carboxyethyl)-N-(4-ethoxyphenyl)-β-alanine (2b) was obtained analogously to 2a from
p-phenetidine hydrochloride 1b (86.75 g, 0.5 mol), AcONa (41 g, 0.5 mol), and acrylic acid (72 g, 1 mol) with a
yield of 59 g (42%); mp 96-98°C. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.27 (3H, t, CH3CH2O); 2.35 (4H, t,
α-CH2); 3.43 (4H, t, β-CH2); 3.91 (2H, q, CH3CH2O); 6.66 (2H, d, HB arom.); 6.78 (2H, d, HA arom.).
Found, %: C 59.6; H 6.83; N 4.98. C14H19NO5. Calculated, %: C 59.82; H 6.81; N 4.98. HRMS (EI):
found 281.1295, calculated 281.1261.
N-(2-Carboxyethyl)-N-(3,4-dimethoxyphenyl)-β-alanine (2c). 3,4-Dimethoxyaniline 1c (7.6 g,
50 mmol) and acrylic acid (7.2 g, 0.1 mol) were dissolved in toluene (50 ml). The mixture was stored at room
temperature for 1 week. The resulting crystals were filtered off, and crystallized from ethanol. Yield 10.62 g
(71.5%); mp 109-110°C. Found, %: C 56.63; H 6.90; N 4.73. C14H19NO6. Calculated, C 56.56; H 6.44; N 4.71.
MS FAB (Ar, glycerol): found 298(9), calculated 297.1212.
425

N-(2-Carboxyethyl)-N-(3,4-diethoxyphenyl)-β-alanine (2d) was obtained from 3,4-diethoxyaniline
1d (9.1 g, 50 mmol) analogously to 2c. Yield 11.2 g (69%); mp 92-94°C. Found, %: C 58.63; H 7.51; N 4.42.
C16H23NO6. Calculated, %: C 59.06; H 7.13; N 4.31. MS FAB (Ar, glycerol): found 326(100), calculated
325.1525.
N-(2-Carboxyethyl)-N-(3,4-methylenedioxyphenyl)-β-alanine
(2e)
was
obtained
from
3,4-methylenedioxyaniline 1e (6.9 g, 50 mmol) analogously to 2c. Yield 9.2 g (65.3%); mp 133-134°C
(ethanol). Found, %: C 56.11; H 5.71; N 5.15. C13H15NO6. Calculated, %: C 55.51; H 5.38; N 4.98. MS FAB
(Ar, NBA): found 282(20), calculated 281.0899.
N-(2-Carboxyethyl)-N-(3,4-ethylenedioxyphenyl)-β-alanine
(2f)
was
obtained
from
3,4-ethylenedioxyaniline 1f (7.6 g, 50 mmol) analogously to compound 2c. Yield 12.0 g (81.6%);
mp 143-144°C. Found, %: C 56.86; H 5.81; N 4.73. C14H17NO6. Calculated, %: C 56.94; H 5.80; N 4.74.
MS FAB (Ar, NBA): found 296(100), calculated 295.1056.
9-Methoxy-2,3,5,6-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione (3a). A mixture of P2O5 (30 g)
and H3PO4 (10 ml) was refluxed at 160°C for 30 min. Alanine 2a (1.335 g, 5 mmol) was introduced and the
mixture was stirred at the same temperature for 10 min. The reaction mixture was cooled, ice water (100 ml)
was poured in, and the mixture was extracted with chloroform (4 x 15 ml). The chloroform was removed on a
rotary evaporator, and the residual crystalline substance was purified by rapid column chromatography [Merck
kieselgel 60 (0.04-0.063 mm), ethyl acetate–hexane, 3:1]. Yield of 3a was 0.14 g (11.4%); mp 190°C (decomp.).
1H NMR spectrum, δ, ppm (DMSO-d6): 2.74 (4H, t, CH2); 3.42 (4H, t, CH2); 3.76 (3H, s, CH3O); 7.50 (2H, s,
H arom.); (C6D6): 2.39-2.44 (4H, 2t, CH2); 2.47-2.54 (4H, 2t, CH2); 3.36 (s, CH3O); 7.26 (1H, s, H arom.); 8.03
(1H, s, H arom.). 13C NMR spectrum (DMSO-d6), δ, ppm: 37.26 (C(2) and C(6)); 49.61 (C(3) and C(5)); 55.82
(OCH3); 118.25 (C(8) and C(10)); 124.62 (C(8a) and C(10a)); 191.79 (C(1) and C(7)). Found, %: C 67.43; H 5.91;
N 6.23. C13H13NO3. Calculated, %: C 67.52; H 5.67; N 6.06. HRMS (EI): found 231.0889, calculated 231.0895.
9-Hydroxy-2,3,5,6-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione (3b) was obtained from 2b
(1.405 g, 5 mmol) analogously to 3a. Yield 0.15 g (13.5%). The eluent was a mixture of ethyl acetate–hexane–
1
acetone, 3:1:1; mp 95°C (decomp.). H NMR spectrum (DMSO-d6), δ, ppm: 2.71 (4H, t, CH2); 3.37 (4H, t,
13
CH2); 7.41 (2H, s, H arom.); 9.28 (1H, s, OH). C NMR spectrum (DMSO-d6), δ, ppm: 37.35 (C(2) and C(6));
49.79 (C(3) and C(5)); 119.40 and 119.49 (C(8) or C(10)); 125.12 (C(8a) and C(10a)); 148.67 and 148.85 (C(9) or C(11));
191.91 (C(1) and C(7)). Found, %: C 66.31; H 5.08; N 6.47. C12H11NO3. Calculated, %: C 66.35; H 5.10; N 6.45.
HRMS (EI): found 217.1067, calculated 217.0739.
8-Hydroxy-9-methoxy-2,3,5,6-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione (4c). A mixture of
P2O5 (30 g) and 85% H3PO4 (10 ml) was refluxed at 100°C for 30 min. Compound 2c (1.485 g, 5 mmol) was
added and the mixture was refluxed for 30 min further. The reaction mixture was cooled, ice water (100 ml) was
added, and the mixture extracted with chloroform (3 x 50 ml). The chloroform was removed from the extract on
a rotary evaporator, and the residual crystals were purified by rapid column chromatography [Merck kieselgel
60 (0.04-0.063 mm), ethyl acetate–hexane–acetone–acetic acid, 30:10:10:5]. Yield 0.71 g (57.5%); mp 144°C
1
(decomp.). H NMR spectrum, δ, ppm (DMSO-d6): 2.63 (2H, t, CH2); 2.85 (2H, t, CH2); 3.41-3.46 (4H, 2t,
CH2); 3.74 (3H, s, CH3O); 7.47 (1H, s, H arom.); 13.56 (1H, s, OH); (C6D6): 2.19 (2H, t, CH2); 2.35 (2H, t,
CH2); 2.42 (2H, t, CH2); 2.54 (2H, t, CH2); 3.50 (3H, s, CH3O); 7.94 (1H, s, H arom.); 14.03 (1H, s, OH).
13C NMR spectrum (DMSO-d6), δ, ppm: 36.25 (C(2)); 36.34 (C(6)); 48.88 (C(3)); 49.82 (C(5)); 56.50 (OCH3);
106.09 (C(8a)); 110.06 (C(10a)); 117.84 (C(10)); 139.73 (C(9)); 150.66 (C(8)); 159.24 (C(11)); 189.37 (C(7)); 200.11
(C(1)). INEPT spectrum (DMSO-d6), δ, ppm: 37.19 (C(2)); 37.28 (C(6)); 49.82 (C(3)); 50.76 (C(5)); 57.30 (OCH3);
118.40 (C(10)). Found, %: C 63.41; H 5.22; N 5.48. C13H13NO4. Calculated, %: C 63.15; H 5.30; N 5.67. HRMS
(EI): found 247.0861, calculated 247.0845.
9-Ethoxy-8-hydroxy-2,3,5,6-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione (4d) was obtained
from compound 2d (1.625 g, 5 mmol) analogously to 4c with a yield of 0.615 g (47.1%); mp 169.5°C
1
(decomp.). H NMR spectrum, δ, ppm, J (Hz) (DMSO-d6): 1.29 (3H, t, CH3); 2.63 (2H, t, CH2); 2.84 (2H, t,
426

CH2); 3.41-3.46 (4H, 2t, CH2); 3.98 (2H, q, J = 6.9, J = 13.9, CH3CH2O); 7.47 (1H, s, H arom.); 13.55 (1H, s,
OH); (C6D6): 1.25 (3H, t, CH3); 2.19 (2H, t, CH2); 2.34 (2H, t, CH2); 2.41 (2H, t, CH2); 2.54 (2H, t, CH2); 3.82
(2H, q, J = 7.0, J = 13.9, CH3CH2O); 8.01 (1H, s, H arom.); 14.05 (1H, s, OH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 14.87 (OCH2CH3); 36.46 (C(2)); 36.56 (C(6)); 49.07 (C(3)); 50.00 (C(5)); 64.93 (OCH2CH3); 106.34 (C(8a));
110.26 (C(10a)); 119.02 (C(10)); 138.86 (C(9)); 150.99 (C(8)); 159.68 (C(11)); 189.85 (C(7)); 200.54 (C(1)). INEPT
spectrum (DMSO-d6), δ, ppm: 15.55 (OCH2CH3); 37.18 (C(2)); 37.29 (C(6)); 49.81 (C(3)); 50.73 (C(5)); 65.90
(OCH2CH3); 120.37 (C(10)). Found, %: C 64.70; H 6.00; N 5.58. C14H15NO4. Calculated, %: C 64.36; H 5.79;
N 5.36. HRMS (EI): found 261.1001, calculated 261.1001.
8-Hydroxy-9-methoxy-2,3,5,6-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione Dioxime (5c). A
solution of benzoquinolizinedione 4c (0.99 g, 4 mmol) in methanol (100 ml) was added dropwise to a mixture of
hydroxylamine hydrochloride (1.112 g, 16 mmol), pyridine (1.9 g, 24 mmol), methanol (10 ml), and water
(0.5 ml). The reaction mixture was refluxed for 4.5 h (TLC), HCl (5 drops) was added, and the light fraction
was distilled off on a rotary evaporator. Compound 4c was purified by rapid column chromatography [Merck
kieselgel 60 (0.04-0.063 mm), ethyl acetate–hexane, 3 : 1]. Yield 1.0 g (90.2%), mp 180.8°C (decomp.).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.73 (2H, t, CH2); 2.88 (2H, t, CH2); 2.97-3.02 (4H, 2t, CH2); 7.36 (1H,
13
s, H arom.); 12.26 (1H, s, OH). C NMR spectrum (DMSO-d6), δ, ppm: 22.76 (C(2) and C(6)); 48.08 and 49.03
(C(3) or C(5)); 56.24 (OCH3); 104.08 (C(8a)); 108.32 (C(10a)); 109.42 (C(10)); 140.82 (C(9)); 141.69 (C(8)); 149.22
(C(11)); 150.26 (C(7)); 155.92 (C(1)). Found, %: C 56.18; H 5.67; N 15.34. C13H15N3O4. Calculated, %: C 56.31;
H 5.45; N 15.15. HRMS (EI): found 277.1075, calculated 277.1063.
9-Ethoxy-8-hydroxy-2,3,5,6-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione Dioxime (5d) was
1
obtained from 4d (1.044 g, 4 mmol) analogously to 5c. Yield 1.0 g (86%), mp 202°C (decomp.). H NMR
spectrum (DMSO-d6), δ, ppm, J (Hz): 1.28 (3H, t, CH3); 2.73 (2H, t, CH2); 2.88 (2H, t, CH2); 2.98-3.03 (4H, 2t,
CH2); 3.94 (2H, q, J = 6.9, J = 13.9, CH3CH2); 7.36 (1H, s, H arom.); 10.59 (1H, s, NOH); 11.39 (1H, s, NOH);
13
12.22 (1H, s, OH). C NMR spectrum (DMSO-d6), δ, ppm: 14.91 (OCH2CH3); 22.69 and 22.76 (C(2) or C(6));
48.01 and 48.95 (C(3) or C(5)); 64.75 (OCH2CH3); 104.08 (C(8a)); 108.34 (C(10a)); 111.51 (C(10)); 139.62 (C(9));
141.84 (C(8)); 149.18 (C(11)); 150.75 (C(7)); 155.87 (C(1)). Found, %: C 57.29; H 6.01; N 14.30. C14H17N3O4.
Calculated, %: C 57.72; H 5.88; N 14.43. HRMS (EI): found 291.1206, calculated 291.1219.
8-Hydroxy-9-methoxy-2,3,5,6-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione Diphenylhydrazone
(6c). Benzoquinolizinedione 4c (1.235 g, 5 mmol) was added to a solution of phenylhydrazine (3.24 g,
30 mmol) in 99.5% ethanol (100 ml) and the mixture refluxed for 3 h. On standing the reaction mixture at 4°C
1
crystals formed, were filtered off, and washed with ether. Yield 1.5 g (70.3%), mp 203°C (decomp.). H NMR
spectrum (DMSO-d6), δ, ppm: 2.77 (2H, t, CH2); 2.94 (2H, t, CH2); 3.11-3.15 (4H, 2t, CH2); 3.79 (3H, s, CH3O);
7.61 (1H, s, H arom.); 6.70-7.36 (10H, m, H arom.); 9.00 (1H, s, NH); 9.46 (1H, s, NH); 13.56 (1H, s, OH).
13C NMR spectrum (DMSO-d6), δ, ppm: 24.60 and 25.03 (C(2) or C(6)); 48.27 and 49.18 (C(3) or C(5)); 56.68
(OCH3); 105.76 (C(8a)); 109.71 (C(10)); 111.22 (C(10a)); 118.36 and 119.79 (C(4′)); 112.47 and 112.60 (C(2′));
128.43 and 128.97 (C(3′)); 139.07 (C(8)); 141.23 (C(9)); 141.42 (C(7)); 145.07 and 146.59 (C(1′)); 147.31 (C(11));
149.65 (C(1)). Found, %: C 69.98; H 6.40; N 16.53. C25H25N5O2. Calculated, %: C 70.22; H 5.88; N 16.39.
HRMS (EI): found 427.2019, calculated 427.2008.
9-Ethoxy-8-hydroxy-2,3,5,6-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione Diphenylhydrazone
(6d) was obtained from 4d (1.3 g, 5 mmol) analogously to 6c. Yield 1.8 g, (81.6%), mp 203°C (decomp.).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.35 (3H, t, CH3); 2.77 (2H, t, CH2); 2.94 (2H, t, CH2); 3.11-3.15 (4H,
2t, CH2); 4.03 (2H, q, CH3CH2O); 7.61 (1H, s, H arom.); 6.70-7.32 (10H, m, H arom.); 8.99 (1H, s, NH); 9.45
13
(1H, s, NH); 13.56 (1H, s, OH). C NMR spectrum (DMSO-d6), δ, ppm: 15.19 (CH3CH2O); 24.62 and 25.05
(C(2) or C(6)); 48.26 and 49.17 (C(3) or C(5)); 64.96 (CH3CH2O); 105.80 (C(8a)); 111.26 (C(10a)); 111.42 (C(10));
112.49 and 112.59 (C(2′)); 118.36 and 119.77 (C(4′)); 128.97 and 129.42 (C(3′)); 139.13 (C(8)); 140.18 (C(9));
141.57 (C(7)); 145.06 and 146.57 (C(1′)); 147.37 (C(11)); 150.07 (C(1)). Found, %:C 69.93; H 6.41; N 15.81.
C26H27N5O2. Calculated, %: C 70.73; H 6.16; N 15.86. HRMS (EI): found 441.2153, calculated 441.2165.
427

8-Hydroxy-9-methoxy-2,3,5,6-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione Diphenylhydrazone
Dihydrochloride (7c). Dry HCl was passed through a solution of the diphenylhydrazone 6c (0.07 g, 0.16 mmol)
in dry methanol (20 ml). The solution was filtered into absolute ether. The crystals were filtered off, and dried.
Yield 0.08 g (98%), mp 170°C (decomp.).
9-Ethoxy-8-hydroxy-2,3,5,6-tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione Diphenylhydrazone
Dihydrochloride (7d) was obtained from 6d (0.1 g, 0.23 mmol) analogously to 7c. Yield 0.1 g (96%),
mp 166°C (decomp.).
The authors are grateful to the Council of Ministers of the North Countries for a scholarship to
probationer K. Kantminene in the University of Oulu.
REFERENCES
1.
2.
R. K. Hill, in: E. W. Pelletier (ed.), Chemistry of Alkaloids, Van Nostrand Reinhold Co, New York
(1970), p. 414.
J. Takagi, T. Nagamatsu, N. Yasuda, H. Kimura, and N. Asahara, Jpn. Patent 63130594; Chem. Abstr.,
109, 149342 (1988).
3.
4.
5.
6.
A. F. Bekhli, L. A. Bolotin, and B. V. Lopatin, Khim. Geterotsikl. Soedin., 1390 (1979).
J. R. Merchant and R. B. Upasani, Chem. Ind. (London), 14, 513 (1984).
J. R. Merchant and P. M. Pathare, Indian J. Chem., 26B, 471 (1987).
E. S. Ibrahim, M. O. Orabi, M. El-Badawi, and M. T. Omar, Commun. Fac. Sci. Univ. Ankara, Ser. B:
Chem. Engl., 1-2, 39 (1993) (publ. 1995).
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